Muscarinic antagonists
A compound, alkyl technology, applied in the direction of organic active ingredients, drug combinations, active ingredients of heterocyclic compounds, etc., can solve the problem of no introduction of anti-cognitive disease activity, etc.
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Embodiment 1
[0091]
[0092] Reaction flow :
[0093]
[0094] Step 1A: To a cooled (0° C.) mixture of DMF (25 ml) and NaH (1.00 g, 60% suspension in oil) was slowly added m-thiocresol (3.10 g) dropwise. After the addition was complete, the cooling bath was removed and the resulting mixture was stirred at room temperature (RT) for 1 hour, 6-bromo-nicotinic acid (5.00 g) was added in one portion and the resulting mixture was heated at reflux for 6 hours. After cooling to room temperature, the mixture was poured into cold water (250ml), the resulting solid was collected, washed with water and dried to give the desired product 1 (4.91g) in 80% yield.
[0095] To a solution of sulfide 1 (0.50 g) and THF (2 ml) was added BH dropwise 3 • DMS (0.61ml). The resulting solution was stirred at room temperature for 1 hour, diluted with ethyl acetate and ice, and stirred for 5 minutes. The pH was adjusted to 11 with 2N NaOH and the resulting mixture was extracted with ethyl acetate (3 x 10 m...
Embodiment 2
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[0102] Intermediate 4 (29mg) of Example 1 was dissolved in dichloromethane (1.0ml), and 2.0M sodium carbonate (0.2ml) was added. The resulting mixture was cooled to 0 °C and CH was added 3 (CH 2 ) 2 SO 2 Cl (7.62 μl). The mixture was stirred at 0°C for 5 minutes and at room temperature for 15 minutes, then magnesium sulfate was added. The dichloromethane layer was removed, the solid was extracted with dichloromethane (3 x 3 ml), the dichloromethane extracts were combined, dried over magnesium sulfate, filtered and evaporated to give a crude foam which was purified by preparative plate chromatography ( 500 [mu]M plate, silica gel adsorbent, 95:5 ethyl acetate:triethylamine developer) to give the product as a foam (33 mg) in 90% yield. C 26 h 38 N 4 o 4 S 2 Calculated HRMS value of HCl salt MH + : 535.2413; measured value: 535.2405; mp(HCl): 146-150°C (decomposition).
Embodiment 3
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[0105] Reaction flow:
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[0107] Step 1: To a cooled (-90°C) solution of 2,5-dibromopyridine (10 g) and THF (264 ml) was added dropwise n-butyllithium (16.9 ml, 2.5M in hexane), which produced The solution was stirred for 5 minutes. DMF (3.27ml) was added dropwise and the resulting solution was warmed to -50°C and stirred at room temperature for 15 minutes. The reaction solution was poured onto ice and extracted with ethyl acetate (3 x 75ml). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated to give 7.8 g of crude material which was purified by silica gel chromatography (4:1 hexane:ethyl acetate as eluent). The desired fractions were combined and the solvent was evaporated to isolate the desired aldehyde 5 (0.89 g) as a solid in 11% yield.
[0108] Step 2: A mixture of 5 (0.20g), DMSO (1.0ml) and sodium 3,4-methylenedioxybenzenesulfinate (0.19g) was heated at 40°C for 21 hours, then cooled and poured into ...
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