133099-07-7

Basic information

• Product Name: Darifenacin hydrobromide
• Synonyms: 2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenyl-ethanamide hydrobromide;2-[(3S)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenyl-acetamide hydrobromide;Darifenacine Hydrobromide;Darifenacin hydrobro;(3S)-1-[2-(2,3-Dihydro-5-benzofuranyl)ethyl]-α-α-diphenyl-3-pyrrolidineacetaMide HydrobroMide;Darifenacin hydrobroMide R;DARFENACIN HYDROBROMIDE;(S)-3-(Carbamoyldiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide
• CAS NO: 133099-07-7
• Molecular Formula: BrH*C₂₈H₃₀N₂O₂
• Molecular Weight: 505.44606
• EINECS: 1308068-626-2
• Product Categories: Amines;Aromatics;Heterocycles;API;APIs;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 133099-07-7.mol

Chemical Properties

• Melting Point: 228-2300C
• Boiling Point: 614.3 °C at 760 mmHg
• Flash Point: 325.3 °C
• Appearance: white to beige/
• Vapor Pressure: 1.11E-16mmHg at 25°C
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: soluble20mg/mL, clear
• CAS DataBase Reference: Darifenacin hydrobromide(CAS DataBase Reference)
• NIST Chemistry Reference: Darifenacin hydrobromide(133099-07-7)
• EPA Substance Registry System: Darifenacin hydrobromide(133099-07-7)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 133099-07-7(Hazardous Substances Data)

Usage

Uses

1. Urinary Incontinence Treatment:
Darifenacin hydrobromide is used as a medication for the treatment of urinary incontinence. It works by blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. This action helps to reduce the smooth muscle tone, allowing for a greater volume of urine to be stored in the bladder, resulting in less urinary incontinence, urgency, and frequency.
2. Overactive Bladder Management:
Darifenacin hydrobromide is used in the management of overactive bladder. It selectively inhibits contractions in isolated guinea pig ileum, bladder, and trachea, tissues that endogenously express high levels of M3 muscarinic acetylcholine receptors. This selective inhibition helps to reduce the symptoms of overactive bladder, such as urge incontinence, urgency, and frequency.
3. Acute Lymphoblastic Leukemia Therapy:
Although not a primary use, darifenacin hydrobromide has been studied for its potential therapeutic effects in acute lymphoblastic leukemia treatment. The exact mechanism of action in this context is not well-established, but it may involve the modulation of certain cellular pathways or interactions with other drugs used in cancer therapy.
4. Calcium Replenisher:
Darifenacin hydrobromide can also be used as a calcium replenisher, although this is not its primary application. The hydrobromide salt form of the compound may contribute to calcium levels in the body, which can be beneficial in certain medical conditions or situations where calcium supplementation is required.

Biochem/physiol Actions

Darifenacin hydrobromide is an antispasmodic muscarinic antagonist, selective for blocking the M3 muscarinic acetylcholine receptor, which is primarily responsible for bladder muscle contractions. Darifenacin hydrobromide has 9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4. Darifenacin is used clinically to treat urinary incontinence and overactive bladder syndrome.

