The preparation method of umeclidinium bromide intermediate
A technology of umeclidinium bromide and intermediates, which is applied in the field of preparation of umeclidinium bromide intermediates, can solve the problems of high cost, low yield, low purity, etc., and achieve the effects of low cost, high yield and high quality
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Embodiment 1
[0028] Embodiment 1: Preparation of ethyl 1-azabicyclo [2.2.2] octane-4-carboxylate hydrochloride
[0029] Add ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (10.0g, purity 98.2%) and toluene (100ml) into a 500mL reaction flask, stir to dissolve, cool to -20°C, and slowly add KHMDS dropwise Toluene solution (364ml, 0.5M), after dropping, stirred at -20°C for 4 hours, TLC detected that the reaction was complete. At 0°C, ethanol (10.0g) and acetic acid (15.0g) were added dropwise successively, stirred for 1 hour at 40°C, potassium carbonate solution (150g, 25%) was slowly added dropwise, stirred for 15 minutes, and the layers were left to stand, The aqueous phase was extracted twice with toluene (50ml), the organic phases were combined, washed once with water, and the organic phase was concentrated under reduced pressure to obtain the crude product of ethyl 1-azabicyclo[2.2.2]oct-4-carboxylate as light yellow Oil.
[0030] At room temperature, add ethanol (80mL) to the above ...
Embodiment 2
[0033] Embodiment 2: Preparation of 1-azabicyclo[2.2.2]oct-4-yl (diphenyl)methanol
[0034] At room temperature, intermediate II-1 (8.0 g) and toluene (120 ml) were added to the reaction flask, and 80 mL of NaOH (22 ml, 2M) aqueous solution was added, and stirred for 10 minutes. The layers were separated, the aqueous phase was extracted once with toluene, the organic phases were combined, washed with water once, and the organic phase was concentrated under reduced pressure to obtain a pale yellow oil-free base of formula II.
[0035] Add the above-mentioned intermediate II free base and toluene (120ml) into a 500mL reaction flask, stir to dissolve, cool to -20°C, slowly add n-butyl ether solution of phenyllithium (42ml, 1.9M) dropwise, dropwise, in- Stir at 20°C for 2 hours, and TLC detects that the reaction is complete. At 0°C, water (25ml) and n-butanol (17ml) were added dropwise successively, stirred at 75°C for 1 hour, allowed to stand for layers, and the organic phase wa...
Embodiment 3
[0036] Embodiment 3: Preparation of ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate hydrochloride
[0037]Add ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (10.0g, purity 98.2%) and toluene (100ml) into a 500mL reaction flask, stir to dissolve, and slowly add KHMDS toluene dropwise at 40°C Solution (110ml, 0.5M), after dropping, stirred at 40°C for 4 hours, TLC detected that the reaction was complete. At 0°C, ethanol (10.0g) and acetic acid (15.0g) were added dropwise successively, stirred for 1 hour at 40°C, potassium carbonate solution (150g, 25%) was slowly added dropwise, stirred for 15 minutes, and the layers were left to stand, The aqueous phase was extracted twice with toluene (50ml), the organic phases were combined, washed once with water, and the organic phase was concentrated under reduced pressure to obtain the crude product of ethyl 1-azabicyclo[2.2.2]oct-4-carboxylate as light yellow Oil.
[0038] At room temperature, add tetrahydrofuran (40mL) to the above cru...
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