JPWO2012133783A1 - Process for producing benzylpyrazole derivative and production intermediate thereof - Google Patents

Abstract

General formula (D): ## STR1 ## wherein R 1 and R 2 are a C 1-6 alkyl group, R 3 is a halogen atom, a C 1-6 alkoxy group, etc., and R 4 is a hydrogen atom, a halogen atom And a compound represented by general formula (E): ## STR2 ## wherein R3 and R4 have the same meaning as described above. Compared with the production method of a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like, and a production method of a conventional benzylpyrazole derivative, an industrially superior production method can be provided. [Selection figure] None

Description

  The present invention relates to a method for producing a benzylpyrazole derivative useful as a pharmaceutical intermediate and a production intermediate thereof.

  The glucopyranosyloxypyrazole derivative is reported to be useful as a therapeutic agent for diabetes, for example (see, for example, Patent Documents 1 to 4).

  So far, a method for producing an intermediate for producing a glucopyranosyloxypyrazole derivative is disclosed in Patent Document 4 in general formula (1):

（上式中の各記号の意味については、特許文献４の記載を参照）を、一般式（２）：

(For the meaning of each symbol in the above formula, refer to the description of Patent Document 4), the general formula (2):

（上式中の各記号の意味については、特許文献４の記載を参照）で表される化合物と、ヒドラジンを縮合させた後、アルキル化、次いで加水分解することにより製造する方法が報告されている。上述した特許文献４には、具体的にはヒドラジンを用いた一般式（１）の製造方法が記載されているが、イソプロピルヒドラジンを用いた製造方法は報告されていない。

(For the meaning of each symbol in the above formula, refer to the description in Patent Document 4) A method of producing a compound by condensing hydrazine and then alkylating and then hydrolyzing has been reported. Yes. Specifically, Patent Document 4 described above describes a production method of the general formula (1) using hydrazine, but no production method using isopropyl hydrazine has been reported.

  In addition, Patent Document 5 includes general formula (3):

（上式中の各記号の意味については、特許文献５の記載を参照）で表される化合物の製造方法が報告されているが、具体的な反応例は記載されていない。

(For the meaning of each symbol in the above formula, a method for producing a compound represented by Patent Document 5) has been reported, but no specific reaction example is described.

International Publication No. 02/053573 International Publication No. 01/16147 International Publication No. 02/068439 International Publication No. 2007/010015 International Publication No. 2004/031203

As a result of investigations by the present inventors, it has been found that when the compound represented by the general formula (A) is reacted with isopropylhydrazine, a benzylpyrazole derivative cannot be obtained efficiently (see Comparative Example). Furthermore, there remains room for improvement in industrial production.
An object of the present invention is to provide an industrially superior production method as compared with a production intermediate of a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like, and a conventional production method of a benzylpyrazole derivative. is there.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained a general formula (E):

（式中のＲ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基である）で表される化合物またはその塩の新規な製造方法、ならびにその製造中間体を見出し、本発明を成すに至った。
すなわち、本発明は、

(In the formula, R ³ represents a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _3-6 cycloalkyloxy group, a C _3-6 cycloalkyl ( C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group or halo C _1-6 alkoxy group, R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 A novel method for producing a compound represented by the following formula: an alkylthio group or a halo C _1-6 alkoxy group, or a salt thereof, and a production intermediate thereof have been found, and the present invention has been accomplished.
That is, the present invention

(1) General formula (A-1):

（式中のＲ¹およびＲ²は同一あるいは異なっていてもよく、それぞれＣ_1-6アルキル基を示すか、またはそれらが結合しＣ_1-6アルキレン基を形成してもよく、Ｒ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁶は、ヒドロキシ基、Ｃ_1-6アルコキシ基、置換可Ｃ_7-11アラルキルオキシ基またはｉ−ＰｒＮＨＮＨ−基である）で表される化合物またはその塩；
（２）Ｒ³がＣ_1-6アルキル基またはＣ_1-6アルコキシ基であり、Ｒ⁴が水素原子またはハロゲン原子である、（１）記載の化合物またはその塩；
（３）Ｒ³がイソプロピルオキシ基であり、Ｒ⁴が水素原子である、（２）記載の化合物またはその塩；
（４）Ｒ¹およびＲ²が互いに結合して、−ＣＨ₂ＣＨ₂−または−ＣＨ₂ＣＨ₂ＣＨ₂−基を形成する、（３）記載の化合物またはその塩；
（５）Ｒ⁶がヒドロキシ基またはｉ−ＰｒＮＨＮＨ−基である、（４）記載の化合物またはその塩；
（６）Ｒ⁶がｉ−ＰｒＮＨＮＨ−基である、（５）記載の化合物またはその塩；
（７）一般式（Ｃ）：