Synthesis

The synthesis of darifenacin is depicted in Scheme 5. Commercially available (2S,4R)-(-)-4-hydroxy-2-pyrrolidinecarboxylic acid (17), anhydrous cyclohexanol and 2-cyclohexen-1-one were heated at 154oC to give de-carboxylated compound 18 in 69 % yield. The 3-(R)-hydroxypyrrolidine (18) was N-tosylated with p-toluenesulfonyl chloride in pyridine yielding compound 19 in 26 % yield . The N-tosylated alcohol 19 was subjected to Mitsunobu reaction in the presence of methyl ptoluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF to afford N-tosyl-3(S)-(tosyloxy) pyrrolidine (20) in 70% yield, which was then condensed with 2,2-diphenylacetonitrile with NaH in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin- 2(S)-yl]acetonitrile (21). The tosyl group of 21 was removed with 48% HBr and phenol in refluxing water to yield 2,2- diphenyl-2-[2(S)-pyrrolidinyl] acetonitrile as its corresponding hydrogen bromide salt (22), which was coupled to 2-(2, 3-dihydrobenzofuran-5-yl) acetic acid (23) by treatment with carbonyldiimidazole (CDI) in ethyl acetate to the corresponding amide 24 in a quantitative yield. The amide (24) was dissolved in toluene and reduced with sodium borohydride in THF with slow addition of boron trifluoride THF complex to keep the temperature below 10°C to give free amine in 88% yield. The free amine was converted to corresponding hydrogen bromide salt (25) with 48% HBr in methanol. Compound 25 was hydrolyzed with potassium hydroxide in refluxing 2-methyl-butan-2-ol for twenty hours to give acetamide which was crystallized from toluene as a toluene solvated form in 84% yield. Finally, the toluene solvated compound was converted to darfenacin hydrobromide (IV) with 48% HBr in 2-methyl-butan-2-ol.

references

[1]. hegde ss1,choppin a,bonhaus d,briaud s,loeb m,moy tm,loury d,eglen rm.functional role of m2 andm3muscarinic receptorsin the urinary bladder of rats in vitro and in vivo.br j pharmacol.1997 apr;120(8):1409-18.[2]. brann mr1,ellis j,jrgensen h,hill-eubanks d,jones sv. muscarinicacetylcholinereceptorsubtypes: localization and structure/function.prog brain res.1993;98:121-7.[3]. miller dw1,hinton m,chen f.evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood-brain and blood-ocular barriers. neurourol urodyn.2011 nov;30(8):1633-8. doi: 10.1002/nau.21110. epub 2011 aug 8.[4]. haab f1,stewart l,dwyer p.darifenacin, anm3selectivereceptorantagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. eur urol.2004 apr;45(4):420-9; discussion 429.

InChI:InChI=1/C28H30N2O2.BrH/c29-27(31)28(23-7-3-1-4-8-23,24-9-5-2-6-10-24)25-14-17-30(20-25)16-13-21-11-12-26-22(19-21)15-18-32-26;/h1-12,19,25H,13-18,20H2,(H2,29,31);1H

Synthetic route

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium hydroxide; triethylmethylammonium chloride In water; toluene at 100℃; for 15.25h; Stage #2: With hydrogen bromide In water; toluene Product distribution / selectivity;	93.2%
Stage #1: (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium hydroxide; triethylmethylammonium chloride In 2-methyltetrahydrofuran; water at 60 - 70℃; Stage #2: 2,3-dihydro-5-(2-bromoethyl)benzofuran In 2-methyltetrahydrofuran; water for 16h; Heating / reflux; Stage #3: With hydrogen bromide In 2-methyltetrahydrofuran; water at 0 - 20℃; for 2h; Product distribution / selectivity;	90.67%
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium hydroxide; triethylmethylammonium chloride In water; butanone at 75℃; for 6h; Stage #2: With hydrogen bromide In water; butanone at 0 - 5℃; for 2h; Product distribution / selectivity;	84.92%

(S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide (133033-99-5) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: (S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide With hydrogen; acetic acid; palladium 10% on activated carbon at 45 - 50℃; for 6 - 7h; Stage #2: With hydrogen bromide In water; butan-1-ol Product distribution / selectivity;	85%

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) + 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (134002-25-8) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With potassium hydroxide; triethylmethylammonium chloride In water; butanone at 75℃; for 6h; Heating / reflux; Stage #2: With hydrogen bromide In water; butanone	84.92%
Stage #1: 2,3-dihydro-5-(2-bromoethyl)benzofuran; 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With potassium carbonate In acetonitrile at 70 - 75℃; for 2h; Stage #2: With hydrogen bromide In water; acetone at 0 - 25℃; Product distribution / selectivity;
With potassium carbonate In acetonitrile

