Crystalline form of tiotropium bromide
A kind of technology of tiotropium bromide and crystallization, applied in the field of crystalline form of tiotropium bromide, can solve the problems such as not describing single use of NMP, not mentioning obtaining crystalline form
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Embodiment 1
[0041] Preparation of desmethyltiotropium bromide (4) in NMP from scopolamine (3) free base
[0042] A mixture of 4.0 g (25.8 mmol) scopolamine (3) and 3.0 g (21.7 mmol, 0.84 equiv) of anhydrous potassium carbonate in 12 ml NMP was stirred at room temperature for 1 hour. After heating to 60°C, 6.56 g (25.8 mmol, 1.00 equivalent) of methyl di-(2-thienyl) glycolate (2) in 8 ml of NMP was added to the mixture, followed by 1.7 g (12.3 mmol , 0.48 equivalent) of anhydrous potassium carbonate. The temperature was raised to 70 °C and the reaction vessel was connected to vacuum (20 mbar) for 19 hours. TLC (ethyl acetate) indicated complete conversion of glycolate. After cooling to 0°C, 32 ml of 9% HCl was slowly added until pH~3. The dense precipitate was diluted with 20 mL of water and washed twice with 10 mL of toluene. The aqueous layer was cooled to 0°C and basified with 4.0 g potassium carbonate until pH~9. After 1 hour, the precipitate was filtered and washed with water unti...
Embodiment 2
[0047] Preparation of desmethyl-tiotropium bromide from scopolamine hydrochloride (4)
[0048]To a suspension of 100 g (0.522 mol) of scopolamine hydrochloride in 350 ml of DMF was added 72 g (0.521 mol, 1.0 equivalent) of anhydrous potassium carbonate. After gas evolution was complete, a solution of 159 g (0.625 mol, 1.2 eq) of methyl di-(2-thienyl)glycolate (2) in 300 mL of DMF was added. The reaction mixture was heated to 70 °C and vacuum (40 mbar) was applied. After one day, the mixture was ice-cooled and the pH was lowered to 3 with 9% hydrochloric acid, keeping the temperature below 25°C. The mixture was washed twice with 400 mL of toluene. The aqueous layer was basified with potassium carbonate and the resulting precipitate was collected by filtration and washed with water until neutral pH. The crude product was purified by crystallization from acetonitrile to afford 142 g (72%) of product as light brown crystals. Purity (HPLC): 99.8%.
[0049] 1 H-NMR (300MHz,d ...
Embodiment 3
[0052] Preparation of Tiotropium Bromide in NMP (1)
[0053] To a solution of 13.2 g (39.1 mmol) of desmethyltiotropium (4) in 30 mL of NMP was added 16.5 mL (115 mmol, 2.93 eq) of methyl bromide in NMP 1:1 (W / W) solution. The mixture was stirred overnight at room temperature whereupon a dense suspension formed. After adding 20 mL of acetonitrile, the suspension was filtered, washed with 20 mL of acetonitrile, and dried overnight at 30° C. under high vacuum to yield 15.51 g of an off-white powder. Residual solvents were detected by GC analysis. XRPD spectrum with figure 1 The spectra shown are consistent.
[0054] 1 H-NMR (300MHz,d 6 -DMSO):7.52(dd,J=5.0Hz,1.1,2H),7.41(s,1H),7.13(dd,J=3.6,1.1Hz,2H),7.01(dd,J=5.0,3.7Hz, 2H),5.12(t,J=5.8Hz,1H),4.13(bd,J=5.8Hz,2H),3.50(s,2H),3.25(s,3H),3.05(s,3H),2.8- 2.6(m,2H),1.93(s,1H),1.87(s,1H).
[0055] 13 C-NMR (75.5MHz,d 6 -DMSO): 170.2, 147.1, 127.3, 126.7, 126.3, 76.8, 65.0, 64.2, 56.5, 54.1, 47.6, 28.7.
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