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} alkoxy group, R ⁶ is hydroxy, C _1-6 alkoxy group, a substitutable C _7-11 aralkyloxy Or i-PrNHNH- compound represented by a group);
(2) The compound or salt thereof according to (1), wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom;
(3) The compound or salt thereof according to (2), wherein R ³ is an isopropyloxy group and R ⁴ is a hydrogen atom;
(4) The compound or a salt thereof according to (3), wherein R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group;
(5) The compound or salt thereof according to (4), wherein R ⁶ is a hydroxy group or an i-PrNHNH- group;
(6) The compound or a salt thereof according to (5), wherein R ⁶ is an i-PrNHNH— group;
(7) General formula (C):

（式中のＲ¹およびＲ²は同一あるいは異なっていてもよく、それぞれＣ_1-6アルキル基を示すか、またはそれらが結合しＣ_1-6アルキレン基を形成してもよく、Ｒ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基である）で表される化合物またはその塩をイソプロピルヒドラジンまたはその塩と反応することによる一般式（Ｄ）：

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} ) or a salt thereof is the same as isopropyl hydrazine or a salt thereof. General formula (D) by responding:

（式中のＲ¹およびＲ²は同一あるいは異なっていてもよく、それぞれＣ_1-6アルキル基を示すか、またはそれらが結合しＣ_1-6アルキレン基を形成してもよく、Ｒ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基である）で表される化合物またはその塩の製造方法；
（８）Ｒ³がＣ_1-6アルキル基またはＣ_1-6アルコキシ基であり、Ｒ⁴が水素原子またはハロゲン原子である（７）記載の製造方法；
（９）Ｒ¹およびＲ²が互いに結合して、−ＣＨ₂ＣＨ₂−または−ＣＨ₂ＣＨ₂ＣＨ₂−基を形成し、Ｒ³がイソプロピルオキシ基であり、Ｒ⁴が水素原子である（８）記載の製造方法；
（１０） 工程１：
一般式（Ａ）：

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6 is a} alkoxy group) or a salt thereof;
(8) The production method according to (7), wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom;
(9) R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group, R ³ is an isopropyloxy group, and R ⁴ is a hydrogen atom. (8) The production method described in;
(10) Step 1:
Formula (A):

（式中のＲ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁵はＣ_1-6アルキル基または置換可Ｃ_7-11アラルキル基である）で表される化合物のカルボニル基を保護することにより、一般式（Ｂ）：

(In the formula, R ³ represents a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _3-6 cycloalkyloxy group, a C _3-6 cycloalkyl ( C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group or halo C _1-6 alkoxy group, R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 An alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁵ is a C _1-6 alkyl group or a substituted C _7-11 aralkyl group). (B):

（式中のＲ¹およびＲ²は同一あるいは異なっていてもよく、それぞれＣ_1-6アルキル基を示すか、またはそれらが結合しＣ_1-6アルキレン基を形成してもよく、Ｒ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁵はＣ_1-6アルキル基または置換可Ｃ_7-11アラルキル基である）で表される化合物を調製する工程；
工程２：
一般式（Ｂ）で表される化合物を、脱保護反応に付すことにより一般式（Ｃ）：

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} is an alkoxy group, represented by R ⁵ is C _1-6 alkyl or optionally substituted C _7-11 aralkyl group) Preparing a compound;
Step 2:
By subjecting the compound represented by the general formula (B) to a deprotection reaction, the general formula (C):

（式中のＲ¹およびＲ²は同一あるいは異なっていてもよく、それぞれＣ_1-6アルキル基を示すか、またはそれらが結合しＣ_1-6アルキレン基を形成してもよく、Ｒ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基である）で表される化合物またはその塩を調製する工程；を包含する、（７）記載の製造方法；
（１１）Ｒ³がＣ_1-6アルキル基またはＣ_1-6アルコキシ基であり、Ｒ⁴が水素原子またはハロゲン原子である（１０）記載の製造方法；
（１２）Ｒ¹およびＲ²が互いに結合して、−ＣＨ₂ＣＨ₂−または−ＣＨ₂ＣＨ₂ＣＨ₂−基を形成し、Ｒ³がイソプロピルオキシ基であり、Ｒ⁴が水素原子であり、Ｒ⁵がメチル基である（１１）記載の製造方法；
（１３）一般式（Ｄ）：

