401566-80-1

Usage

Uses

Used in Pharmaceutical Industry:
(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester is used as an orally anti-diabetic agent for the inhibition of dipeptidylpeptidase IV (DPP-4). This application is due to its ability to regulate glucose levels in the body, making it a potential treatment for type 2 diabetes.

Upstream product

• 13726-69-7 (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid 
• 24424-99-5 di-tert-butyl dicarbonate 
• 51-35-4 4R-4-hydroxyproline 
• 84348-37-8 N-tert-butoxycarbonyl-4-oxo-L-proline 
• 87691-27-8 N-tert-butoxycarbonyl-L-cis-4-hydroxyproline 
• 618-27-9 hydroxy L-proline 
• 591-50-4 iodobenzene 
• 41327-15-5 5-bromo-3-methyl-1-phenyl-1H-pyrazole 
• 629616-63-3 1-(1,1-dimethylethyl) 2-methyl (2S,4R)-4-{[(4-nitrophenyl)sulfonyl]oxy}-2,3,4,5-tetrahydro-1H-pyrrole-1,2-dicarboxylate 
• 74844-91-0 1-tert-butyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate 
• 14446-47-0 thiazolidine hydrochloride 
• 100-63-0 phenylhydrazine 
• 401564-36-1 (2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester 
• 906093-30-9 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine acetate 

Downstream Products

• 760937-92-6 3-{(2S,4S)-1-(1,1-dimethylethyloxycarbonyl)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazin-1-yl]pyrrolidine-2-ylcarbonyl}thiazolidine 

Relevant academic research and scientific papers

AN IMPROVED PROCESS FOR THE PREPARATION OF TENELIGLIPTIN HYDROBROMIDE HYDRATE

The present invention provides an improved process for the preparation of Teneligliptin HBr more particularly relates to a process for the preparation of Teneligliptin 2.5HBr hydrate salt.

MANUFACTURING METHOD OF PROLINE AMIDE COMPOUND

PROBLEM TO BE SOLVED: To provide an industrially advantageous manufacturing method of teneligliptin useful as an antidiabetic drug or the like and a synthesis intermediate. SOLUTION: There is provided a manufacturing method of a thiazolidine derivative represented by the formula (2a) using a following condensation reaction. The compound represented by the formula (2a) is useful as a manufacturing intermediate of teneligliptin. DIPEA represents N,N-diisopropylethylamine. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT

Method for preparing hydrobromic acid teneligliptin

The invention provides a method for preparing hydrobromic acid teneligliptin. The method includes steps of preparing L-hydroxyproline; mixing the L-hydroxyproline and sodium bicarbonate with each other to obtain mixtures, dissolving the mixtures in water, adding acetone into the water, dropping di-tert-butyl dicarbonate into the water, carrying out room-temperature reaction overnight and then treating reaction products to obtain t-butyloxycarboryl-N-hydroxyproline; preparing t-butyloxycarboryl-N-4-oxo-proline from the t-butyloxycarboryl-N-hydroxyproline; preparing (2S)-4-oxo-2-(3-thiazolidine carbonyl)-1-pyrrolidine carboxylic acid tert-butyl ester from the t-butyloxycarboryl-N-4-oxo-proline; preparing compounds III from compounds IV; preparing compounds II from the compounds III; preparing compounds 1-(3-methyl-1-phenyl-1H-pyrazole-5-base) piperazine from the compounds II; preparing intermediates I; preparing the hydrobromic acid teneligliptin from the intermediates I. The method has the advantages that the method is low in cost, and the cost of the method is only two-thirds of the cost of an existing method in the prior art; the yield of the hydrobromic acid teneligliptin is higher than 95%, and the purity of the hydrobromic acid teneligliptin is higher than 98%.

PROCESS FOR THE PREPARATION OF (4R)-1-(TERT-BUTOXYCARBONYL)-4-HYDROXY-L-PROLINE

The present invention provides a process for the preparation of (4R)-1-(tert- butoxycarbonyl)-4-hydroxy-L-proline of Formula IV. The present invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-1-yl] pyrrolidin-2-yl}(1,3-thiazolidin-3-yl) methanone of Formula II, or salts thereof, using (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline of Formula IV.

PROCESS FOR THE PREPARATION OF 1-(3-METHYL-1-PHENYL-1H-PYRAZOL-5-YL)PIPERAZINE

The present invention provides a process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine of Formula III, or salts thereof. The invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-

PROCESS FOR THE PREPARATION OF TENELIGLIPTIN AND ITS NOVEL INTERMEDIATES

The present invention relates to a novel process for the preparation of Teneligliptin or its pharmaceutically acceptable salts and its hydrates thereof. The invention also relates to novel intermediates used in the synthesis of Teneligliptin and their preparation.

PROCESS FOR THE PREPARATION OF N-PROTECTED (5S)-5-(1,3-THIAZOLIDIN-3-YLCARBONYL)PYRROLIDIN-3-ONE

The present invention provides a process for the preparation of an N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. The invention also provides a process for the preparation of {(25',45)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin-l-yl]pyrrolidin-2-yl}(l,3-thiazolidin-3-yl)methanone, or salts thereof, using the N-protected (55)-5-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one of Formula III. (III)

PROCESS FOR THE PREPARATION OF 1-(3-METHYL-1-PHENYL-1H-PYRAZOL-5-YL)PIPERAZINE

The present invention provides a process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine of Formula (III), or salts thereof. The invention also provides a process for the preparation of {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5- yl)piperazin-1-yl]pyrrolidin-2-yl}(1,3-thiazolidin-3-yl)methanone, or salts thereof, using 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine of Formula (III), or salts thereof.

Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3- methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl] thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5- yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S2 extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.