3-Oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol, 9-methyl-, hydrochloride (1:1), (1α,2β,4β,5α,7β)-

Scopine Hcl salt is the metabolite of anisodine, which is a α1-adrenergic receptor agonist and used in the treatment of acute circulatory shock.

Preparation of Desmethyl-Tiotropium (4) From Scopine Hydrochloride A suspension of 100 g (0.522 mol) Scopine HCl was taken in DMF (5vol), cooled to 5°C, and NaH (1.7eq) was added slowly maintaining the temperature at 5°C. The reaction was stirred for 1 hour at 100C and DBU (leq) and methyl di(2-thienyl)glycolate (leq) were added. The reaction was heated to 600C for 1 hour and a second portion of DBU (2eq) was added. The reaction was heated for a further 4 hours at 600C and monitored by TLC. After completion of the reaction, the mixture was cooled to 5°C and a solution of cone. HCl (2.5vol) in cold water (lOvol) at 100C (pH 2) was added. The mixture was washed with toluene and basified with aqueous sodium carbonate (7.5eq) to pH 10 and extracted with DCM (3 x lOvol). The combined DCM layer was washed with water (3 x lOvol) and DCM was distilled under vacuum (150 mbar) at 300C. The product was obtained as light brown solid. Molar Yield = 60percent; HPLC purity = 98percent.The crude base (3) was recrystallized from acetonitrile (5vol). Yield of crystallization = 86percent; HPLC purity > 99.8percent.Tiotropium Base (3)Scopine HCl (1 eq with respect to methyl di-(2-thienyl)glycolate) was dissolved in dimethylformamide (2 vol with respect to methyl di-(2-thienyl)glycolate) at 20-250C and stirred for 5 minutes. Potassium carbonate (1 eq) was added under nitrogen at 20-250C and stirred at 20-250C for 1 hour. DBU (1 eq) and methyl di-(2-thienyl)glycolate (1 eq) were added and the reaction mixture was heated to 600C and maintained at 600C for 1 hour. A further amount of DBU (2 eq) was added at 600C and heating continued for 12 hours. After completion of the reaction, the reaction mixture was cooled to 0-50C and a solution of cone. HCl (2.5 vol) in water (5 vol) was added slowly through an addition funnel maintaining the temperature at 0-50C. Water (10 vol) was added and the mixture stirred for 1 hour at 0-50C. The reaction mass was basified with 20percent aqueous sodium carbonate solution (3 vol) and the sticky mass formed was removed by filtration. The filtrate was again cooled to 0-50C and 20percent aqueous sodium carbonate solution (11 vol) was added. The precipitated solid was filtered and washed with water (5 vol) to afford the product, tiotropium base (3), as a white solid.Molar yield = 60percentHPLC purity > 98percent (e.g. 98.7percent)Pure Tiotropium Base (3)Acetonitrile (8 vol with respect to crude tiotropium base (3)) and crude tiotropium base (3) (1 eq) were charged at 25-300C and stirred for 5 minutes. The mixture was heated to 75- 78°C and heating was continued at 75-78°C for 30 minutes. The clear solution was hot filtered under vacuum at 75-78°C. The clear filtrate obtained was cooled to 0 to -5°C and maintained at 0 to -5°C for 2 hours. The solid was filtered under vacuum and washed with chilled acetonitrile (0.5 vol with respect to crude tiotropium base (3)). Molar yield = 80-82percentHPLC purity > 99.90percent

Intermediate in the production of Tiotropium Bromide, a long-acting bronchodilator.

Molecular Weight:191.65
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Exact Mass:191.0713064
Monoisotopic Mass:191.0713064
Topological Polar Surface Area:36
Heavy Atom Count:12
Complexity:179
Defined Atom Stereocenter Count:4
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes