760937-92-6

Basic information

• Product Name: Teneligliptin
• Synonyms: teneligliptin;3-[[(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl]carbonyl]thiazolidine;Methanone,[(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl]-3-thiazolidinyl-;Teneligptin WS
• CAS NO: 760937-92-6
• Molecular Formula: C22H30N6OS
• Molecular Weight: 426.58
• Mol File: 760937-92-6.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 663.4±55.0 °C(Predicted)
• Appearance: /
• Density: 1.38
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 8.70±0.10(Predicted)
• CAS DataBase Reference: Teneligliptin(CAS DataBase Reference)
• NIST Chemistry Reference: Teneligliptin(760937-92-6)
• EPA Substance Registry System: Teneligliptin(760937-92-6)

Safety Data

• Hazardous Substances Data: 760937-92-6(Hazardous Substances Data)

Usage

Description

Teneligliptin was approved in September 2012 in Japan for the treatment of patients with Type 2 diabetes mellitus (T2DM). Teneligliptin is a member of the dipeptidyl peptidase 4 (DPP-4) inhibitor class of antidiabetes agents. DPP-4 is an enzyme that degrades GLP-1, a 30-amino acid peptide that is secreted in response to food intake. GLP-1 stimulates insulin secretion and inhibits glucagon secretion, which leads to lower levels of plasma glucose. Teneligliptin is one of a growing numbers of DPP-4 inhibitors to be approved worldwide. The discovery of teneligliptin was guided by structure-based design, with a key element being binding of the phenyl group in the S2 pocket, which not only increases potency for DPP-4, but also improves selectivity versus DPP-8 and DPP- 9. Teneligliptin is a potent inhibitor of DPP-4 in the enzyme inhibition assay (IC50=0.37 nM).

Originator

Mitsubishi Tanabe Pharma (Japan)

Uses

Teneligliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used to treat type 2 diabetes. It is eliminated via excretion, and has a half-life of 24.2 hours in the human body.

Brand name

Tenelia

Synthetic route

tert-butyl (2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidine-1-carboxylate (401566-80-1) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Stage #1: tert-butyl (2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidine-1-carboxylate With trifluoroacetic acid In dichloromethane at 20℃; for 19h; Stage #2: With sodium hydrogencarbonate In water	93%
With ethyl acetate; trifluoroacetic acid In dichloromethane at 20℃; for 19h;	93%
With hydrogenchloride at 20 - 40℃; Reagent/catalyst;

tert-butyl 4-(3-oxobutanoyl)piperazine-1-carboxylate (401566-77-6) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / ethanol / 14 h / 20 °C 1.2: 20 h / 20 °C / pH 3 2.1: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C 3.1: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 13 h / 20 °C 4.1: ethyl acetate; trifluoroacetic acid / dichloromethane / 19 h / 20 °C View Scheme

1-tert-butoxycarbonyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C 2: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 13 h / 20 °C 3: ethyl acetate; trifluoroacetic acid / dichloromethane / 19 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 1.5 h / 25 - 30 °C 1.2: 0 - 5 °C 2.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 3.1: piperidine / dichloromethane / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: trifluoroacetic acid / methanol 2: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 3: hydrogenchloride / 20 - 40 °C View Scheme

1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 13 h / 20 °C 2: ethyl acetate; trifluoroacetic acid / dichloromethane / 19 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 2: hydrogenchloride / 20 - 40 °C View Scheme

1-Phenyl-3-methyl-5-aminopyrazole (1131-18-6) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 - 5 °C 1.2: 0 - 30 °C 1.3: 2 h / 0 - 5 °C 2.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 3.1: piperidine / dichloromethane / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 5 °C 1.2: 0 - 30 °C 2.1: trifluoroacetic acid / dichloromethane / 1.5 h / 25 - 30 °C 2.2: 0 - 5 °C 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 4.1: piperidine / dichloromethane / 25 - 30 °C View Scheme

C37H40N6O3S → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
With piperidine In dichloromethane at 25 - 30℃;	10.5 g

4R-4-hydroxyproline (51-35-4) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: water / 3 h / 40 - 50 °C 2.1: benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 0.5 h / 0 - 5 °C 2.2: 24 h / 25 - 30 °C 3.1: triethylamine; sulfur trioxide pyridine complex / dichloromethane / 2 h / 0 - 5 °C 4.1: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 5.1: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydrogencarbonate / water; tetrahydrofuran / 25 - 30 °C 2.1: benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 0.5 h / 0 - 5 °C 2.2: 24 h / 25 - 30 °C 3.1: triethylamine; sulfur trioxide pyridine complex / dichloromethane; dimethyl sulfoxide / 2 h / 0 - 5 °C 4.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 5.1: piperidine / dichloromethane / 25 - 30 °C View Scheme

oxaceprol (33996-33-7) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 0.5 h / 0 - 5 °C 1.2: 24 h / 25 - 30 °C 2.1: triethylamine; sulfur trioxide pyridine complex / dichloromethane / 2 h / 0 - 5 °C 3.1: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 4.1: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme

N-Fmoc-trans-4-Hydroxy-L-Proline (88050-17-3) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; 4-methyl-morpholine / dichloromethane / 0.5 h / 0 - 5 °C 1.2: 24 h / 25 - 30 °C 2.1: triethylamine; sulfur trioxide pyridine complex / dichloromethane; dimethyl sulfoxide / 2 h / 0 - 5 °C 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 4.1: piperidine / dichloromethane / 25 - 30 °C View Scheme

3-[(2S,4R)-1-fluorenylmethoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl]1,3-thiazolidine → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; sulfur trioxide pyridine complex / dichloromethane; dimethyl sulfoxide / 2 h / 0 - 5 °C 2: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 3: piperidine / dichloromethane / 25 - 30 °C View Scheme

1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine acetate (906093-30-9) + 9H-fluoren-9-ylmethyl (2S)-4-oxo-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidine-1-carboxylate → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 2: piperidine / dichloromethane / 25 - 30 °C View Scheme

1-[2(S)-4-hydroxy-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-1-yl]ethanone → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; sulfur trioxide pyridine complex / dichloromethane / 2 h / 0 - 5 °C 2: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 3: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme

1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine + (5S)-1-acetyl-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 2: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme

3-methyl-1-phenylpyrazolin-5(4H)-one (19735-89-8) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: trichlorophosphate / 0.67 h / 10 - 30 °C 1.2: 1 h / 110 - 115 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 15 h / 120 - 130 °C 3.1: sodium carbonate; toluene-4-sulfonic acid / methanol / 80 °C 4.1: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 5.1: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme

5-chloro-4-formyl-3-methyl-1-phenyl-1H-pyrazole (947-95-5) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 15 h / 120 - 130 °C 2: sodium carbonate; toluene-4-sulfonic acid / methanol / 80 °C 3: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 4: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme

tert-butyl-4-(4-formyl-3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine-1-carboxylate → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium carbonate; toluene-4-sulfonic acid / methanol / 80 °C 2: acetic acid; sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 3: hydrogen bromide / water; isopropyl alcohol / 16 h / 80 - 85 °C View Scheme

1-1(2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)-2-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-1-yl ethanone → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
With hydrogen bromide In water; isopropyl alcohol at 80 - 85℃; for 16h; Time;	0.360 g

phenylhydrazine (100-63-0) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 4 h / 110 - 115 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 - 5 °C 2.2: 0 - 30 °C 2.3: 2 h / 0 - 5 °C 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 4.1: piperidine / dichloromethane / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 4 h / 110 - 115 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 - 5 °C 2.2: 0 - 30 °C 3.1: trifluoroacetic acid / dichloromethane / 1.5 h / 25 - 30 °C 3.2: 0 - 5 °C 4.1: sodium tris(acetoxy)borohydride / dichloromethane / 25 - 30 °C 5.1: piperidine / dichloromethane / 25 - 30 °C View Scheme

5-bromo-3-methyl-1-phenyl-1H-pyrazole (41327-15-5) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium t-butanolate / N,N-dimethyl-formamide 2: trifluoroacetic acid / methanol 3: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 4: hydrogenchloride / 20 - 40 °C View Scheme

iodobenzene (591-50-4) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / acetonitrile 2: sodium t-butanolate / N,N-dimethyl-formamide 3: trifluoroacetic acid / methanol 4: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 5: hydrogenchloride / 20 - 40 °C View Scheme

hydroxy L-proline (618-27-9) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydrogencarbonate / water; acetone / 20 °C 2: Jones reagent / acetone 3: formaldehyd; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / -10 - 20 °C 4: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 5: hydrogenchloride / 20 - 40 °C View Scheme

N-tert-butoxycarbonyl-L-cis-4-hydroxyproline (87691-27-8) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: Jones reagent / acetone 2: formaldehyd; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / -10 - 20 °C 3: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 4: hydrogenchloride / 20 - 40 °C View Scheme

N-tert-butoxycarbonyl-4-oxo-L-proline (84348-37-8) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: formaldehyd; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / -10 - 20 °C 2: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 3: hydrogenchloride / 20 - 40 °C View Scheme

(2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester (401564-36-1) → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / toluene; tetrahydrofuran / 20 - 40 °C 2: hydrogenchloride / 20 - 40 °C View Scheme

teneligliptin dibenzoyl-L-tartaric acid → ((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6)

Conditions	Yield
With sodium carbonate In dichloromethane; water for 0.5h;

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) → teneligliptin hydrobromide

Conditions	Yield
With hydrogen bromide at 30 - 50℃;	96%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine sulfate

Conditions	Yield
With sulfuric acid In tetrahydrofuran; water at 20℃; for 0.5h;	94%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + (R)-10-camphorsulfonic acid (35963-20-3) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine di-(-)-camphorsulfonate

Conditions	Yield
In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 1h;	91%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl-carbonyl}thiazolidine hemipentahydrobromide

Conditions	Yield
With hydrogen bromide In ethanol at 20℃; for 2h; Reflux;	90%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + 3,4,5-trihydroxybenzoic acid (149-91-7) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine gallate

Conditions	Yield
In isopropyl alcohol at 20℃; for 1h;	85%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + toluene-4-sulfonic acid (104-15-4) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine ditosylate

Conditions	Yield
In isopropyl alcohol at 20℃; for 1.5h;	82%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + benzenesulfonic acid (98-11-3) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine dibesylate

Conditions	Yield
In isopropyl alcohol at 20℃; for 1h;	80%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + L-Tartaric acid (87-69-4) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine ditartrate

Conditions	Yield
In isopropyl alcohol at 20℃; for 3h;	78%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + (2E)-but-2-enedioic acid (110-17-8) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine difumarate

Conditions	Yield
In ethanol at 0 - 20℃; for 2h;	77%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + 1-naphthalenesulfonic acid (85-47-2) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine dinaphthalene-1-sulfonate

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	75%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + naphthalene-2-sulfonate (120-18-3) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine dinaphthalene-2-sulfonate

Conditions	Yield
In ethyl acetate at 20℃; for 12h;	74%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + methanesulfonic acid (75-75-2) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine trimesylate

Conditions	Yield
In tetrahydrofuran at 20℃; for 1.5h;	72%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + methanesulfonic acid (75-75-2) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine dimesylate

Conditions	Yield
In isopropyl alcohol at 20℃; for 2h;	72%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + maleic acid (110-16-7) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine dimaleate

Conditions	Yield
In ethanol at 20℃; for 1h;	71%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) + (1S)-10-camphorsulfonic acid (3144-16-9) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine di-(+)-camphorsulfonate

Conditions	Yield
In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 5h;	58%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) → 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine hydrochloride

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; ethyl acetate at 20℃; for 1h;	48%

((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl)(1,3-thiazolidin-3-yl)methanone (760937-92-6) → Teneligliptin hydrobromide

Conditions	Yield
With hydrogen bromide In ethanol; water at 20℃; for 2h; Product distribution / selectivity; Heating / reflux;
With hydrogen bromide In methanol; water; tert-butyl alcohol at 70 - 75℃; for 1h;	8 g
With hydrogen bromide In ethanol; water at 80℃; for 0.5h;	80 mg

Upstream product

• 401564-36-1 (2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester 
• 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 
• 100-63-0 phenylhydrazine 
• 947-95-5 5-chloro-4-formyl-3-methyl-1-phenyl-1H-pyrazole 
• 19735-89-8 3-methyl-1-phenylpyrazolin-5(4H)-one 
• 401566-79-8 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine 
• 906093-30-9 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine acetate 
• 88050-17-3 N-Fmoc-trans-4-Hydroxy-L-Proline 
• 33996-33-7 oxaceprol 
• 51-35-4 4R-4-hydroxyproline 

Relevant articles and documents

OXALATE SALTS OF TENELIGLIPTIN AND SOLVATES THEREOF, INTERMEDIATES, PROCESS OF PREPARATION

The present invention provides oxalate salts of teneligliptin and solvates thereof exhibiting superior physiochemical properties. In particular, crystalline form of teneligliptin 2.5 oxalate 1.0 hydrate and crystalline form of teneligliptin 3.0 oxalate 1.0 hydrate are disclosed. Also provided are methods of preparing the same, and uses thereof.

Process for the preparation of teneligliptin

A process for the preparation of teneligliptin.

CONCOMITANT PHARMACEUTICAL AGENTS AND USE THEREOF

A concomitant agent to be used simultaneously or separately, comprising a combination of (a) 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, a salt of the compound with an organic or inorganic and mono- or di-basic acid or a solvate thereof, and (b) at least one kind of active ingredient selected from the group consisting of an active ingredient of a pharmaceutical agent selected from (i) an antidiabetic drug, (ii) a lipid lowering drug, (iii) an antihypertensive drug, (iv) a therapeutic drug for diabetic complications, (v) an antiobesity drug, (vi) an antiplatelet drug and (vii) an anticoagulant, a pharmaceutically acceptable salt thereof and a solvate thereof.