JP2007320930A - Method for producing phenyltetrazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrial production method by which phenyltetrazole derivatives (7) and (8) useful as intermediates for synthesizing pharmaceutical compounds can be produced in safe and mild conditions at low costs. <P>SOLUTION: In this production method, a phenolic hydroxy group is protected with a 2 to 4C lower alkanoyl group, and methane sulfonic acid is used as both a reagent and a solvent in a formylation reaction from the compound (7) to the compound (8). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel production method of a phenyltetrazole derivative useful as an intermediate for producing a pharmaceutical compound, and a novel intermediate compound in the production method.

およびそのホルミル体である式（８）：

のフェニルテトラゾール誘導体は、例えばタキキニン拮抗作用を有する医薬化合物を製造するための中間体として、特表平１０−５１９９７３号公報（特許文献１）および特開２００４−２８５０３８号公報（特許文献２）に報告されている。
また、診断的撮像に有用な放射標識化ニューロキニン−１受容体拮抗薬を製造するための中間体としても、特表２００２−５２５３２５号公報（特許文献３）に報告されている。 Formula (7):

And its formyl form (8):

As an intermediate for producing a pharmaceutical compound having a tachykinin antagonistic action, for example, JP 10-199973 A (Patent Document 1) and JP-A 2004-285038 (Patent Document 2) It has been reported.
Moreover, as an intermediate for producing a radiolabeled neurokinin-1 receptor antagonist useful for diagnostic imaging, it is reported in JP-T-2002-525325 (Patent Document 3).

  Furthermore, a method for producing the above compound (7) by protecting the phenol hydroxyl group with a methyl group is described in JP-T-2003-522739 (Patent Document 4), wherein the phenol hydroxyl group is protected with a benzyl group. Are described in JP-T-11-502810 (Patent Document 5) and Patent Document 3, respectively.

When a phenol hydroxyl group is protected with a methyl group, according to Patent Document 4, it takes 48 hours at 100 ° C. in hydrobromic acid-acetic acid for deprotection. However, since a tetrazole compound is generally unstable to heat, such a long-time treatment at a high temperature is not preferable.
On the other hand, when the phenolic hydroxyl group is protected with a benzyl group, it can be deprotected under a mild condition of catalytic reduction at room temperature under atmospheric pressure or under pressure (see Patent Documents 4 and 5). Necessary. In addition, since the protecting group is a discarded part, the benzyl group is inferior in the atom economy from the viewpoint that the smaller the ratio of the molecular weight of the protecting group to the target product is, the better the economy and the environmental impact, It is not suitable as a protecting group in industrial production methods.

Furthermore, in the formylation reaction from the compound of formula (7) to the phenyltetrazole derivative of formula (8), in Patent Documents 4 and 5, trifluoroacetic acid is used as a reaction reagent and a solvent. It takes 48 hours at ° C. and Patent Document 5 requires 16 hours at 100 ° C.
On the other hand, in Japanese Patent Application Laid-Open No. 2005-154420 (Patent Document 6) and International Publication WO2005 / 012267 (Patent Document 7), a compound in which a phenol hydroxyl group is protected with an alkyl group is used. In the step of obtaining the phenyltetrazole derivative of 8), the reaction is performed at 100 ° C. for 2 hours using a mixed solvent of methanesulfonic acid and trifluoromethanesulfonic acid. However, in this reaction, trifluoromethanesulfonic acid, which requires careful handling, is used, which is not preferable as an industrial synthesis method.
Japanese National Patent Publication No. 10-519973 JP 2004-285038 A Special table 2002-525325 gazette JP-T-2003-522739 Japanese National Patent Publication No. 11-502810 JP 2005-154420 A International Publication WO2005 / 012267

  The present invention provides an industrial production method capable of producing phenyltetrazole derivatives (7) and (8), which are useful as intermediates for producing pharmaceutical compounds, under safe and mild conditions and at low cost. The issue is to provide.

As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention have protected the phenolic hydroxyl group of the starting compound (2) with a C _2-4 lower alkanoyl group. The present invention was completed by finding that the above problem can be solved by using methanesulfonic acid as a reaction reagent and a solvent for the formylation reaction from the compound to the phenyltetrazole derivative of formula (8).

の４−アミノフェノールをトリフルオロアセチル化反応に付して、式（２）：

の化合物を得、 Thus, according to the present invention, the following manufacturing method is provided.
Step (a): Formula (1):

4-aminophenol of the formula (2):

To obtain a compound of

（式中、Ｒは上記で定義したとおりである）
で表される化合物を得、 Step (b): Compound (2) above is converted to formula (3):
R-COOH (3)
(Wherein R is a C _1-3 alkyl group)
Is subjected to an acylation reaction using a carboxylic acid represented by formula (I) or a reactive derivative at the carboxy group, to give a formula (4):

(Wherein R is as defined above)
To obtain a compound represented by

（式中、Ｒは上記で定義したとおりである）
で表される化合物を得、 Step (c): The above compound (4) is reacted with triphenylphosphine and carbon tetrachloride to obtain the formula (5):

(Wherein R is as defined above)
To obtain a compound represented by

（式中、Ｒは上記で定義したとおりである）
で表される化合物を得、 Step (d): The above compound (5) is reacted with an azide to give a compound of formula (6):

(Wherein R is as defined above)
To obtain a compound represented by

の化合物を得、 Step (e): The above compound (6) is hydrolyzed to obtain the formula (7):

To obtain a compound of

のフェニルテトラゾール誘導体を製造する方法。 Step (f): After reacting the above compound (7) with hexamethylenetetramine in methanesulfonic acid, the reaction product is hydrolyzed to obtain the formula (8):

A method for producing a phenyltetrazole derivative.

（式中、ＲはＣ_1-3アルキル基である）
で表される化合物、
一般式（５）：

（式中、ＲはＣ_1-3アルキル基である）
で表される化合物、および一般式（６）：

（式中、ＲはＣ_1-3アルキル基である）
で表される化合物が提供される。 Moreover, according to the present invention,
General formula (4):

(Wherein R is a C _1-3 alkyl group)
A compound represented by
General formula (5):

(Wherein R is a C _1-3 alkyl group)
And a compound represented by the general formula (6):

(Wherein R is a C _1-3 alkyl group)
Is provided.

Hereinafter, the present invention will be described in detail.
The term “C _1-3 alkyl group” used in the present invention means a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Among them, a methyl group is particularly preferable.

Hereinafter, each step will be described.
Step (a):
This step consists in subjecting 4-aminophenol (1) to a trifluoroacetylation reaction to obtain compound (2).
The trifluoroacetylation reaction in this step is performed by reacting 4-aminophenol with a trifluoroacetylation reagent such as trifluoroacetic acid or trifluoroacetic anhydride.
This reaction is performed in the presence or absence of a base, and examples of the base include organic bases such as triethylamine and pyridine, and inorganic bases such as potassium carbonate.

  When trifluoroacetic acid is used in this reaction, it is usually diisopropylcarbodiimide, dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide, diphenylphosphoryl azide, 1,1′-carbonyldiimide. The reaction is carried out in the presence of a dehydrating condensation agent such as imidazole.

The reaction solvent is not particularly limited, and n-hexane, cyclohexane, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine, or other that does not adversely influence the reaction. An organic solvent is used.
The reaction temperature is not particularly limited, and the reaction is performed under cooling to heating.

When trifluoroacetic anhydride is used as a trifluoroacetylating reagent, a dehydrating condensing agent may not be used. In this case, the reaction conditions such as reaction solvent and reaction temperature are the same as above.
In the above trifluoroacetylation reaction, since it is not necessary to protect the hydroxyl group of 4-aminophenol, it is preferable to use 4-aminophenol and trifluoroacetylating reagent in equimolar amounts.

Step (b):
This step consists of subjecting compound (2) to an acylation reaction using carboxylic acid (3) or a reactive derivative at its carboxy group to give compound (4).
Examples of the reactive derivative at the carboxy group of the carboxylic acid (3) include acid halides (for example, acid chloride, acid bromide, etc.) and acid anhydrides (such as symmetrical acid anhydrides and mixed acid anhydrides). Acid anhydrides are particularly preferred.

This reaction is performed in the presence or absence of a base, and examples of the base include organic bases such as triethylamine and pyridine, and inorganic bases such as potassium carbonate.
The reaction solvent is not particularly limited, and n-hexane, cyclohexane, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), dioxane, chloroform, methylene chloride, ethylene chloride, ethyl acetate, pyridine, or other that does not adversely influence the reaction. An organic solvent is used.
Furthermore, when an acid anhydride is used as the reactive derivative at the carboxy group, the acid anhydride can also be used as a solvent.