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- (6} ) an alkoxy group), or a salt thereof. Production method;
(11) The production method according to (10), wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom;
(12) R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group, R ³ is an isopropyloxy group, and R ⁴ is a hydrogen atom. And the production method according to (11), wherein R ⁵ is a methyl group;
(13) General formula (D):

（式中のＲ¹およびＲ²は同一あるいは異なっていてもよく、それぞれＣ_1-6アルキル基を示すか、またはそれらが結合しＣ_1-6アルキレン基を形成してもよく、Ｒ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基である）で表される化合物またはその塩を環化させることによる一般式（Ｅ）：

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _1- A general formula (E) by cyclization of a compound represented by ( ₆ alkoxy group) or a salt thereof:

（式中のＲ³は、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基であり、Ｒ⁴は、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、ハロＣ_1-6アルキル基、Ｃ_3-6シクロアルキル基、Ｃ_3-6シクロアルキルオキシ基、Ｃ_3-6シクロアルキル（Ｃ_1-6アルコキシ）基、Ｃ_1-6アルコキシ基、Ｃ_1-6アルキルチオ基またはハロＣ_1-6アルコキシ基である）で表される化合物またはその塩の製造方法；
（１４）Ｒ³がＣ_1-6アルキル基またはＣ_1-6アルコキシ基であり、Ｒ⁴が水素原子またはハロゲン原子である、（１３）記載の製造方法；および
（１５）Ｒ¹およびＲ²が互いに結合して、−ＣＨ₂ＣＨ₂−または−ＣＨ₂ＣＨ₂ＣＨ₂−基を形成し、Ｒ³がイソプロピルオキシ基であり、Ｒ⁴が水素原子である、（１４）記載の製造方法；等を提供するものである。

(In the formula, R ³ represents a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _3-6 cycloalkyloxy group, a C _3-6 cycloalkyl ( C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group or halo C _1-6 alkoxy group, R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 A method for producing a compound represented by an alkylthio group or a halo C _1-6 alkoxy group) or a salt thereof;
(14) The production method according to (13), wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom; and (15) R ¹ and R ² Are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group, R ³ is an isopropyloxy group, and R ⁴ is a hydrogen atom. And so on.

  In the present invention, the following terms have the following meanings unless otherwise specified.

  A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

C _1-6 alkyl group means methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group. , 1-methylbutyl group, 2-methylbutyl group, hexyl group and the like, which are linear or branched alkyl groups having 1 to 6 carbon atoms.

A halo C _1-6 alkyl group refers to the above C _1-6 alkyl group substituted with a different or the same halogen atom, and includes, for example, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, Examples include 2,2,2,1,1-pentafluoroethyl group, 2-fluoroethyl group and the like.

The C _3-6 cycloalkyl group refers to a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

C _1-6 alkoxy group means methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-butyloxy A straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as a group, a tert-pentyloxy group, a 1-methylbutoxy group, a 2-methylbutoxy group, and a hexyloxy group.

The halo C _1-6 alkoxy group refers to the above C _1-6 alkoxy group substituted with the above or different halogen atoms, and examples thereof include a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, 2 , 2,2,1,1-pentafluoroethoxy group and the like.

The C _3-6 cycloalkyloxy group refers to a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
The C _3-6 cycloalkyl (C _1-6 alkoxy) group means the C _1-6 alkoxy group substituted with the C _3-6 cycloalkyl group.

The C _1-6 alkylthio group refers to a linear or branched alkylthio group having 1 to 6 carbon atoms such as a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, and a hexylthio group.

The optionally substituted C _7-11 aralkyl group, have one to three substituents of a heterologous or homologous means good C _7-11 aralkyl group, as a substituent in the substitutable C _7-11 aralkyl group Examples include a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a nitro group. Examples of the replaceable C _7-11 aralkyl group include a benzyl group, a 4-methoxybenzyl group, a naphthylmethyl group, and the like.

The optionally substituted C _7-11 aralkyloxy group, a substituent of heterologous or homologous means 1-3 have good C _7-11 also be aralkyloxy group, a substitutable C _7-11 aralkyloxy group Examples of the substituent include a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a nitro group, and the like. Examples of the replaceable C _7-11 aralkyloxy group include a benzyloxy group, a 4-methoxybenzyloxy group, a naphthylmethyloxy group, and the like.

