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Method for manufacturing pyrazole derivative

A compound and production formula technology, applied in the field of piperazinyl pyrazole compounds, achieves the effect of superior storage stability

Active Publication Date: 2014-03-19
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in this report, production examples of substituted pyrazole compounds are all on the scale of tens of milligrams, and it is unknown whether this method can be used on an industrial scale

Method used

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  • Method for manufacturing pyrazole derivative
  • Method for manufacturing pyrazole derivative
  • Method for manufacturing pyrazole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Preparation of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-3-methyl-1-phenylpyrazole

[0124]

[0125] To a solution of 4-tert-butoxycarbonyl-1-[3-(2-phenylhydrazone)butyryl]piperazine (compound 3b) (721 mg) and sodium carbonate (254 mg) in THF (10 mL) was added phosphorus pentasulfide (267 mg), and the mixture was heated under reflux for 30 minutes. The solvent was evaporated under reduced pressure, diethyl ether (30 mL) was added to the residue, and the mixture was filtered. Water (20 mL) was added to the filtrate, and the mixture was separated. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to produce 5-(4-tert-butoxycarbonylpiperazin-1-yl)-3-methyl-1-phenylpyrazole (compound 2b) (580 mg, yield 85%).

[0126] 1H-NMR (500MHz, DMSO-d 6 )Δ1.39(9H,s), 2.15(3H,s), 2.73(4H,m), 3.37(4H,m), 5.83(1H,s), 7.28(1H,t,J=7.4Hz), 7.46 (2H, t, J=7.4Hz), 7.76 (2H, d, J=...

Embodiment 2

[0128] Preparation of 3-methyl-1-phenyl-5-(1-piperazinyl)pyrazole acetate

[0129]

[0130] Dissolve 1-ethoxycarbonylpiperazine (Compound 4a) (37.5 kg) in THF (550 L). The solution was cooled, diketene (19.9 kg) was added dropwise at 0-7°C, and the mixture was stirred at 1°C-5°C for 1.5 hours. A solution of phenylhydrazine (25.6 kg) in THF (10 L) was added dropwise to the reaction mixture, and the mixture was stirred at 20°C-26°C for 7 hours. The reaction mixture was concentrated under reduced pressure until the residual amount became 100 L, and THF (260 L) was added to the remaining reaction mixture. To this reaction mixture were added sodium carbonate (25.1 kg) and phosphorus pentasulfide (26.3 kg), and the mixture was stirred at 36° C.-44° C. for 1.5 hours and at 45° C.-52° C. for 3 hours. The reaction mixture was cooled, phosphorus pentasulfide (5.3 kg) was added, and the mixture was stirred at 45°C-51°C for 1 hour and cooled. To this reaction mixture were added toluene (3...

Embodiment 3

[0133] Synthesis of 4-tert-Butoxycarbonyl-1-[3-(2-phenylhydrazone)butyryl]piperazine

[0134]

[0135] To a solution of 1-tert-butoxycarbonylpiperazine (compound 4b) (80 g) in N,N-dimethylformamide (256 mL) under ice cooling was added diketene (34.7 mL) dropwise, and the mixture Stir at room temperature for 1 hour. To this reaction mixture was added dropwise a mixed solution of phenylhydrazine (48.7 g) in ethanol (192 mL) and water (192 mL) under water cooling, and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added water (320 mL) dropwise, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with a 1:1 mixture of methanol and water, and dried under vacuum to produce 4-tert-butoxycarbonyl-1-[3-(2-phenylhydrazone)butyryl]piperazine ( Compound 3b) (149 g, yield 97%, regioisomer ratio 1:1).

[0136] 1H-NMR (300MHz, CDCl 3 )Δ1.46, 1.48 (9H, s), 1.95 (1.5H, s), 2.11 (1.5H, s), 2.88 (0.5H...

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Abstract

The present invention provides a prolinamide compound useful as a drug or the like and an industrially advantageous method for producing a piperazinyl pyrazole compound that is a production intermediate of the prolinamide compound. Specifically, the invention is a method for producing a compound represented by general formula (1) as represented by the following formula (where the symbols in the formula are the same as defined in the specification) or a salt thereof, wherein a compound represented by general formula (2) is produced, a pyrazole ring being formed via a reaction between a compound represented by general formula (3) and phosphorus pentasulfide; and, once the compound represented by general formula (2) is deprotected, a carboxylate of a compound represented by general formula (6) is produced, the compound obtained by forming a carboxylic acid and a salt.

Description

Technical field [0001] The present invention relates to a new preparation method of piperazinylpyrazole compounds which can be used as synthetic intermediates for medicines and the like. In addition, the present invention relates to a method of preparing a prolineamide compound that can be used as a therapeutic drug for diabetes and the like by using the new preparation method of the piperazinylpyrazole compound. Background technique [0002] A prolineamide compound having a side chain containing a piperazinylpyrazole moiety has been reported (for example, 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H- Pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, etc.) show DPP-IV inhibitory activity and can be used for the treatment or prevention of diabetes and the like (see Patent Documents 1 and 2). [0003] With respect to such a prolineamide compound, a preparation method thereof and a preparation method of a piperazinylpyrazole compound as a synthesis intermediate thereof are d...

Claims

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Application Information

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IPC IPC(8): C07D231/38A61K31/496A61P3/10A61P43/00C07D417/14
CPCC07D417/14C07D231/38A61P3/10A61P43/00
Inventor 赤星文彦桐原伸治
Owner MITSUBISHI TANABE PHARMA CORP
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