JP3440196B2 - Method for producing thiobenzamide derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing a thiobenzamide derivative and a benzothiazole derivative which are intermediates for producing a 2- (3-cyanophenyl) thiazole derivative useful as a medicine. More specifically, the present invention provides a thiol which is a production intermediate of a 2- (3-cyanophenyl) thiazole derivative useful as a xanthine oxidase (hereinafter referred to as “XOD”) inhibitor such as a therapeutic agent for gout and hyperuricemia. The present invention relates to a method for producing a benzamide derivative and a 2-phenylthiazole derivative.

[0002]

2. Description of the Related Art Gout is a basic disease of hyperuricemia, and after remission of an attack, improvement therapy for hyperuricemia is performed. The therapeutic agents for hyperuricemia are roughly classified into uric acid excretion agents and uric acid synthase inhibitors (XOD inhibitors), and are appropriately selected according to the mode and degree of the disease. As the XOD inhibitor, 2- (3
-Cyanophenyl) thiazole derivatives are known (see International Publication WO92 / 09279 pamphlet).

Usually, as a method of constructing 1,3-thiazole, which is a basic skeleton of a 2- (3-cyanophenyl) thiazole derivative, a method of reacting α-haloketones with thioamide is used (New Experimental Chemistry Course 14). Organic synthesis and reaction [IV] p2192). In fact, even in the synthesis of 2- (3-cyanophenyl) thiazole derivative,
After isolating hydroxybenzonitrile as a thiobenzamide derivative, it was reacted with ethyl 3-chloroacetoacetate,
A 2-phenylthiazole derivative is used (JP-A-6-
329647).

Therefore, in order to produce a 2-phenylthiazole derivative, a method for producing a thiobenzamide derivative which is a synthetic precursor thereof is important. In the generally known reaction for synthesizing thioamides, hydrogen sulfide and phosphorus pentasulfide are used as a sulfur source (see New Experimental Chemistry Course 14 Organic Synthesis and Reaction [III] p1828-1829). -Using a dimethylformamide hydrochloride solution (J. Med. Chem., 29, 6, 1065-10
80 (1986)). The 6N-dimethylformamide hydrochloride solution is corrosive, and there are problems that a toxic hydrochloric acid gas is used for this preparation and that hydrochloric acid gas is generated during operation. Further, hydrogen sulfide and phosphorus pentasulfide are poisonous substances, and there is a problem in using them in large quantities in industrial production.

By the way, it is known that a benzonitrile derivative can be converted into a benzamide derivative at a high yield by heating a benzonitrile derivative in polyphosphoric acid (J. Am. Chem. Soc.,
76, 3039 (1954)). However, there is no example in which thioacetamide was added as a sulfur source in polyphosphoric acid to react with a benzonitrile derivative to convert it into a thiobenzamide derivative.

[0006]

DISCLOSURE OF THE INVENTION In view of the above-mentioned prior art, the present inventors have found that 2- (3) useful as an XOD inhibitor.
As a result of earnest research on thioamidation reaction and thiazolization reaction aiming at development of a production method of a thiobenzamide derivative and a 2-phenylthiazole derivative useful as a production intermediate of a -cyanophenyl) thiazole derivative, the present invention has been achieved. It was done.

[0007]

That is, the first aspect of the present invention is to provide the following formula (1):

[0008]

[Chemical 5]

[Wherein R ₁ is a substituent on the aromatic ring, and is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C ₁ -C ₅ alkyl group, or an unsubstituted or substituted C 1 an alkoxyl group having ₁ -C _5. ] The benzonitrile derivative represented by the following formula (2) characterized by reacting with thioacetamide in polyphosphoric acid

[0010]

[Chemical 6]

[In the formula, the definition of R ₁ is the same as in the above formula (1). ] It is a manufacturing method of the thiobenzamide derivative represented by this.

Furthermore, the present invention secondly provides the benzonitrile derivative represented by the above formula (1) after the reaction with thioacetamide in polyphosphoric acid without isolation, and the following formula (3)

[0013]

[Chemical 7]

[Wherein R ₂ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, R ₃ represents a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkylcarbonyl group, C _{1 to} C ₄ alkyl (mono or disubstituted) aminocarbonyl group, carbamoyl group, C _{1 to} C ₄ alkoxycarbonyl group, or carboxyl group, X is a chlorine atom, a bromine atom,
Or represents an iodine atom. ] The following formula (4) characterized by reacting α-haloketones represented by

[0015]

[Chemical 8]