The C _1-6 alkylene group means a divalent linear or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as —CH ₂ —, —CH ₂ CH ₂ —, —CH. _{(CH 3) -, - CH} (CH 3) CH 2 -, - CH 2 CH (CH 3) -, - C (CH 3) 2 -, - C (CH 3) 2 CH 2 -, - CH 2 C Examples include (CH ₃ ) ₂ —, —CH ₂ CH ₂ CH ₂ —, —C (CH ₃ ) ₂ CH ₂ CH ₂ —, —CH (CH ₃ ) CH (CH ₃ ) —, and the like.

  Examples of the salt in the present invention include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. Examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N 2, N′-dibenzylethylenediamine and the like. Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. And salts with sulfonic acid and the like. Examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

  Hereinafter, the specific manufacturing method of this invention is illustrated.

（式中のＲ¹、Ｒ²、Ｒ³、Ｒ⁴およびＲ⁵は前記と同じ意味をもつ）

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as described above)

(Process 1)
By subjecting compound (A) to a carbonyl group protection reaction according to the method described in Protective Groups in Organic Synthesis (TWGreene et al., John Wiley & Sons, Inc., 1991, Second Edition) or a method analogous thereto. A compound (B) can be obtained. For example, compound (B) can be obtained by subjecting compound (A) to a dehydration reaction with an alcohol in the presence of an acid in a solvent-free or inert solvent. Examples of the inert solvent include hydrocarbon solvents such as cyclohexane, toluene, and xylene. Preferably, toluene and xylene are used. Examples of acids include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid and methanesulfonic acid, Lewis acids such as boron trifluoride diethyl ether complex and trimethylchlorosilane, and acids such as Amberlyst (registered trademark). An ion exchange resin is mentioned. Preferable examples include sulfonic acids such as sulfuric acid, p-toluenesulfonic acid, and methanesulfonic acid, and more preferable examples include p-toluenesulfonic acid and methanesulfonic acid. The amount of the solvent can be 5 to 10 times the amount of the compound (A). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 to 20 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

(Process 2)
The compound (C) can be obtained by subjecting the compound (B) to an ester hydrolysis reaction in the presence of a base in an inert solvent. Examples of the inert solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The amount of the base is preferably 1 to 3 equivalents relative to the compound (B). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 hours to 3 days, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
In addition, when R ⁵ is a substitutable C _7-11 aralkyl group, the compound (C) may be obtained by subjecting the compound (B) to a deprotection reaction according to a known method or a method analogous thereto. it can.

(Process 3)
The compound (D) can be obtained by subjecting the compound (C) to an amidation reaction with isopropylhydrazine or a salt thereof in an inert solvent in the presence of a base and a condensing agent. Examples of the inert solvent include ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, amide solvents such as dimethylformamide, or a mixed solvent thereof. Examples of the base include triethylamine or pyridine. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, carbonyldiimidazole, and thionyldiimidazole, and carbonyldiimidazole and thionyldiimidazole are preferable. A commercial item may be used for these condensing agents, and you may prepare and use at the time of reaction. The amount of the base and the condensing agent is preferably 1 to 2 equivalents relative to the compound (C). The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 0.5 to 20 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

  Using the compound (D) obtained in the above scheme 1, a production intermediate (E) of a compound useful as a therapeutic agent for diabetes can be produced by the method shown in the following scheme 3.

（式中のＲ¹、Ｒ²、Ｒ³およびＲ⁴は前記と同じ意味をもつ）

(Wherein R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above)

(Process 4)
Compound (E) can be obtained by subjecting compound (D) to a cyclization reaction in an inert solvent in the presence of an acid. Examples of the inert solvent include nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, hydrocarbon solvents such as toluene, amide solvents such as dimethylformamide, Water or a mixed solvent thereof can be used. Preferably, a mixed solvent of tetrahydrofuran, dimethylformamide, and water is used. Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and hydrochloric acid is preferable. The amount of the solvent can be used 5 to 20 times the amount of the compound (D). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 to 35 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

  A glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes can be produced from the compound (E) obtained in Scheme 2 according to the method described in Patent Document 1 or a method analogous thereto.

  The compound (A) used as a starting material in the scheme 1 can be produced by the method shown in the following scheme 3, the method described in Patent Document 4, or a method analogous thereto.