When the free carboxylic acid (3) is used, the reaction is usually carried out in the presence of the dehydration condensation agent as described above.
The reaction temperature is not particularly limited, and the reaction is performed under cooling to heating.
In the above steps (a) and (b), the compound (2) obtained in the step (a) may be isolated and subjected to the reaction in the step (b), or the compound (2) may not be isolated. You may perform reaction of the following process (b).

Step (c):
This step consists of reacting compound (4) with triphenylphosphine and carbon tetrachloride to obtain compound (5).
The solvent for this reaction is not particularly limited, and diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, carbon tetrachloride, chloroform, methylene chloride, ethylene chloride, benzene, toluene, or other organic solvents that do not adversely affect the reaction should be used. Can do.
The reaction temperature is not particularly limited, and the reaction is performed at room temperature to heating.

Step (d):
This step consists of reacting compound (5) with azide to give compound (6).
Examples of the azide include alkali metal azides such as sodium and potassium, and alkaline earth metal azides such as calcium and magnesium. Among them, alkali metal azides are preferable, and sodium azide is preferable. Particularly preferred.

Solvents for this reaction include aromatic hydrocarbon solvents such as benzene, toluene, xylene, N, N-dimethylformamide (DMF), tetrahydrofuran, alcohol (eg, methanol, ethanol, etc.), mixtures thereof, and this reaction. Other organic solvents that do not have an adverse effect are mentioned.
The reaction temperature is not particularly limited, and the reaction is performed under cooling to heating.
In the reactions of steps (c) and (d), compound (5) obtained in step (c) may be isolated and subjected to the reaction of step (d), or compound (5) may not be isolated. You may perform reaction of the following process (d).

Step (e):
This step consists of hydrolyzing compound (6) to obtain compound (7).
The hydrolysis reaction is preferably performed in the presence of an acid such as a Lewis acid.

Examples of the acid include organic acids (for example, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). Of these, inorganic acids are preferred, and sulfuric acid is particularly preferred.
The solvent for this reaction is not particularly limited, and water, alcohol (eg, methanol, ethanol, etc.), tetrahydrofuran, dioxane, benzene, toluene, a mixture thereof, or other organic solvents that do not adversely influence the reaction can be used. Of these, a mixed solvent of methanol and toluene is particularly preferable.
The reaction temperature is not particularly limited, and the reaction is performed at room temperature to heating.
In the reaction of steps (d) and (e), the compound (6) obtained in step (d) may be isolated and subjected to the reaction of step (e), or the compound (6) may not be isolated. You may perform reaction of the following process (e).

Step (f):
This step consists of reacting the compound (7) with hexamethylenetetramine in methanesulfonic acid and then hydrolyzing the reaction product to obtain the phenyltetrazole derivative (8).
This reaction is carried out by heating compound (7) and hexamethylenetetramine in methanesulfonic acid and then adding water to hydrolyze the reaction product.
Furthermore, it is preferable to add an acid (preferably acetic acid) to the reaction mixture at the time of the above hydrolysis because the reaction product can be easily taken out from the reaction system.

  The compound obtained in each of the above steps can be separated from the reaction mixture and purified by conventional methods such as powdering, recrystallization, column chromatography, reprecipitation and the like.

According to the present invention, by protecting the phenolic hydroxyl group with a lower alkanoyl group, for example, when the phenolic hydroxyl group is protected with an acetyl group, in the presence of sulfuric acid in methanol at about 50 ° C. for 4 hours under mild conditions. Can be deprotected. Further, by using methanesulfonic acid as a reaction reagent and a solvent in the formylation reaction from compound (7) to compound (8), the reaction can be carried out at a short time of about 90 ° C. for 5 hours.
Therefore, this invention is excellent as an industrial manufacturing method of the phenyltetrazole derivative (8) useful as an intermediate for manufacturing a pharmaceutical compound.

The following examples further illustrate the present invention, but the present invention is not limited to these examples.
In the following examples:
Melting point is MICRO MELTING POINT APPARATUS
NMR uses JEOL (JEOL) AL-400,
IR uses Horiba FT-720 (ATR method)
MASS (MS) is Shimadzu GCMS-QP5050A (DI / EI method)
It measured using.

