Asymmetric synthesis method for galanthamine and lycoramine

A technology of galantamine and synthetic method, which is applied in the field of asymmetric synthesis of natural products, and can solve the problems of lack of large-scale production, high-efficiency asymmetric catalytic construction of chiral centers, etc.

Active Publication Date: 2015-05-13
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is still a lack of asymmetric synthesis methods for the efficient asymmetric catalytic construction of chiral centers that can be produced on a large scale

Method used

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  • Asymmetric synthesis method for galanthamine and lycoramine
  • Asymmetric synthesis method for galanthamine and lycoramine
  • Asymmetric synthesis method for galanthamine and lycoramine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of compound 3a

[0026] Add compound 1a (15.1g, 74.3mmol), compound 2 (30.0g, 89.2mmol) and anhydrous potassium carbonate (10.3g, 74.3mmol) successively to a dry 250mL two-necked flask with a reflux condenser, add 150mL DMF Dissolve under electromagnetic stirring, and heat the oil bath to 80°C for 8 hours. The reaction was stopped after the disappearance of compound 2 was detected by TLC, and the system was cooled to room temperature. Suction filtration through celite, and the filtrate was concentrated in vacuo to obtain an oily liquid. Add 100 mL of ethyl acetate to dissolve the oil, and wash with water and saturated brine successively. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed. The resulting oily liquid was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 18.6 g of a white solid, with a yield of 70%.

[0027] Mp: 88-90°C; 1 HNMR (400MHz, CDCl 3 )δ7.13(d, J=8.0H...

Embodiment 2

[0029] Preparation of compound 3b

[0030] Using the same operation as in Example 1, 22.5 g of a white solid was obtained, with a yield of 75%.

[0031] Mp: 77-78°C; 1 HNMR (400MHz, CDCl 3 )δ7.34(dd, J=7.9, 1.0Hz, 1H), 6.85(d, J=8.1 Hz, 1H), 6.75(t, J=8.0Hz, 1H), 5.05(dd, J=10.5, 8.1 Hz), 4.01-3.96(m, 4H), 3.76(s, 3H), 2.70-2.59(m, 1H), 2.53(dt, J=14.1, 4.3Hz, 1H), 2.43-2.36(m, 2H) , 2.04 (dd, J=11.1, 4.6Hz, 2H). 13 CNMR (100MHz, CDCl 3 )δ205.2, 151.8, 146.6, 131.1, 125.6, 113.0, 107.6, 92.7, 81.2, 64.8, 64.7, 56.1, 42.1, 35.9, 34.6. HRMS (ESI, [M+Na] + ): calculated: 427.0013, found: 427.0010.

Embodiment 3

[0033] Preparation of compound 4a

[0034] Weigh out RuCl in the glove box 2 -(R)-SDP / (S,S)-DPEN (11.0mg, 0.01mmol) was placed in the inner tube of a 100mL reactor, sealed with a sealant, taken out, placed in the reactor, and injected into 8.0mL i PrOH, after peeling off the sealant, quickly replace the hydrogen and keep the hydrogen pressure at 25atm. Stir at room temperature for about 5 minutes to fully dissolve the catalyst, release hydrogen under reduced pressure, and then add dissolved compound 3 (3.57g, 10mmol) i PrOH solution 22mL O t Bu's i PrOH solution (0.2 mmol / mL, 5.0 mL. 1.0 mmol). After the addition is complete, the hydrogen is replaced again and the initial hydrogen pressure is 30 atm, and the reaction is carried out under electromagnetic stirring at room temperature for 3 hours until the hydrogen pressure does not drop. The remaining hydrogen was released under reduced pressure, the inner tube was taken out, the solvent was spin-dried, water was added, ext...

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Abstract

The invention relates to an asymmetric synthesis method for galanthamine and lycoramine. The method adopts alpha-aryloxy substituted Cyclohexanedione monoethylene acetal as raw material and carries out asymmetric catalytic hydrogenation, oxidation, reductive Heck reaction and other a plurality of reaction steps to synthesize chiral medicines galanthamine (shown in structural formula I) and lycoramine (shown in structural formula II). The synthesis method of the invention has the advantages that the steps are simple, the yield is high, the cost is low, and optically active product can be directly obtained. The synthesis method of the invention is suitable for large-scale production of chiral medicines galanthamine and lycoramine.

Description

technical field [0001] The invention relates to an asymmetric synthesis method of natural products with complex structures, in particular to an asymmetric synthesis method of chiral drugs galantamine and ricolamine. Background technique [0002] Galanthamine is a biologically active tetracyclic alkaloid isolated from Amaryllidaceae plants such as Lycoris, daffodils, snowdrops, etc. Naturally extracted galantamine is a chiral compound with levorotatory optical properties. It is a highly selective and potent reversible acetylcholinesterase inhibitor, and has a good effect on the conformation of neuronal nicotinic receptors. Regulatory effect. It has the advantages of easy tolerability and no liver toxicity. It is widely used clinically in the treatment of diseases such as Alzheimer's disease and myasthenia gravis, and the application prospect is very broad (Razay, G.; Wilcock, G.K. Expert Rev.Neurother.2008, 8, 9; Yano, K.; Koda, K .; Ago, Y.; et al. Br. J. Pharmacol. 2009,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/107
Inventor 周其林谢建华陈继强王立新
Owner NANKAI UNIV
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