(Process 5)
Compound (I) is obtained by subjecting compound (G) to a condensation reaction with compound (H) in a solvent-free or inert solvent in the presence of a base or an acid and a base, if necessary, using a dehydrating agent. be able to. Examples of the inert solvent include nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran and tert-butyl methyl ether, hydrocarbon solvents such as toluene, alcohol solvents such as ethanol, or These mixed solvents are mentioned, and it is preferable to react without solvent. Examples of the acid include acetic acid, propionic acid, benzoic acid, sulfuric acid, p-toluenesulfonic acid, titanium chloride and the like, and acetic acid is preferable. Examples of the base include organic amines such as piperidine, pyrrolidine, pyridine, diethylamine and triethylamine, and piperidine is preferable. Examples of the dehydrating agent include molecular sieves. 0-10 times amount can be used for the amount of solvent with respect to the said compound (G). The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 0.5 hours to 5 days, although it varies depending on the raw material used, solvent, reaction temperature, and the like.

(Step 6)
Compound (A) can be obtained by subjecting compound (I) to a reduction reaction. For example, in the presence or absence of an acid such as acetic acid in the presence of an acid such as acetic acid in an alcoholic solvent such as methanol or ethanol, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, or a mixed solvent thereof. The compound (A) can be obtained by reduction using a metal catalyst such as palladium under a hydrogen atmosphere of 0.1 to 0.5 MPa, usually at room temperature to reflux temperature. The reaction time varies depending on the raw material used, solvent, catalyst, reaction temperature, etc., but is usually 2 to 24 hours.

  Among the intermediates for producing the benzylpyrazole derivative (E) of the present invention, the compound having an unsaturated bond includes two geometric isomers, a cis (Z) isomer compound and a trans (E) isomer compound. However, any of these compounds may be used in the present invention, or a mixture thereof may be used.

  Among the production intermediates of the benzylpyrazole derivative (E) of the present invention, compounds having an asymmetric carbon atom include a compound having an R configuration and a compound having an S configuration for each asymmetric carbon. Any optical isomer may be used, and a mixture of these optical isomers may be used.

  Various tautomers may exist in the production intermediate of the benzylpyrazole derivative (E) of the present invention, and the compounds of the present invention also include these tautomers.

  By the production method of the present invention, the introduction of isopropyl group can be carried out with high regioselectivity, and the compound (E) which is a pharmaceutical production intermediate can be obtained with high yield and high purity. Furthermore, a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like can be produced using the compound (E).

The content of the present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the content.

Reference example 1
2-[(4-Isopropoxyphenyl) methylidene] -3-oxo-butanoic acid methyl 4-isopropoxybenzaldehyde (10.0 g), methyl acetoacetate (14 g), acetic acid (5.0 g) in a solution of piperidine (1 .6 g) was added and the mixture was stirred at room temperature for 115 hours. This reaction mixture was used in the next step without purification (solution A).

Reference example 2
2- (4-Isopropoxybenzyl) -3-oxo-butanoic acid methyl ester To solution A described in Reference Example 1, 2-propanol (80 g) and 10% palladium carbon powder (3.2 g) were added, and the mixture was hydrogenated. The mixture was stirred at room temperature for 6 hours. The insoluble material was removed by filtration, and the insoluble material was washed with tert-butyl methyl ether (80 g). The filtrate and washings were combined and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (60 g), and water (60 g) was added to the mixture. The separated organic layer was washed sequentially with 5% aqueous sodium bicarbonate (60 g) and 10% brine (60 g). The organic layer was dried over anhydrous magnesium sulfate, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain methyl 2- (4-isopropoxybenzyl) -3-oxo-butanoate (19.1 g). It was.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.31 (6H, d, J = 6.0Hz), 2.17 (3H, s), 3.09 (2H, d, J = 8.0Hz), 3.69 (3H, s), 3.75 (1H, t, J = 7.6Hz), 4.44-4.56 (1H, m), 6.75-6.83 (2H, m), 7.02-7.10 (2H, m)

２−（４−イソプロポキシベンジル）−３−オキソブタン酸メチル（１６．１ｇ）のトルエン（１６０ｇ）溶液にエチレングリコール（１８ｇ）、ｐ−トルエンスルホン酸一水和物（０．４６ｇ）を加えた。この混合物を水の除去をしながら8時間加熱還流した。この反応混合物を室温まで冷却し、５％重曹水（８０ｇ）を加えた。分離した有機層を水（４０ｇ）で洗浄した後、溶媒を減圧下留去し、３−（４−イソプロポキシフェニル）−２−（２−メチル−１，３−ジオキソラン−２−イル）プロパン酸メチル（２３．０ｇ）を得た。
¹H-NMR (CDCl₃) δ ppm:
1.31 (6H, d, J=6.0Hz), 1.46 (3H, s), 2.84-3.03 (3H, m), 3.56 (3H, s), 3.95-4.07 (4H, m), 4.42-4.58 (1H, m), 6.73-6.83 (2H, m), 7.00-7.10 (2H, m)Example 1
3- (4-Isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid methyl ester