Example 1
(1) N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide 40.0 g (367 mmol) of 4-aminophenol and 160.0 mL of THF were placed in a 1500 mL flask, and then diluted with 40.0 mL of THF. 77.1 g (367 mmol) of trifluoroacetic anhydride was added dropwise at 20 ° C. to 50 ° C., and the mixture was stirred at about 20 ° C. for 2 hours. After completion of the reaction, 74.3 g (734 mmol) of triethylamine and 65.6 g (643 mmol) of acetic anhydride were added at 20 ° C. to 40 ° C. and stirred at about 25 ° C. for 2.5 hours, and then 600.0 mL of water was added. After cooling to about 10 ° C., the precipitated crystals were collected by filtration, and the crystals were washed with a mixed solvent (THF 30.0 mL and water 90.0 mL). By drying under reduced pressure, 86.5 g (yield 95.4%) of N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide was obtained as a pale pink solid.
Melting point: 157.0-158.0 ° C
IR (cm ⁻¹ ): 3321, 1757, 1703, 1556, 1508, 1147
¹ H-NMR (DMSO-d ₆ ): δ = 2.25 (s, 3H), 7.16 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H) ), 11.29 (bs, 1H)
MS m / z: 247 (M ⁺ )

(2) 1- (4-acetoxyphenyl) -5-trifluoromethyl-1H-tetrazole N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide 10.0 g (40 mmol) in a 300 mL flask, 40.0 mL of toluene, 17.0 g (65 mmol) of triphenylphosphine and 9.3 g (61 mmol) of carbon tetrachloride were added and stirred at about 70 ° C. for 4 hours. After completion of the reaction, the mixture was cooled to about 30 ° C., 100.0 mL of heptane was added, the precipitate was filtered off, and washed with a mixed solvent (22.0 mL of heptane and 10.0 mL of toluene). The mother liquor and washing solution were combined and concentrated under reduced pressure to about 30 mL. Into a 200 mL flask were placed 63.9 mL of toluene, 2.9 g (44 mmol) of sodium azide, 0.1 g (8 mmol) of water, the above concentrated solution and 0.2 g (4 mmol) of acetic acid in this order, and 4.5 hours at about 25 ° C. Stir. The reaction mixture was washed with 39.4 mL of 1.6% aqueous sodium hydrogen carbonate solution and 20% brine (31.5 mL × 2), and concentrated under reduced pressure to about 30 mL. 78.7 mL of heptane was added to the concentrated solution, the precipitated crystals were collected by filtration, and the crystals were washed with a mixed solvent (23.6 mL of heptane and 5.9 mL of toluene). Drying under reduced pressure gave 9.2 g (yield 85.3%) of 1- (4-acetoxyphenyl) -5-trifluoromethyl-1H-tetrazole as a white solid.
Melting point: 77.6-78.2 ° C
IR (cm ⁻¹ ): 1751, 1508, 1151
¹ H-NMR (CDCl ₃ ): δ = 2.37 (s, 3H), 7.33 (d, J = 9.3 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H)
MS m / z: 272 (M ⁺ )

(3) 1- (4-Hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole 9.0 g (33 mmol) of 1- (4-acetoxyphenyl) -5-trifluoromethyl-1H-tetrazole in a 100 mL flask and methanol 27.0 mL, 9.0 mL of toluene and 0.3 g (3 mmol) of sulfuric acid were added and stirred at about 50 ° C. for 4 hours. The reaction mixture was extracted with 18.0 mL of toluene and 28.8 mL of 20% brine. The aqueous layer was separated and re-extracted with 27.0 mL of toluene. The organic phases were combined and washed with 28.8 mL of 20% brine. After concentration under reduced pressure to about 65 mL, 90.0 mL of heptane was added and cooled to about 5 ° C. The precipitated crystals were collected by filtration, and the crystals were washed with a mixed solvent (heptane 23.0 mL and toluene 4.0 mL). It dried under reduced pressure and obtained 6.2 g (yield 80.8%) of 1- (4-hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole as a white solid.
Melting point: 111.0-112.0 ° C
IR (cm ⁻¹ ): 3271, 1739, 1514, 1159
¹ H-NMR (CDCl ₃ ): δ = 6.04 (bs, 1H), 7.07 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H)
MS m / z: 230 (M ⁺ )