2-(2,3-dihydrobenzofuran-5-yl)ethylchloride (943034-50-2) + (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride; (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium carbonate In water at 101 - 103℃; for 2.5 - 5h; Stage #2: With hydrogen bromide In water; butan-1-ol Product distribution / selectivity;	77.2%

darifenacin (133099-04-4) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
With hydrogen bromide In water; acetone at 0 - 20℃; for 7h;	75%
With hydrogen bromide In water; acetone	65%
With hydrogen bromide In water; acetone for 1.25 - 2.33333h; Product distribution / selectivity;

(-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide With potassium hydroxide; tert-Amyl alcohol at 60℃; for 22 - 23h; Heating / reflux; Stage #2: With hydrogen bromide In water; butanone Product distribution / selectivity;	72%
Stage #1: (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide With potassium hydroxide In tert-Amyl alcohol at 60 - 108℃; Stage #2: With water Stage #3: With hydrogen bromide In acetic acid; acetone at 20℃;	72%
Stage #1: (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide With potassium hydroxide In iso-butanol at 105 - 110℃; for 50h; Stage #2: With hydrogen bromide; acetic acid In acetone for 1h; Stage #3: With sodium hydroxide; water; hydrogen bromide; acetic acid Product distribution / selectivity; more than 3 stages;	27.5%

2-(2,3-dihydrobenzofuran-5-yl)ethylchloride (943034-50-2) + 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (134002-25-8) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With sodium hydroxide; water In ethyl acetate at 25 - 35℃; for 0.25h; Stage #2: 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride With triethylamine at 95℃; for 15h; Stage #3: With hydrogen bromide In water; acetone for 1h; Product distribution / selectivity;	70%
Stage #1: 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride; 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With potassium carbonate In water at 101 - 103℃; for 2 - 5h; Stage #2: With hydrogen bromide In water; butan-1-ol Product distribution / selectivity;

2,3-dihydro-5-(2-bromoethyl)benzofuran (127264-14-6) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 2: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile 2: ammonia / methanol / 5 - 7 h / 28 - 45 °C 3: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

(S)-darifenamine → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: (S)-darifenamine With sodium tetrahydroborate In ethanol at 20℃; for 3h; Stage #2: With water In ethanol Stage #3: With hydrogen bromide In water; butan-1-ol Product distribution / selectivity;

darifenacin hydrobromide → (S)-darifenacin hydrobromide (133099-07-7) + (3R)-2-{1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-yl}-2,2-diphenylacetamide hydrobromide (1092800-15-1)

Conditions	Yield
Purification / work up; Resolution of enanthiomeric mixture;	A 50.8 - 51.8 %Chromat. B 48.0 - 49.0 %Chromat.

(S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate + 2-(2,3-dihidrobenzofuran-5-yl)ethyl tosylate (79679-49-5) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Stage #1: (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate; 2-(2,3-dihidrobenzofuran-5-yl)ethyl tosylate With potassium carbonate In acetonitrile at 25 - 70℃; Inert atmosphere; Stage #2: With hydrogen bromide In dichloromethane; water at 5 - 30℃; pH=2 - 9;

5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (87776-76-9) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0 - 25 °C / Inert atmosphere 2.1: potassium carbonate / acetonitrile / 25 - 70 °C / Inert atmosphere 2.2: 5 - 30 °C / pH 2 - 9 View Scheme

(S)-2,2-diphenyl-2-[1-(tert-butyloxycarbonyl)-3-pyrrolidinyl]acetonitrile (1189753-52-3) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / methanol / 7 h / 20 - 30 °C 2.1: sulfuric acid / 12 h / 85 - 90 °C 3.1: ethanol / 1 h 4.1: potassium carbonate / water / 0.5 h / 25 - 30 °C 4.2: 12 h / 25 - 75 °C 5.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C View Scheme

