Pyrrolidine derivative, its preparation method and application thereof
A technology of pyrrolidine and derivatives, applied in drug combination, nervous system diseases, organic chemistry, etc., can solve the problems of slow onset, poor patient compliance, and many side effects, to reduce side effects, enhance curative effect, and have a good application prospect. Effect
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Embodiment 1
[0034] Example 1 Preparation of tert-butyl 3-phenyl-3-hydroxypyrrolidine-1-carboxylate
[0035]
[0036] 4.71 g of bromobenzene and 14 ml of n-BuLi (2.26M hexane solution) were dissolved in anhydrous THF (10 ml), cooled to -40°C and stirred. After 1 h, the temperature was raised to 0° C., an anhydrous THF solution (10 ml) of 5.55 g of N-Boc-3-pyrrolidone was added dropwise, and the mixture was returned to room temperature and stirred for 10 min. Pour the reaction system into saturated NH 4 In the Cl solution, adjust the pH=6, extract with ethyl acetate, separate the liquids, repeat the extraction of the aqueous phase with ethyl acetate twice (10ml×2), combine the organic phases, anhydrous Na 2 SO 4 Dry, filter, and concentrate to a dark red oil. Flash silica gel column (ethyl acetate / petroleum ether=15%-25%) eluted to give 2.05 g of tert-butyl 3-phenyl-3-hydroxypyrrolidine-1-carboxylate as a light yellow solid, MP (melting point)=133°C .
[0037] Its structural identif...
Embodiment 2
[0040] Example 2 Preparation of tert-butyl 3-(4-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylate
[0041]
[0042] Stir 1.2g of Mg powder and 8.75g of 4-fluorobromobenzene in 10ml of anhydrous THF solution for 3h. Add 20 ml of anhydrous THF solution of 8.88 g of N-Boc-3-pyrrolidone dropwise, stir for 30 min, pour the system into saturated NH 4 Cl, extracted with ethyl acetate, separated, the aqueous phase was repeatedly extracted 3 times with ethyl acetate (10ml×3), the organic phase was combined, anhydrous Na 2 SO 4 Dry, filter, and concentrate to give a yellow solid. Isopropyl ether was recrystallized to obtain 10.2 g of tert-butyl 3-(4-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylate as a light yellow powder solid, MP (melting point) = 130°C.
[0043] Its structural identification data are as follows:
[0044] ESI-MS=282(M+H);
[0045] 1 H-NMR (DMSO-d 6 , 400MHz): δ=1.51(9H, s), 1.94(1H, s), 2.21-2.29(2H, m), 3.66(4H, s), 7.06-7.10(2H, m), 7.46-7.50(2H , m).
Embodiment 3
[0046] Example 3 Preparation of tert-butyl 3-(1-naphthyl)-3-hydroxypyrrolidine-1-carboxylate
[0047]
[0048] 1.2 g of Mg powder and 10.4 g of 1-bromonaphthalene were stirred in anhydrous THF solution (10 ml) for 3 h. Anhydrous THF solution (20 ml) of 8.88 g of N-Boc-3-pyrrolidone was added dropwise, and stirred for 30 min. Pour the system into saturated NH 4 Cl, extracted with ethyl acetate, separated, the aqueous phase was repeatedly extracted 3 times with ethyl acetate (10ml×3), the organic phase was combined, anhydrous Na 2 SO 4 Dry, filter, and concentrate to give a yellow solid. Recrystallization from isopropyl ether gave 9.82 g of tert-butyl 3-(1-naphthyl)-3-hydroxypyrrolidine-1-carboxylate as a light yellow powder solid, MP (melting point) = 125°C.
[0049] Its structural identification data are as follows:
[0050] ESI-MS=314(M+H)
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