Darifenacin

Base Information

• Chemical Name: Darifenacin
• CAS No.: 133099-04-4
• Molecular Formula: C28H30N2O2
• Molecular Weight: 426.558
• European Community (EC) Number: 603-704-1
• UNII: APG9819VLM
• DSSTox Substance ID: DTXSID2048290
• Nikkaji Number: J615.836F
• Wikipedia: Darifenacin
• Wikidata: Q166476
• NCI Thesaurus Code: C65363
• RXCUI: 136198
• Pharos Ligand ID: WY2ABUL6FDCR
• Metabolomics Workbench ID: 42840
• ChEMBL ID: CHEMBL1346
• Mol file: 133099-04-4.mol

Synonyms:(S)-1-(2-(2,3-dihydro-5-benzofuranyl)ethyl)-alpha,alpha-diphenyl-3-pyrrolidineacetamide;darifenacin;darifenacin hydrobromide;darifenacin hydrochloride;darifenacine;darifenicin;Emselex;Enablex;UK-88525

Chemical Property of Darifenacin

Chemical Property:

• Vapor Pressure: 5E-15mmHg at 25°C
• Refractive Index: 1.624
• Boiling Point: 614.3 °C at 760 mmHg
• PKA: pKa (25°): 9.2
• Flash Point: 325.3 °C
• PSA: 55.56000
• Density: 1.192 g/cm³
• LogP: 4.59570
• Storage Temp.: 2-8°C
• XLogP3: 4.6
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 7
• Exact Mass: 426.230728204
• Heavy Atom Count: 32
• Complexity: 607

Purity/Quality:

98%,99%, ^*data from raw suppliers

Darifenacin-d4 ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Anticholinergic Agents
• Canonical SMILES: C1CN(CC1C(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)N)CCC4=CC5=C(C=C4)OCC5
• Isomeric SMILES: C1CN(C[C@@H]1C(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)N)CCC4=CC5=C(C=C4)OCC5
• Recent ClinicalTrials: A Two-week Open-label Pharmacodynamic and Pharmacokinetic Study of Multiple Doses of a Darifenacin Liquid Oral Suspension in Children (2 - 15 Years) With Neurogenic Detrusor Overactivity
• Recent EU Clinical Trials: A 4-week, open-label, multicenter, urodynamic pilot study to explore the efficacy, tolerability and safety of darifenacin (7.5 mg with up-titration to 15 mg) in patients with multiple sclerosis and neurogenic detrusor overactivity
• Description: Darifenacin is a novel muscarinic M3 selective antagonist for the once-daily oral treatment of urinary incontinence and overactive bladder. The majority of overactive bladder symptoms are thought to result from the overactivity of the detrusor muscle, which is primarily mediated by acetylcholine-induced stimulation of muscarinic M3 receptors in the bladder. Consequently, antimuscarinic agents have become the mainstay of overactive bladder treatment. Darifenacin has a higher level of M3 selectivity than the previously marketed antimuscarinic agents. It has Ki values of 16nM for M1, 50 nM for M2, and 1.6 nM for M3 receptors. It is slightly more M3 selective than solifenacin (M1:Ki=25 nM, M2:Ki=126 nM, M3:Ki=10 nM), which was launched in 2004. Darifenacin is significantly more selective than other muscarinics such as tolterodine, oxybutynin, and trospium, which are all essentially equipotent against M1, M2, and M3 receptors. In addition,darifenacin demonstrates greater effect on tissues in which the predominant receptor type is M3 rather than M1 or M2. In vitro darifenacin inhibits carbacholinduced contractions with greater potency in isolated guinea-pig bladder (M3) than in guinea-pig atria (M2) or dog saphenous vein (M1). In animal models, it shows greater selectivity for inhibition of detrusor contraction over salivation or tachycardia.Darifenacin is supplied as a controlled release formulation, and the recommended dosage is 7.5 mg once, daily. Darifenacin is rapidly and completely absorbed from the GI tract after oral administration, with maximum plasma levels achieved after about 7 h. The elimination half-life is approximately 3 h, but because of the controlled release characteristics of the formulation, the drug is suitable for once-daily dosing. Steady-state plasma levels are achieved within 6 days of commencing treatment. Darifenacin exhibits high-protein binding (98%), a volume of distribution of 163 L, and a clearance of 40 L/h. It has low oral bioavailability (15–19%) due to extensive first-pass metabolism by CYP3A4 and CYP2D6, but this can be saturated after multiple administrations. The major circulating metabolites are produced by monohydroxylation and N-dealkylation; however, none contribute significantly to the overall clinical effect of darifenacin. Approximately 58% of the dose is excreted in urine and 44% in feces; only a small percentage (3%) of the excreted dose is unchanged darifenacin.
• Uses: Treatment for an overactive bladder.
• Clinical Use: Symptomatic treatment of urinary incontinence,frequency or urgency
• Drug interactions: Potentially hazardous interactions with other drugsAnti-arrhythmics: increased risk of antimuscarinic side effects with disopyramideAntifungals: concentration increased by ketoconazole - avoid; avoid with itraconazole.Antivirals: avoid with fosamprenavir, atazanavir, indinavir, lopinavir, ritonavir, saquinavir and tipranavir.Calcium-channel blockers: avoid with verapamilCiclosporin: avoid concomitant use.

Technology Process of Darifenacin

There total 27 articles about Darifenacin 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: 80.0%

(3S)-3-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidine → darifenacin (133099-04-4,133033-93-9)

Guidance literature:

With tetrabutylammomium bromide; potassium hydroxide; In iso-butanol; for 48h; Reflux;

Reference yield: 9.0%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (134002-25-8,103887-32-7) → darifenacin (133099-04-4,133033-93-9)

Guidance literature:

With potassium carbonate; In acetonitrile; for 2h; Heating / reflux;

Reference yield:

(S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide (133033-99-5) → darifenacin (133099-04-4,133033-93-9)

Guidance literature:

(S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide; With hydrogen; acetic acid; palladium 10% on activated carbon; at 40 ℃; for 6h; under 760.051 Torr;

With sodium hydroxide; In dichloromethane; water; Product distribution / selectivity;

upstream raw materials:

(S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide

3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl]-pyrrolidine hydrochloride

2,3-dihydro-5-(2-bromoethyl)benzofuran

2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide

Downstream raw materials:

(S)-darifenacin hydrobromide

darifenacin hydrochloride

Refernces

• 1、 Pramanik, Chinmoy,Bapat, Kiran,Chaudhari, Ashok,Tripathy, Narendra K.,Gurjar, Mukund K.. "A new solvent system (Cyclopentyl methyl ether-water) in process development of darifenacin HBr". . p. 1591 - 1597. Retrieved 2013/02/23.
• 2、 -. "SUBSTITUTED PYRROLIDINES". Page/Page column 33. . Retrieved 2009/01/24.