Ethylene glycol (18 g) and p-toluenesulfonic acid monohydrate (0.46 g) were added to a solution of methyl 2- (4-isopropoxybenzyl) -3-oxobutanoate (16.1 g) in toluene (160 g). . The mixture was heated to reflux for 8 hours while removing water. The reaction mixture was cooled to room temperature and 5% aqueous sodium bicarbonate (80 g) was added. The separated organic layer was washed with water (40 g), and the solvent was evaporated under reduced pressure to give 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propane. Methyl acid (23.0 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.31 (6H, d, J = 6.0Hz), 1.46 (3H, s), 2.84-3.03 (3H, m), 3.56 (3H, s), 3.95-4.07 (4H, m), 4.42-4.58 (1H, m), 6.73-6.83 (2H, m), 7.00-7.10 (2H, m)

３−（４−イソプロポキシフェニル）−２−（２−メチル−１，３−ジオキソラン−２−イル）プロパン酸メチル（１８．８ｇ）のメタノール（１９ｇ）溶液に２５ｇ／L水酸化ナトリウム水溶液（１４ｍL）を加えた。この混合物を８０℃で７時間撹拌した後、反応混合物を減圧下濃縮した。残渣を水（５７ｇ）、ｔｅｒｔ−ブチルメチルエーテル（９５ｇ）に溶解させ、水層を分離した。水層をｔｅｒｔ−ブチルメチルエーテル（９５ｇ）で洗浄した。水層にｔｅｒｔ−ブチルメチルエーテル（９５ｇ）及び２ｍｏｌ／Ｌ塩酸（３７ｍL）を加え、有機層を分離した。得られた有機層を１０％塩水（５７ｇ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、不溶物をろ去した後、溶媒を減圧下留去し、３−（４−イソプロポキシフェニル）−２−（２−メチル−１，３−ジオキソラン−２−イル）プロパン酸（１５．２ｇ）を得た。
¹H-NMR (CDCl₃) δ ppm:
1.31 (6H, d, J=6.0Hz), 1.47 (3H, s), 2.85-3.02 (3H, m), 3.93-4.13 (4H, m), 4.42-4.56 (1H, m), 6.74-6.84 (2H, m), 7.04-7.12 (2H, m), 8.00-12.00 (1H, br)Example 2
3- (4-Isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid

To a solution of methyl 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoate (18.8 g) in methanol (19 g) was added 25 g / L aqueous sodium hydroxide solution ( 14 mL) was added. The mixture was stirred at 80 ° C. for 7 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (57 g) and tert-butyl methyl ether (95 g), and the aqueous layer was separated. The aqueous layer was washed with tert-butyl methyl ether (95 g). To the aqueous layer, tert-butyl methyl ether (95 g) and 2 mol / L hydrochloric acid (37 mL) were added, and the organic layer was separated. The resulting organic layer was washed with 10% brine (57 g). The organic layer was dried over anhydrous magnesium sulfate, insolubles were filtered off, and the solvent was evaporated under reduced pressure to give 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolane-2. -Yl) propanoic acid (15.2 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.31 (6H, d, J = 6.0Hz), 1.47 (3H, s), 2.85-3.02 (3H, m), 3.93-4.13 (4H, m), 4.42-4.56 (1H, m), 6.74-6.84 ( 2H, m), 7.04-7.12 (2H, m), 8.00-12.00 (1H, br)

