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Novel method for splitting and producing natural (-)-huperzine and non- natural (+)-huperzine by racemate of diastereoisomer salt

A technology of diastereomer and huperzine A, applied in the field of medicinal chemistry, can solve the problems of expensive optically active natural products and the like

Inactive Publication Date: 2008-02-27
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the preparation of a large amount of optically active natural products by Mosher esters is very expensive, and the separation of Mosher esters by column chromatography is limited to the preparation of enantio-pure products in small quantities in the laboratory.

Method used

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  • Novel method for splitting and producing natural (-)-huperzine and non- natural (+)-huperzine by racemate of diastereoisomer salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] According to the synthetic route steps of racemic huperzine A, starting from β-ketoester 2, the racemic compound (±)-5 was prepared.

Embodiment 2

[0027] Dissolve 0.314g (1mmol) (±)-5 in a mixed solvent of 40ml tetrahydrofuran and 50ml methanol, add 10.18g NaOH and 50ml distilled water, heat to reflux, cool, evaporate the solvent under reduced pressure, add 100ml distilled water, NaCl saturated aqueous phase , extracted with 6×25ml chloroform, combined the organic phases, and dried over anhydrous potassium carbonate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.240 g of product (±)-6, with a yield of 94%, as a yellow oil.

Embodiment 3

[0029] Add 0.358g (1mmol) (-)-2,3-dibenzoyl-L-tartaric acid to 0.256g (1mmol) (±)-6, add an appropriate amount of ethanol, heat to dissolve all, drain the solvent, add acetone, Heating to boiling, crystallization after cooling. Suction filtration to obtain a white solid. After recrystallization, about 0.100 g of white solid was obtained, mp: 170-171°C, and the yield was 16.2%.

[0030] Free with NaOH, and saturated aqueous phase with NaCl, proper amount of CHCl 3 Extraction, combined organic phase, anhydrous K 2 CO 3 dry. Filter and concentrate to get (-)-60.040g, [a] D 20 =-59.5° (c=0.5, CHCl 3 ) by chiral high-pressure liquid phase detection (CHIRALCEL OD-RH, 280nm detection, 0.32ml / min, acetonitrile / water=8 / 2), the enantiomeric excess value almost reaches 100%.

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Abstract

The invention discloses a new making method of (-)-Huperzine and non-natural Huperzine detached from racemate of diastereoisomer salt, which comprises the following steps: forming diastereoisomer salt through chemically synthesized racemic O-methyl-Huperzine and (-)-2,3-dibenzoyl-L-tartaric acid to form diastereoisomer salt; recrystallizing and purifying through organic solvent; obtaining the needed pure diastereoisomer salt; obtaining (-)-O-methyl-Huperzine after liberating; obtaining the product through deprotecting reaction; using (+)-2,3-dibenzoyl-D-tartaric acid as antimorph of acid detaching agent to make the non-natural (+)-Huperzine through the same steps.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more specifically to a new method for preparing natural (-)-huperzine A and non-natural (+)-huperzine A through the racemate resolution of diastereomer salts . Background technique [0002] Natural (-)-Huperzine A (Huperzine A) is a chiral alkaloid, its chemical name: (5R, 9R, 11E)-5-amino-11-ethylene-5,6,9,10-tetra Hydrogen-7-methyl-5,9-methylene ring aryl octane-2(1H)-pyridone, it was in the mid-1980s, Chinese scientific and technological personnel from the Chinese herbal medicine Lycopodium melaleuca, and A novel alkaloid obtained from the phenolic part of the famous snake foot grass [Huperzia serrata (Thunb) Thev.]. Pharmacological studies have shown that natural (-)-huperzine A is a highly active and reversible acetylcholinesterase inhibitor. At present, natural (-)-huperzine A has been sold in the United States as a health product to improve memory function; in China it has bee...

Claims

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Application Information

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IPC IPC(8): C07D221/22
Inventor 何煦昌白东鲁齐创宇
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI