Linagliptin

Base Information

• Chemical Name: Linagliptin
• CAS No.: 668270-12-0
• Molecular Formula: C₂₅H₂₈N₈O₂
• Molecular Weight: 472.55
• Hs Code.: 29335990
• European Community (EC) Number: 620-351-9
• UNII: 3X29ZEJ4R2
• DSSTox Substance ID: DTXSID201021653
• Nikkaji Number: J2.712.937D
• Wikipedia: Linagliptin
• Wikidata: Q909745
• NCI Thesaurus Code: C83887
• RXCUI: 1100699
• Pharos Ligand ID: VMG5TXYCPR3B
• Metabolomics Workbench ID: 65122
• ChEMBL ID: CHEMBL237500
• Mol file: 668270-12-0.mol

Synonyms:(R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione;1356, BI;1H-purine-2,6-dione, 8-((3r)-3-amino-1-piperidinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-((4-methyl-2-quinazolinyl)methyl)-;BI 1356;BI-1356;BI1356;Linagliptin;Tradjenta;Trajenta

Chemical Property of Linagliptin

Chemical Property:

• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 202 °C
• Refractive Index: 1.717
• Boiling Point: 661.189 °C at 760 mmHg
• PKA: 10.01±0.20(Predicted)
• Flash Point: 353.675 °C
• PSA: 116.86000
• Density: 1.398 g/cm³
• LogP: 1.91270
• Storage Temp.: Refrigerator
• Solubility.: Chloroform (Sparingly), DMSO (Slightly), Methanol (Slightly)
• XLogP3: 1.9
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 4
• Exact Mass: 472.23352217
• Heavy Atom Count: 35
• Complexity: 885

Purity/Quality:

99% ,99.9%, ^*data from raw suppliers

Linagliptin ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antidiabetic Agents
• Canonical SMILES: CC#CCN1C2=C(N=C1N3CCCC(C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
• Isomeric SMILES: CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C
• Recent ClinicalTrials: A Study of Multiple Immunotherapy-Based Treatment Combinations in Patients With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Cancer (G/GEJ) or Esophageal Cancer (Morpheus-Gastric and Esophageal Cancer)
• Recent EU Clinical Trials: Geriatric outcomes among older Type 2 diabetic patients treated with DPP4 inhibitors or glinides: focus on cognitive functioning (GOOD-WP3)
• Recent NIPH Clinical Trials: Examination of medication adherence and physical / mental function improvement effect of combination tablets (SGLT2-I and DPP4-I)
• Uses: Linagliptin (TrajentaR, TradjentaTM, TrazentaTM, TrayentaTM) is an oral, highly selective inhibitor of dipeptidyl peptidase-4 and is the first agent of its class to be eliminated predominantly via a nonrenal route. Linagliptin is indicated for once daily use for the treatment of adults with type 2 diabetes mellitus. A novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor with potential use in the treatment of type 2 diabetes. dipeptidypeptidase inhibitor, antidiabetic highly potent CD26 inhibitor Labeled Linagliptin, intended for use as an internal standard for the quantification of Linagliptin by GC- or LC-mass spectrometry.
• Description: Linagliptin (trade names Tradjenta and Trajetna) is an inhibitor of dipeptidyl peptidase-4 (DPP-4) that was approved by the U.S. FDA in May 2011 for the treatment of Type 2 diabetes along with diet and exercise. Linagliptin (BI-1356) has been described as a potent highly selective, slow-off rate and long acting inhibitor of DPP-4. Linagliptin arose from optimization efforts of xanthine-based DPP-4 inhibitors with the initial lead identified from an HTS campaign. After optimizing the activity of the initial micromolar lead, two issues that needed to be addressed were activity for hERG and muscarinic receptor M1. Introduction of a butynyl group at the N7 position of the xanthine ring gave much reduced M1 affinity with no measureable hERG activity. Linagliptin inhibits DPP-4 with an IC50=1 nM and is highly selective (>10,000-fold) against DPP-8 and DPP-9. Linagliptin shows no interactions with CYPs up to 50 mM. The described synthesis of linagliptin starts with 8-bromoxanthine, which is alkylated at the N-7 position to introduce the butyne group, followed by alkylation of the N-1 group to introduce the methyl-quinazoline group. Displacement of the bromide with (R)-Boc-3-amino-piperidine followed by deprotection gives linagliptin. When administered to db/db mice orally, linagliptin dose dependently reduced glucose excursion from 0.1 mg/kg (15% inhibition) to 1 mg/kg (66% inhibition).
• Clinical Use: Type 2 diabetes mellitus
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: effects possibly reduced by rifampicin.

Technology Process of Linagliptin

There total 99 articles about Linagliptin which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.2%

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine → Linagliptin (668270-12-0)

Guidance literature:

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine; With hydrogenchloride; In dichloromethane; water; at 20 ℃; for 3h;

With hydrogenchloride; In ethanol; water; at 35 ℃; for 2h; Temperature;

Reference yield: 96.7%

3-(R)-aminopiperidine dihydrochloride (334618-23-4) + 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (853029-57-9) → Linagliptin (668270-12-0)

Guidance literature:

With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60 - 70 ℃; for 7h; Large scale;

Reference yield: 96.1%

C40H36N8O4 → Linagliptin (668270-12-0)

Guidance literature:

With ethanol; palladium 10% on activated carbon; at 20 ℃;

upstream raw materials:

(R)-7-(but-2-yn-1-yl)-8-(3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine2,6-dione

(R)-piperidine-3-carboxylic acid ethyl ester*l-tartaric acid

2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione

3-(R)-aminopiperidine dihydrochloride

Refernces

• 1、 -. "Method for preparing high-purity linagliptin". Paragraph 0015-0016. . Retrieved 2021/03/31.
• 2、 -. "Novel preparation process of linagliptin". Paragraph 0043; 0048-0049; 0056-0057. . Retrieved 2021/01/24.