イミダゾール（７．７６ｇ）のテトラヒドロフラン（１５０ｇ）溶液にピリジン（９．０２ｇ）を加えた。得られた溶液に、氷冷下、塩化チオニル（６．７９ｇ）を滴下した後、この混合物を１時間撹拌した。反応混合物を室温まで加熱し、３−（４−イソプロポキシフェニル）−２−（２−メチル−１，３−ジオキソラン−２−イル）プロパン酸（１５．２ｇ）のテトラヒドロフラン（６０ｇ）溶液を加え、この混合物を１時間撹拌した。更に、この混合物にＮ，Ｎ−ジメチルホルムアミド（３１ｇ）、トリエチルアミン（１０．５ｇ）、イソプロピルヒドラジン塩酸塩（８．６１ｇ）を順次加え、この混合物を８０℃で６時間撹拌した。この反応混合物は精製する事なく次工程に用いた（溶液Ｂ）。
¹H-NMR (CDCl_３) δ ppm:
0.86 (3H, d, J=6.4Hz), 0.96 (3H, d, J=6.4Hz), 1.30 (6H, d, J=6.0Hz), 1.42 (3H, s), 2.54 (1H, dd, J=3.2, 11.2Hz), 2.84-3.07(3H, m), 3.90-4.10 (4H, m), 4.40-4.70 (1H, br), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m), 7.02-7.15 (3H, m) Example 3
N′-isopropyl-3- (p-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid hydrazide

Pyridine (9.02 g) was added to a solution of imidazole (7.76 g) in tetrahydrofuran (150 g). To the obtained solution was added dropwise thionyl chloride (6.79 g) under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was heated to room temperature and a solution of 3- (4-isopropoxyphenyl) -2- (2-methyl-1,3-dioxolan-2-yl) propanoic acid (15.2 g) in tetrahydrofuran (60 g) was added. The mixture was stirred for 1 hour. Further, N, N-dimethylformamide (31 g), triethylamine (10.5 g) and isopropylhydrazine hydrochloride (8.61 g) were sequentially added to the mixture, and the mixture was stirred at 80 ° C. for 6 hours. This reaction mixture was used in the next step without purification (solution B).
¹ H-NMR (CDCl ₃ ) δ ppm:
0.86 (3H, d, J = 6.4Hz), 0.96 (3H, d, J = 6.4Hz), 1.30 (6H, d, J = 6.0Hz), 1.42 (3H, s), 2.54 (1H, dd, J = 3.2, 11.2Hz), 2.84-3.07 (3H, m), 3.90-4.10 (4H, m), 4.40-4.70 (1H, br), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m ), 7.02-7.15 (3H, m)

実施例３記載の溶液Ｂに６ｍｏｌ／Ｌ塩酸（６５ｍＬ）を加え、この混合物を８０℃で１７時間撹拌した。反応混合物を室温まで冷却し、重曹（３５ｇ）を加え、有機層を分離した。水層をトルエン（７２ｇ）で抽出し、先の有機層と合わせた後、その有機層を減圧下濃縮した。残渣を８０℃でアセトニトリル（３６ｇ）に溶解させた。この混合物を６０℃まで冷却した後、水（３６ｇ）を滴下し、結晶を析出させた。得られた懸濁液を室温まで冷却し、水（１８ｇ）を滴下した後、この懸濁液を３時間撹拌した。析出物をろ取し、アセトニトリル（９ｇ）、水（９ｇ）の混合溶液で２回洗浄した後、減圧乾燥し、１−イソプロピル−４−（４−イソプロポキシベンジル）−５−メチル−１，２−ジヒドロ−３Ｈ−ピラゾール−３−オン（１１．３ｇ、純度：９９．３％）を得た。
¹H-NMR (CDCl₃) δ ppm:
1.30 (6H, d, J=6.0Hz), 1.39 (6H, d, J=6.8Hz), 2.05 (3H, s), 3.62 (1H, s), 4.18-4.32 (1H, m), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m), 7.10-7.18 (2H, m), 10.00-13.00 (1H, br)Example 4
1-isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1,2-dihydro-3H-pyrazol-3-one

6 mol / L hydrochloric acid (65 mL) was added to the solution B described in Example 3, and the mixture was stirred at 80 ° C. for 17 hours. The reaction mixture was cooled to room temperature, sodium bicarbonate (35 g) was added, and the organic layer was separated. The aqueous layer was extracted with toluene (72 g) and combined with the previous organic layer, and then the organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (36 g) at 80 ° C. After cooling this mixture to 60 ° C., water (36 g) was added dropwise to precipitate crystals. The obtained suspension was cooled to room temperature, water (18 g) was added dropwise, and the suspension was stirred for 3 hours. The precipitate was collected by filtration, washed twice with a mixed solution of acetonitrile (9 g) and water (9 g), dried under reduced pressure, and 1-isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1, 2-Dihydro-3H-pyrazol-3-one (11.3 g, purity: 99.3%) was obtained.
¹ H-NMR (CDCl ₃ ) δ ppm:
1.30 (6H, d, J = 6.0Hz), 1.39 (6H, d, J = 6.8Hz), 2.05 (3H, s), 3.62 (1H, s), 4.18-4.32 (1H, m), 4.40-4.54 (1H, m), 6.72-6.82 (2H, m), 7.10-7.18 (2H, m), 10.00-13.00 (1H, br)