(4) 2-hydroxy-5- (5-trifluoromethyl-1H-tetrazol-1-yl) -benzaldehyde In a 100 mL flask, 30.0 mL of methanesulfonic acid, 9.9 g (70 mmol) of hexamethylenetetramine and 1- (4 -Hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole (6.0 g, 26 mmol) was added and stirred at about 90 ° C. for 5 hours, and then 18.0 mL of acetic acid was added. After dripping the reaction solution in 40.0 mL of water, 39.2 mL of 25% aqueous sodium hydroxide solution was added. The precipitated crystals were collected by filtration, and the crystals were washed successively with 48.0 mL of water and a mixed solvent (7.2 mL of methanol and 16.8 mL of water). Drying under reduced pressure gave 5.3 g (yield 78.8%) of 2-hydroxy-5- (5-trifluoromethyl-1H-tetrazol-1-yl) -benzaldehyde as pale yellow crystals.
Melting point: 113.8-114.8 ° C
IR (cm ⁻¹ ): 3024, 1739, 1660, 1491, 1151
¹ H-NMR (CDCl ₃ ): δ = 7.25 (d, J = 9.0 Hz, 1H), 7.64 (dd, J = 9.0, 2.7 Hz, 1H), 7.76 (s , J = 2.7 Hz, 1H), 9.98 (s, 1H), 11.39 (bs, 1H)
MS m / z: 258 (M ⁺ )

Example 2
(1) N- (4-hydroxyphenyl) -2,2,2-trifluoroacetamide In a 50 mL flask, 2.0 g (18 mmol) of 4-aminophenol, 5.0 mL of THF and 3.9 g (18 mmol) of trifluoroacetic anhydride After stirring at about 25 ° C. for 1 hour, 30.0 mL of water was added. After cooling to about 10 ° C., the precipitated crystals were collected by filtration. Drying under reduced pressure gave 3.1 g (yield 82.2%) of N- (4-hydroxyphenyl) -2,2,2-trifluoroacetamide as a pale blue solid.
Melting point: 171.5-172.0 ° C
IR (cm ⁻¹ ): 3313, 1689, 1554, 1514, 1153
¹ H-NMR (DMSO-d ₆ ): δ = 6.76 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 9.48 (bs, 1H) ), 10.96 (bs, 1H)
MS m / z: 205 (M ⁺ )

(2) N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide 500.0 mg (2 mmol) of N- (4-hydroxyphenyl) -2,2,2-trifluoroacetamide in a 30 mL flask , 1.0 mL of pyridine and 270.0 mg (3 mmol) of acetic anhydride were added and stirred at about 25 ° C. for 3.5 hours. After completion of the reaction, 3.0 mL of water was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give 480.0 mg (yield 80.0%) of N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide as a pale pink solid. Got as.
IR (cm ⁻¹ ): 3321, 1757, 1703, 1556, 1508, 1147
¹ H-NMR (DMSO-d ₆ ): δ = 2.25 (s, 3H), 7.16 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H) ), 11.29 (bs, 1H)

(3) N- (4-acetoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride 10.0 g of N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide in a 200 mL flask ( 41 mmol), 40.0 mL of toluene, 15.9 g (61 mmol) of triphenylphosphine and 13.7 g (89 mmol) of carbon tetrachloride were added and stirred at about 70 ° C. for 5 hours. After completion of the reaction, 100.0 mL of heptane was added, and the precipitate was filtered off and washed with a mixed solvent (9.9 mL of heptane and 21.6 mL of toluene). The mother liquor and the washing solution were combined, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (dry silica gel, ethyl acetate: hexane = 1: 20), and N- (4-acetoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride 10 0.1 g (94.0% yield) was obtained as a pale yellow solid.
Melting point: 40.4-40.8 ° C
IR (cm ^-1 ): 1761, 1703, 1500, 1153, 939
¹ H-NMR (CDCl ₃ ): δ = 2.32 (s, 3H), 7.19 (m, 4H)
MS m / z: 265 (M ⁺ )

