A kind of asymmetric synthesis method of escitalopram intermediate and its intermediate
A technology of escitalopram and a synthesis method, applied in the field of drug synthesis, can solve the problems of being unable to be suitable for industrialized large-scale production, low product yield, long route and the like, and achieve the effects of novel synthesis route, good product purity and high yield
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Embodiment 1
[0032] Synthesis of compound (6)
[0033] Under nitrogen protection, at -30°C, add 1.0kg (5mol) of compound (7) to 5L anhydrous tetrahydrofuran into a 10L four-neck reaction flask, slowly add 2L s-BuLi (2.5M tetrahydrofuran solution), and stir for half After 1 hour, 250 g of dry ice was added, and after stirring for 1 hour, it was slowly raised to room temperature, adjusted to about pH=6.5 with 15% acetic acid, filtered, and dried to obtain 1.2 kg (4.89 mol) of compound (6), with a yield of 97.8% and a purity of 98.1%.
[0034] [M+H]+=250
[0035] Synthesis of compound (4)
[0036] At 0°C, add 1.2kg (4.89mol) of compound (6) to 6L of dichloromethane into a 10L four-neck reaction flask, slowly add 1.67kg (5mol) of triphenylphosphine chlorine complex, and monitor the reaction by TLC. The reaction was completed after 12 hours, filtered, and the filtrate was directly used for the next reaction.
[0037] Synthesis of compound (2)
[0038] Under nitrogen protection, at -20°C, 5...
Embodiment 2
[0041] Preparation of compound (1)
[0042] At -20°C, under the protection of nitrogen, add 4.4L of compound (3) (2.5M tetrahydrofuran solution) in 5L of anhydrous dichloromethane as a reaction solvent to a 20L reactor, and add the catalyst CuBr-SMe 2 21g (0.1mol) and chiral ligand T006 81g (0.1mol), after stirring for 1 hour, slowly add compound (2) 3.18kg (10.0mol) in 5L anhydrous dichloromethane solution, TLC monitors the reaction, and reacts for 12 hours After the end, it was raised to room temperature, slowly poured into 10L 5% acetic acid aqueous solution, separated, the aqueous phase was extracted twice with dichloromethane, the organic phase was combined, and the organic phase was concentrated under reduced pressure to obtain the crude product of compound (1). Recrystallized from methanol / water to obtain 3.28kg (9.59mol) of the refined product, with a molar yield of 95.9% and a purity of 99.5% by HPLC.
[0043] 1 H NMR (400MHz, DMSO-d 6 )δ7.88(s,1H),7.70–7.39(m,4H)...
Embodiment 3
[0046] According to the synthesis method of Example 1, the difference is that the reaction temperature is 20° C., the reaction solvent tetrahydrofuran is replaced by anhydrous dichloromethane, the catalyst is replaced by cuprous bromide (0.1 mol), and the chiral ligand is replaced by T005 ( 0.12mol), compound (3) (20mol) and compound (2) (20mol). Compound (1) has a molar yield of 95.1%, and a purity of 98.8% by HPLC.
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