(S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetonitrile (133099-11-3) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sulfuric acid / 12 h / 85 - 90 °C 2.1: ethanol / 1 h 3.1: potassium carbonate / water / 0.5 h / 25 - 30 °C 3.2: 12 h / 25 - 75 °C 4.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid / 10 h / 95 - 100 °C 1.2: 25 - 30 °C 2.1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 3.1: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (134002-25-8) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ethanol / 1 h 2.1: potassium carbonate / water / 0.5 h / 25 - 30 °C 2.2: 12 h / 25 - 75 °C 3.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 2: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: water / 50 - 60 °C 2: potassium hydroxide / acetonitrile / 25 - 45 °C 3: hydrogen bromide / acetone / 10 - 25 °C View Scheme

1-(2,3-dihydrobenzofuran-5-yl)ethanone (90843-31-5) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / methanol / 0.5 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 5 - 10 °C / Inert atmosphere 2.2: 4 h / 45 - 50 °C / Inert atmosphere 3.1: potassium carbonate / water / 0.5 h / 25 - 30 °C 3.2: 12 h / 25 - 75 °C 4.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C View Scheme

2-bromo-1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one (151427-19-9) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 5 - 10 °C / Inert atmosphere 1.2: 4 h / 45 - 50 °C / Inert atmosphere 2.1: potassium carbonate / water / 0.5 h / 25 - 30 °C 2.2: 12 h / 25 - 75 °C 3.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C View Scheme

2,3-Dihydrobenzofuran (496-16-2) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / 0 - 5 °C / Inert atmosphere 1.2: 0.5 h / 0 - 5 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / methanol / 0.5 h / 0 - 5 °C 2.2: 6 h / 0 - 5 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 1 h / 5 - 10 °C / Inert atmosphere 3.2: 4 h / 45 - 50 °C / Inert atmosphere 4.1: potassium carbonate / water / 0.5 h / 25 - 30 °C 4.2: 12 h / 25 - 75 °C 5.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C View Scheme

2-(2,3-dihydrobenzofuran-5-yl)ethylchloride (943034-50-2) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium bromide / acetone / 48 h / Heating / reflux 2: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 3: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme
Multi-step reaction with 4 steps 1: sodium bromide / acetone / 48 h / Heating / reflux 2: potassium carbonate / acetonitrile 3: ammonia / methanol / 5 - 7 h / 28 - 45 °C 4: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

(S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / water / 0.33 h / 25 - 60 °C / pH 12 - 14 2: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 3: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

(S)-diphenyl-[1-(toluene-4-sulfonyl)-pyrrolidin-3-yl]-acetonitrile (133099-09-9) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogen bromide / water; phenol / 4 h / Heating / reflux 2.1: sulfuric acid / 10 h / 95 - 100 °C 2.2: 25 - 30 °C 3.1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 4.1: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

2,2-diphenyl-2-((S)-pyrrolidin-3-yl)-acetic acid methyl ester (1072227-71-4) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile 2: ammonia / methanol / 5 - 7 h / 28 - 45 °C 3: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

methyl 2,2-diphenyl-2-((S)-1-tosyl-pyrrolidin-3-yl)-acetate (1072227-66-7) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen bromide; acetic acid 2: potassium carbonate / acetonitrile 3: ammonia / methanol / 5 - 7 h / 28 - 45 °C 4: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

2,2-diphenyl-2-{(S)-1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-acetic acid methyl ester (1072227-73-6) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonia / methanol / 5 - 7 h / 28 - 45 °C 2: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

Diphenylacetonitrile (86-29-3) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide / 2 h 1.2: 5 h / 95 - 100 °C 2.1: hydrogen bromide / water; phenol / 4 h / Heating / reflux 3.1: sulfuric acid / 10 h / 95 - 100 °C 3.2: 25 - 30 °C 4.1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 5.1: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

methyl 2,2-diphenylacetate (3469-00-9) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydride / toluene / 1 h / 55 - 60 °C 1.2: 3 h / 25 - 30 °C / Heating / reflux 2.1: hydrogen bromide; acetic acid 3.1: potassium carbonate / acetonitrile 4.1: ammonia / methanol / 5 - 7 h / 28 - 45 °C 5.1: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

2-chloro-1-(2,3-dihydrobenzofuran-5-yl)ethanone (64089-34-5) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate; sulfuric acid / tetrahydrofuran / 10 h / -5 - 0 °C 2: sodium bromide / acetone / 48 h / Heating / reflux 3: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 4: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme
Multi-step reaction with 5 steps 1: sodium tetrahydroborate; sulfuric acid / tetrahydrofuran / 10 h / -5 - 0 °C 2: sodium bromide / acetone / 48 h / Heating / reflux 3: potassium carbonate / acetonitrile 4: ammonia / methanol / 5 - 7 h / 28 - 45 °C 5: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

C2H2O4*C18H18N2 → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide; water / 0.25 h / 50 - 60 °C / pH 12 2.1: sulfuric acid / 10 h / 95 - 100 °C 2.2: 25 - 30 °C 3.1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C 4.1: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C View Scheme

(3R)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-3-ol (1190695-09-0) → (S)-darifenacin hydrobromide (133099-07-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triphenylphosphine; benzoic acid; diethylazodicarboxylate / toluene / 0 - 20 °C 1.2: 5 h / 20 °C 2.1: triethylamine / dichloromethane / -10 - 20 °C 3.1: sodium hydride / toluene / 2 h / Reflux 3.2: 9 h / Reflux 4.1: tetrabutylammomium bromide; potassium hydroxide / iso-butanol / 48 h / Reflux 5.1: hydrogen bromide / water; acetone View Scheme

(S)-darifenacin hydrobromide (133099-07-7) → darifenacin (133099-04-4)

Conditions	Yield
With sodium hydroxide In water at 20 - 25℃; pH=12;

Upstream product

• 127264-14-6 2,3-dihydro-5-(2-bromoethyl)benzofuran 
• 134002-26-9 (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate 
• 943034-50-2 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride 
• 134002-25-8 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide 
• 133033-99-5 (S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide 
• 133099-04-4 darifenacin 
• 79679-49-5 2-(2,3-dihidrobenzofuran-5-yl)ethyl tosylate 
• 87776-76-9 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran 
• 1189753-52-3 (S)-2,2-diphenyl-2-[1-(tert-butyloxycarbonyl)-3-pyrrolidinyl]acetonitrile 
• 133099-11-3 (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetonitrile 
• 90843-31-5 1-(2,3-dihydrobenzofuran-5-yl)ethanone 
• 151427-19-9 2-bromo-1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one 
• 496-16-2 2.3-dihydrobenzofuran 
• 133099-09-9 (S)-diphenyl-[1-(toluene-4-sulfonyl)-pyrrolidin-3-yl]-acetonitrile 

Downstream Products

• 133099-04-4 darifenacin 

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During the process development in the laboratory, the purity of darifenacin hydrobromide has been tested by HPLC. Three byproduct peaks along with darifenacin 1 peak have been observed whose area percentage ranged from 0.06-0.20% by HPLC. As per the strin

A new solvent system (Cyclopentyl methyl ether-water) in process development of darifenacin HBr

Darifenacin is a potent and competitive M3 selective receptor antagonist (M3SRA), and its hydrobromide salt (1) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromide (1).

AN IMPROVED PROCESS FOR THE PREPARATION OF DARIFENACIN HYDROBROMIDE

The present invention relates to an improved process for the preparation of Darifenacin hydrobromide of Formula (I). (i) condensing 3-(S)-(-)-1l-carbamoyl-1,1-diphenylmethyl)pyrrolidine (III), or its salt, with a compound of Formula XIII in the presence of a. base in a solvent, wherein X represents Cl, Br, C1-3 alkyl sulfonate or C6-10 arγl sulfonate; to produce (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl]-2,2-diphenylacetamide (Darifenacin) (Ia), (ix) treating (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]- 2,2-diphenylacetamide (Darifenacin) (Ia) with an acid in a solvent and water mixture, (x) isolating pure (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3- pyrrolidinyl]-2,2-diphenylacetamide (Darifenacin) (Ia), (xi) treating pure Darifenacin (Ia) with HBr to produce Darifenacin hydrobromide (I).