Comparative Example 1-Isopropyl-4- (4-isopropoxybenzyl) -5-methyl-1,2-dihydro-3H-pyrazol-3-one Isopropylhydrazine hydrochloride (1.67 g) in ethanol (3 mL) suspension To this was added triethylamine (2.68 g). The mixture was stirred at room temperature for 1 hour. Toluene solution of methyl 2- (4-isopropoxybenzyl) -3-oxobutanoate (1.05 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 40 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: tert-butyl methyl ether / n-hexane = 1/3) to give 1-isopropyl-4- (4-isopropoxybenzyl). -5-methyl-1,2-dihydro-3H-pyrazol-3-one (0.08 g) was obtained.

  The compound (D) of the present invention is extremely useful as an intermediate for producing a pharmaceutical product, and a series of production methods via the compound (D) can regioselectively produce an isopropyl group on the pyrazole ring. Since it is a high yield and high purity, it turns out that it is very useful as an industrial manufacturing method.

According to the present invention, a glucopyranosyloxypyrazole derivative useful as a therapeutic agent for diabetes and the like can be produced with high yield and high purity.

Claims (15)

General formula (A-1):

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} alkoxy group, R ⁶ is hydroxy, C _1-6 alkoxy group, a substitutable C _7-11 aralkyloxy Or i-PrNHNH- compound represented by a is) group. The compound or a salt thereof according to claim 1, wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom. The compound or a salt thereof according to claim 2, wherein R ³ is an isopropyloxy group and R ⁴ is a hydrogen atom. The compound or a salt thereof according to claim 3, wherein R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group. The compound or its salt of Claim 4 whose R < ⁶ > is a hydroxy group or i-PrNHNH- group. The compound or its salt of Claim 5 whose R < ⁶ > is i-PrNHNH- group. Formula (C):

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} ) or a salt thereof is the same as isopropyl hydrazine or a salt thereof. General formula (D) by responding:

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6 is an} alkoxy group) or a salt thereof. The process according to claim 7, wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom. 9. R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group, R ³ is an isopropyloxy group, and R ⁴ is a hydrogen atom. The manufacturing method as described. Step 1:
Formula (A):

(In the formula, R ³ represents a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _3-6 cycloalkyloxy group, a C _3-6 cycloalkyl ( C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group or halo C _1-6 alkoxy group, R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 An alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁵ is a C _1-6 alkyl group or a substituted C _7-11 aralkyl group). (B):

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} is an alkoxy group, represented by R ⁵ is C _1-6 alkyl or optionally substituted C _7-11 aralkyl group) Preparing a compound;
Step 2:
By subjecting the compound represented by the general formula (B) to a deprotection reaction, the general formula (C):

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _1- A compound represented by ( ₆ ) alkoxy group) or a salt thereof. Manufacturing method. The production method according to claim 10, wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom. R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group, R ³ is an isopropyloxy group, R ⁴ is a hydrogen atom, R ⁵ The production method according to claim 11, wherein is a methyl group. Formula (D):

(R ¹ and R ² in the formula may be the same or different, or show a C _1-6 alkyl group, respectively, or may form them bonded C _1-6 alkylene group, R ³ is , Halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group A C _1-6 alkoxy group, a C _1-6 alkylthio group or a halo C _1-6 alkoxy group, wherein R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group, or halo C _{1- 6} ) or a salt thereof is cyclized to form a compound represented by the general formula (E):

(In the formula, R ³ represents a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _3-6 cycloalkyl group, a C _3-6 cycloalkyloxy group, a C _3-6 cycloalkyl ( C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 alkylthio group or halo C _1-6 alkoxy group, R ⁴ is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, C _3-6 cycloalkyl (C _1-6 alkoxy) group, C _1-6 alkoxy group, C _1-6 A method for producing a compound represented by the following formula: an alkylthio group or a halo C _1-6 alkoxy group. The production method according to claim 13, wherein R ³ is a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁴ is a hydrogen atom or a halogen atom. R ¹ and R ² are bonded to each other to form a —CH ₂ CH ₂ — or —CH ₂ CH ₂ CH ₂ — group, R ³ is an isopropyloxy group, and R ⁴ is a hydrogen atom. 14. The production method according to 14.