Quaternary ammonium salt of penehyclidine optical isomer, medicinal composition and medical application thereof
A technology of optical isomers and penehyclidine, which is applied in the field of selective M3 receptor antagonists, salts or solvates, can solve problems such as the inability to predict whether the isomer is effective or ineffective
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Embodiment 1
[0075] Embodiment 1, Preparation of (R)-α-phenyl-α-cyclopentyl-1,2-oxirane (IX)
[0076] 1.1、 Preparation of (2R,5R)-2-tert-butyl-5-phenyl-1,3-dioxan-4-one (II)
[0077] Add 20 g (0.13 mol) of R-mandelic acid in 200 mL of n-pentane, then add 21.2 mL of pivalaldehyde (content 80%, 0.16 mol, purchased from Fluka Company), and then add 0.5 mL of trifluoromethanesulfonic acid to make the The mixture was refluxed for 6 hours. Remove the generated water with a water separator. Cool to room temperature, add 100 mL of 8% sodium bicarbonate solution, distill under reduced pressure, remove n-pentane, and filter to obtain (2R,5R)-2-tert-butyl-5-phenyl-1,3-dioxane- 4-ketone (II), yield 27.1g, melting point 100-102°C, yield 95%, elemental analysis, theoretical value %: C 70.89, H 7.32; experimental value %: C 70.81, H 7.39. 1 H-NMR, δ (ppm, CDCl 3 ): 1.10(s, 9H), 5.25(s, 1H), 5.38(s, 1H), 7.47(m, 5H).
[0078] 1.2、 Preparation of (2R,5S)-2-tert-butyl-5-phenyl-5-(cyclopentyl-1-hydr...
Embodiment 2
[0089] Embodiment 2, Preparation of 3-(R)-[2'-(R)-2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy]-quinuclidane (X)
[0090] Under the protection of nitrogen, put 0.6g (15mmol) of NaH in a dry three-necked flask, add 10mL of anhydrous DMSO, after stirring for 5min, dropwise add 1.8g (14.2mmol) of 3-(R)-quinuclidinol ) in 10 mL DMSO, and the reaction was stirred at 60 °C for 1 h. After cooling to room temperature, a solution of (R)-α-phenyl-α-cyclopentyl-1,2-oxirane (IX) 2.61 g (14 mmol) in 10 mL of DMSO was slowly added dropwise. The reaction was stirred at 50 °C for 3 h, cooled, and 20 mL of water was carefully added dropwise. Extract with ether, wash with water, wash the ether layer with 10% hydrochloric acid solution, combine the water phases; basify the obtained hydrochloric acid extract with 40% NaOH, extract with ether, dry with anhydrous sodium sulfate, distill, remove the solvent, The colorless liquid of X was obtained, 2.84g, yield 65%, (MeOH, c=0.35). 1 H NMR, δ (pp...
Embodiment 3
[0091] Embodiment 3, N-methyl-3-(R)-[2′-(R)-2′-hydroxy-2′-cyclopentyl-2′-phenylethoxy]-quinuclidinyl bromide (I 1 ) preparation
[0092] Dissolve 3.15g (10mmol) of X in 20ml of acetone, add 1.04g (11mmol) of methyl bromide and stir, react at 50-60°C for 3-10 hours, spot the plate until the raw material point disappears, stop the reaction, cool down to 10-20°C, slowly Slowly add anhydrous diethyl ether dropwise until no solid precipitates out, filter with suction, and dry in vacuo to give I 1 3.89g, yield 95%, (EtOH, c=0.01). 1 H-NMR, δ (ppm, D 2 O): 7.32(m, 2H), 7.21(m, 2H), 7.11(m, 1H), 4.28(m, 1H), 3.79(d, 1H), 3.71(br t, 1H), 3.46(d, 1H), 3.38(m, 1H), 3.11(m, 1H), 2.99(m, 2H), 2.84(m, 2H), 2.65(s, 3H), 2.24(m, 1H), 2.16(br, 1H ), 1.80 (m, 1H), 1.20-1.61 (m, 9H), 0.94-1.09 (m, 2H).
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