[In the formula, the definition of R ₁ is the same as that in the above formula (1), and the definitions of R ₂ and R ₃ are the same as those in the above formula (3). ] It is a manufacturing method of the 2-phenyl thiazole derivative represented by these.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the compounds represented by the above formulas (1), (2), and (4), R ₁ is a substituent on the aromatic ring, which is a hydrogen atom, a halogen atom, a hydroxyl group, unsubstituted or It represents a substituted C ₁ -C ₅ alkyl group or an unsubstituted or substituted C ₁ -C ₅ alkoxyl group.
Examples of such a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and of these, a bromine atom is preferable. As an unsubstituted or substituted C ₁ -C ₅ alkyl group,
Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-
Examples thereof include a butyl group, a pentyl group, a 3-pentyl group, a neo-pentyl group and a cyclopentyl group. As an unsubstituted or substituted C ₁ -C ₅ alkoxyl group,
Methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group, sec-
Examples thereof include a butyloxy group, a tert-butyloxy group, a pentyloxy group, a 3-pentyloxy group, a neo-pentyloxy group and a cyclopentyloxy group.

In the compounds represented by the above formulas (3) and (4), R ₂ represents a hydrogen atom or a C ₁ -C ₄ alkyl group. Examples of the C _{1 to} C ₄ alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Among them, preferably a methyl group,
An ethyl group and a propyl group are mentioned, and a methyl group is more preferable. In the compounds represented by the above formulas (3) and (4), R ₃ is a hydrogen atom, a C _{1 to} C ₄ alkyl group, a C _{1 to} C ₄ alkylcarbonyl group, a C _{1 to} C ₄ alkyl (mono Or (di-substituted) aminocarbonyl group, carbamoyl group, C ₁ -C ₄ alkoxycarbonyl group, or carboxyl group. The alkyl group of C ₁ -C _4, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, te
Examples thereof include an rt-butyl group. Examples of the C ₁ -C ₄ alkylcarbonyl group include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group and a butylcarbonyl group. Examples of the C ₁ -C ₄ alkyl (mono or di-substituted) aminocarbonyl group include a methylaminocarbonyl group, a dimethylaminocarbonyl group, an ethylaminocarbonyl group, a diethylaminocarbonyl group, a butylaminocarbonyl group, a dibutylaminocarbonyl group and the like. Examples of the C _{1 to} C ₄ alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group,
Examples thereof include a tert-butoxycarbonyl group, and preferably a methoxycarbonyl group and an ethoxycarbonyl group.

In the compounds represented by the above formulas (3) and (4), the most preferred combination of R ₂ , R ₃ and X is R ₂ is a methyl group, R ₃ is an ethoxycarbonyl group and X is a chlorine atom. The combination of

In the production method of the present invention, the amount of polyphosphoric acid used in the reaction from compound (1) to compound (2) (thioamidation reaction) is sufficient if the reaction proceeds smoothly. Although it is good, it is usually used in an amount of 3 to 15 times, preferably 5 to 10 times the weight of the raw material. The amount of thioacetamide used in the thioamidation reaction may be an amount sufficient to allow the reaction to proceed smoothly, but is usually 1 to 5 times mol of the raw material, preferably 1.5 to 2 times mol. Used. Further, the reaction temperature for carrying out the thioamidation reaction is usually in the range of 25 to 150 ° C., preferably 7
It is 0 to 100 ° C. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed in about 30 minutes to 1 day.

After the reaction, the obtained product is separated and purified from the reaction solution by a conventional means. For example, extraction, washing, chromatography, recrystallization, or a combination thereof is performed.

Further, the reaction from the compound (1) to the compound (4) can be continuously carried out in one pot (thioamidation-thiazolization reaction), and the embodiment at that time is up to the thioamidation reaction. , Subject to the above conditions. The amount of the α-haloketones represented by the above formula (3) used at the end of the thioamidation reaction may be an amount sufficient for the reaction to proceed smoothly.
It is used in an amount of 2 times, preferably 2 to 3 times. The reaction temperature for carrying out the thiazole-forming reaction is usually in the range of 25 to 150 ° C, preferably 70 to 100 ° C. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed in about 30 minutes to 1 day.

After the reaction, the obtained product is separated and purified from the reaction solution by a conventional means. For example, extraction, washing, chromatography, recrystallization, or a combination thereof is performed.

[0024]

【Example】

Example 1 Synthesis of 4-hydroxythiobenzamide

[0025]

[Chemical 9]

To a 100 mL three-necked flask, 7.51 g of thioacetamide and 40 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. To this, 5.96 g of 4-hydroxybenzonitrile was added and heated and stirred at 85 ° C. for 4 hours. After cooling, 8 mL of ethyl acetate and 8 mL of water were added when the internal temperature reached 60 ° C., and the mixture was allowed to cool to room temperature with stirring. Transfer the reaction mixture to a 500mL beaker and add 240mL of ethyl acetate.
And 180 mL of water were added, and the mixture was stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 120 mL of ethyl acetate. Water each organic layer 110
After washing twice with 10 mL of 10% brine 110 mL, combining, drying over anhydrous magnesium sulfate, and filtering off the desiccant,
The filtrate was concentrated to obtain 8.4 g of a crude product. This was purified by silica gel column chromatography (silica 250 g, hexane / ethyl acetate = 2/1 to 1/2) to obtain the desired product 7.
85 g (yield quant) was obtained. ¹ H-NMR (DMSO-d6) δ: 6.75 (d, J = 8.8H
z, 2H), 7.86 (d, J = 8.8Hz, 2H), 9.2 (br, 1H), 9.5 (br,
1H), 10.11 (s, 1H)

Example 2 Synthesis of 4-methylthiobenzamide

[0028]

[Chemical 10]

To a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. Here, 4-methylbenzonitrile 2.9
3 g was added, and the mixture was heated with stirring at 85 ° C. for 3 hours and 40 minutes. After standing to cool, when the internal temperature reached 60 ° C, 4 mL of ethyl acetate
And 4 mL of water were added, and the mixture was allowed to cool to room temperature with stirring. 3 reaction liquids
Transfer to a 00 mL beaker, 120 mL of ethyl acetate and water 9
0 mL was added and stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 70 mL of ethyl acetate. Each organic layer twice with 60 mL of water,
After washing with 60 mL of 10% saline, they were combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated to obtain 5.17 g of a crude product. This was subjected to silica gel column chromatography (silica 150 g, hexane / ethyl acetate =
4/1 to 2/1) and then 3.93 g of the desired product (yield qu
ant). ¹ H-NMR (DMSO-d6) δ: 2.33 (s, 3H), 7.
21 (d, J = 8.3Hz, 2H), 7.82 (d, J = 8.3Hz, 2H), 9.41 (br,
1H), 9.76 (br, 1H)

Example 3 Synthesis of thiobenzamide

[0031]

[Chemical 11]

To a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and the mixture was heated and stirred at 85 ° C. To this, 2.58 g of benzonitrile was added, and the mixture was heated and stirred at 85 ° C. for 4 hours and 15 minutes. After allowing to cool, when the internal temperature reached 60 ° C, 4 mL of ethyl acetate and 4 m of water
L was added and the mixture was allowed to cool to room temperature with stirring. 300 mL of reaction solution
The mixture was transferred to a beaker, 120 mL of ethyl acetate and 90 mL of water were added, and the mixture was stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. 70m ethyl acetate from the water layer
Extracted with L. Each organic layer was washed twice with 60 mL of water, 60 mL of 10% brine, combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated to give a crude product 4.6.
6 g was obtained. This was subjected to silica gel column chromatography (silica 150 g, hexane / ethyl acetate = 4/1).
And purified to obtain 2.41 g of the desired product (yield 70%). ¹ H-NMR (DMSO-d6) δ: 7.3 to 7.7 (m, 3
H), 7.8 ~ 8.0 (m, 2H), 9.51 (br, 1H), 9.89 (br, 1H)

Example 4 Synthesis of 4-bromothiobenzamide

[0034]

[Chemical 12]

To a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. Here, 4-bromobenzonitrile 4.5
5 g was added, and the mixture was heated with stirring at 85 ° C. for 4 hours and 15 minutes. After standing to cool, when the internal temperature reached 60 ° C, 4 mL of ethyl acetate
And 4 mL of water were added, and the mixture was allowed to cool to room temperature with stirring. 3 reaction liquids
Transfer to a 00 mL beaker, 120 mL of ethyl acetate and water 9
0 mL was added and stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 70 mL of ethyl acetate. Each organic layer twice with 60 mL of water,
After washing with 60 mL of 10% saline, they were combined, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated.
This is subjected to silica gel column chromatography (silica 1
The product was purified with 50 g and hexane / ethyl acetate = 4/1) to obtain 2.78 g of the desired product (yield 51%). ¹ H-NMR (DMSO-d6) δ: 7.62 (d, J = 8.6H
z, 2H), 7.82 (d, J = 8.6Hz, 2H), 9.58 (br, 1H), 9.97 (b
r, 1H)

Example 5 Synthesis of 4-isobutyloxythiobenzamide

[0037]

[Chemical 13]

In a 50 mL three-necked flask, 3.76 g of thioacetamide and 20 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. 5.354 g of 4-isobutyloxy benzonitrile was added here, and it heat-stirred at 85 degreeC for 4 hours and 40 minutes. After cooling, 4 mL of ethyl acetate and 4 mL of water were added when the internal temperature reached 60 ° C., and the mixture was cooled to room temperature with stirring. Transfer the reaction mixture to a 300 mL beaker, and add ethyl acetate 1
20 mL and 90 mL of water were added and stirred for 30 minutes. The insoluble matter of this liquid was separated by filtration, transferred to a separating funnel and separated. The aqueous layer was extracted with 70 mL of ethyl acetate. Water each organic layer 6
After washing twice with 0 mL and 60 mL of 10% saline, they were combined, dried over anhydrous magnesium sulfate, and the desiccant was filtered off.
The filtrate was concentrated. This was subjected to silica gel column chromatography (silica 300 g, hexane / ethyl acetate = 4 /
The product was purified in 1) to obtain 4.62 g of the desired product (yield 89%). ¹ H-NMR (DMSO-d6) δ: 6.94 (d, J = 9Hz,
3H), 7.94 (d, J = 9Hz, 3H), 9.32 (br, 1H), 9.63 (br, 1
H)

Example 6 2- (4-hydroxyphenyl) -4-methyl-5-thio
Synthesis of ethyl azolecarboxylate

[0040]

[Chemical 14]

In a 200 mL three-necked flask, 7.6 g of thioacetamide and 40 g of polyphosphoric acid were placed, and heated and stirred at 85 ° C. To this, 8.0 g of 4-hydroxybenzonitrile was added, and the mixture was heated with stirring at 85 ° C. for 3 hours. 18.31 g of ethyl 3-chloroacetoacetate was added dropwise thereto, and then heated and stirred at 85 ° C. for 1 hour. After cooling, 8 mL of water was added when the internal temperature reached 60 ° C., and the mixture was cooled to room temperature with stirring. 80 mL of water was added to the reaction solution, and the temperature was again 60 ° C.
The mixture was heated and stirred for 15 minutes, allowed to cool, and the precipitate was collected by filtration. After washing the obtained solid twice with 40 mL of ethanol,
It was dried to obtain 8.12 g of the desired product (yield 46%). ¹ H-NMR (DMSO-d6) δ: 1.29 (t, J = 7.3H
z, 3H), 2.66 (s, 3H), 3.9 (br, 1H), 4.28 (q, J = 7.2H
z), 6.87 (d, J = 8.6Hz, 2H), 7.84 (d, J = 8.6Hz, 2H)

[0042]

According to the present invention, using a safe reagent,
A thiobenzamide derivative and a 2-phenylthiazole derivative can be obtained easily and inexpensively.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-6-345724 (JP, A) JP-A-6-65222 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07C 327/48 C07D 277/22 C07D 277/32

Claims (6)

(57) [Claims] 1. The following formula (1): [Wherein, R ₁ is a substituent on the aromatic ring, and is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C _{1 to} C ₅ alkyl group, or an unsubstituted or substituted C ₁ to
Represents a C ₅ alkoxyl group. ] The benzonitrile derivative represented by the formula is reacted with thioacetamide in polyphosphoric acid, and is represented by the following formula (2): [In the formula, the definition of R ₁ is the same as in the above formula (1). ] The manufacturing method of the thiobenzamide derivative represented by these. 2. The method for producing a thiobenzamide derivative according to claim 1, wherein R ₁ is a substituent at the 4-position on the aromatic ring. 3. The method for producing a thiobenzamide derivative according to claim 2, wherein R ₁ is a hydrogen atom, a bromine atom, a hydroxyl group, a methyl group, or an isobutyloxy group. 4. A benzonitrile derivative represented by the above formula (1) is reacted with thioacetamide in polyphosphoric acid and then isolated without being isolated from the following formula (3): [In the formula, R ₂ represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, R ₃ represents a hydrogen atom, a C _{1 to} C ₄ alkyl group, and a C _{1 to} C 4
₄ alkylcarbonyl group, C ₁ -C ₄ alkyl (mono- or di-substituted) aminocarbonyl group, carbamoyl group, C ₁ -C ₄ alkoxycarbonyl group, or carboxyl group, X is a chlorine atom, a bromine atom, Or represents an iodine atom. ] An α-haloketone represented by the formula: [In the formula, the definition of R ₁ is the same as that in the above formula (1), and the definitions of R ₂ and R ₃ are the same as those in the above formula (3). ] The manufacturing method of the 2-phenyl thiazole derivative represented by these. 5. The method for producing a 2-phenylthiazole derivative according to claim 4, wherein R ₁ is a substituent at the 4-position on the aromatic ring. 6. The method according to claim 5, wherein R ₁ is a hydroxyl group.
-A method for producing a phenylthiazole derivative.