(4) 1- (4-acetoxyphenyl) -5-trifluoromethyl-1H-tetrazole 0.6 g (10 mmol) of sodium azide, 8 mL of DMF and N- (4-acetoxyphenyl) -2,2,2 in a 50 mL flask -Trifluoroacetimidoyl chloride 1.6 g (6 mmol) DMF solution 8mL was put in order, and it stirred at about 25 degreeC for 1.5 hours. After completion of the reaction, 8 mL of water was added and extracted with ethyl acetate (16 mL × 2). The obtained organic phase was washed with 16 mL of 20% brine, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (silica gel, ethyl acetate: hexane = 1: 8) to obtain 1.4 g of 1- (4-acetoxyphenyl) -5-trifluoromethyl-1H-tetrazole (yield). Yield 86.6%) as a white solid.
Melting point: 77.6-78.2 ° C
IR (cm ⁻¹ ): 1751, 1508, 1151
¹ H-NMR (CDCl ₃ ): δ = 2.37 (s, 3H), 7.33 (d, J = 9.3 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H)
MS m / z: 272 (M ⁺ )

(5) 1- (4-Hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole Example using the 1- (4-acetoxyphenyl) -5-trifluoromethyl-1H-tetrazole obtained above Treatment as in 1 (3) gave the title compound.

(6) 2-hydroxy-5- (5-trifluoromethyl-1H-tetrazol-1-yl) -benzaldehyde 1- (4-hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole obtained above And used in the same manner as Example 1 (4) to give the title compound.

Example 3
(1) N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide The title compound was obtained in the same manner as in Example 1 (1) using 4-aminophenol.

(2) N- (4-acetoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride Using the N- (4-acetoxyphenyl) -2,2,2-trifluoroacetamide obtained above In the same manner as in Example 2 (3), the title compound was obtained.

(3) 1- (4-Hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole 0.51 g (8 mmol) of sodium azide and 6 mL of methanol were placed in a 50 mL flask and cooled to about 5 ° C. Thereto was added 2.0 g (8 mmol) of N- (4-acetoxyphenyl) -2,2,2-trifluoroacetimidoyl chloride dissolved in 2 mL of THF, and the mixture was stirred at about 10 ° C. for 1 hour. Next, 1 mL of 5% aqueous sodium nitrite solution and 0.76 g (8 mmol) of concentrated sulfuric acid were added to the reaction solution at about 10 ° C. and stirred for 1 hour, and then stirred at about 50 ° C. for 2 hours. After completion of the reaction, 5 mL of water and 8 mL of ethyl acetate were added and extracted. 8 mL of ethyl acetate was added to the aqueous layer for re-extraction, and the organic layers were combined and washed with 4 mL of 10% brine. The washed organic layer was concentrated under reduced pressure to about 6 mL, then 20 mL of toluene was added, and the mixture was concentrated under reduced pressure to about 8 mL. After adding 10 mL of heptane to the concentrate and cooling to about 5 ° C., the precipitated crystals were collected by filtration, and the crystals were washed with a mixed solvent (1.2 mL of toluene and 4 mL of heptane). The obtained crystals were dried under reduced pressure to obtain 1.57 g (90.8%) of 1- (4-hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole as a white solid.
Melting point: 111.0-112.0 ° C
IR (cm ⁻¹ ): 3271, 1739, 1514, 1159
_{^{1 H-NMR (CDCl 3)}} : δ = 6.04 (bs, 1H), 7.07 (d, J = 9.0Hz, 2H), 7.37 (d, J = 8.8Hz, 2H)

(4) 2-hydroxy-5- (5-trifluoromethyl-1H-tetrazol-1-yl) -benzaldehyde 1- (4-hydroxyphenyl) -5-trifluoromethyl-1H-tetrazole obtained above And used in the same manner as Example 1 (4) to give the title compound.

Claims (4)

Formula (1):

4-aminophenol of the formula (2):

Of the formula (3):
R-COOH (3)
(Wherein R is a C _1-3 alkyl group)
Is subjected to an acylation reaction using a carboxylic acid represented by formula (I) or a reactive derivative at the carboxy group, to give a formula (4):

(Wherein R is as defined above)
Which is reacted with triphenylphosphine and carbon tetrachloride to give a compound of formula (5):

(Wherein R is as defined above)
And is reacted with an azide to give a compound of formula (6):

(Wherein R is as defined above)
A compound represented by formula (7) is obtained by hydrolysis.

This was reacted with hexamethylenetetramine in methanesulfonic acid, and then the reaction product was hydrolyzed to obtain the formula (8):

A process for producing a phenyltetrazole derivative, characterized in that General formula (4):

(Wherein R is a C _1-3 alkyl group)
A compound represented by General formula (5):

(Wherein R is a C _1-3 alkyl group)
A compound represented by General formula (6):

(Wherein R is a C _1-3 alkyl group)
A compound represented by