Method for obtaining 1,3-difunctionalized pyrrolidine derivatives

The present invention relates to a method for obtaining 1,3-difunctionalized pyrrolidine derivatives, such as 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine, commonly known as Darifenacin, as well as to the i

Novel Polymorphs of Darifenacin Free Base and its Hydrobromide Salt

The present invention provides a novel and stable amorphous form of darifenacin free base, process for preparation, pharmaceutical compositions, and method of treating thereof. The present invention further provides a novel and stable polymorphic form of darifenacin hydrobromide, process for preparation, pharmaceutical compositions, and method of treating thereof.

NOVEL PROCESS FOR THE PREPARATION OF (3SM-[2-(2 J-DIHYDRO-5- BENZOFURANYL?ETHYL]-α.α -DIPHENYL-3-PYRROLIDINEACETAMIDE HYDROBROMIDE

The present invention is directed to a novel, industrially viable and cost effective process for manufacturing (3 S)- 1 -[2-(2,3-Dihydro-5-benzofuranyl)ethyl]-a,a-diphenyl-3-pyrrolidineacetamide hydrobromide also known as Darifenacin hydrobromide.

IMPROVED PROCESS FOR PRODUCING DARIFENACIN

The present invention discloses an improved process for producing darifenacin, the process comprising decarboxylating (2S,4R)-4-hydroxy-2-pyrrolidine carboxylic acid followed by in situ tosylation to give l-tosyl-3-(R)-(-)-hydroxypyrrolidine, tosylating the l-tosyl-3-(R)-(-)-hydroxypyrrolidine with methyl-p-toluenesuolphonate to give l-tosyl-3- (S)-(-)-tosyloxy pyrrolidine, reacting l-tosyl-3-(S)-(-)-tosyloxy pyrrolidine with diphenyl acetonitrile in presence of a base to give 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine, de-protecting 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl)-l- tosylpyrrolidine in the presence of phenol in acidic medium to give 3-(S)-(+)-(l-cyano- 1,1-diphenylmethyl) pyrrolidine, hydrolyzing 3-(S)-(+)-(l-cyano-l,l-diphenylmethyl) pyrrolidine followed by salt formation to obtain 3-(S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine.L-(+)-tartrate, condensing 3-(S)-(+)-( 1 -carbamoyl- 1,1- diphenylmethyl)pyrrolidine-L(+)-tartrate with 5-(2-bromoethyl)-2,3-dihydrobenzofuran employing a base in a solvent to give darifenacin.

A METHOD FOR THE PREPARATION OF DARIFENACIN HYDROGEN BROMIDE

A method of preparing (3S)-l-[2-(2,3-dihydro-5-benzofuranyl)ethyl}-α,α-diphenyl-3- pyrrolidine acetamide hydrogen bromide, wherein 3-(S)-(I -carbamoyl- 1,1- diphenylmethyl)pyrrolidine or its salt with an organic acid is alkylated in the presence of an ino

Method For Determining Enantiomeric Purity Of Darifenacin And Intermediates

The present invention relates to a method for differentiating and quantifying the enantiomers, thereby determining the enantiomeric purity, of darifenacin and its intermediate compounds and salts thereof. In addition, the invention relates to a method for

PREPARATION OF DARIFENACIN AND ITS SALTS

Provided are various processes and compounds related to darifenacin and/or its salts. For example, there is provided a process for preparing a free base of darifenacin: Formula, or the salt thereof, the process including reacting 3-(S)-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine of the Formula (IV), or a salt thereof: Formula (IV) with a base effective to convert the nitrile group of the compound of the Formula (IV) to the amide group of the darifenacin in an organic solvent, the reaction being carried out in the organic solvent, with a proviso that the solvent is not 2-methyl-butan-2-ol, and with further proviso that the reaction produces less than about 0.5 % of the compound of the Formula (Ic): Formula (Ic) in the reaction mass, as measured by HPLC. Various embodiments and variants are provided.