Asymmetric synthesis for chiral huperzine A

A huperzine A, asymmetric technology, applied in the field of organic synthesis of natural products, can solve the problems of low yield, large amount of -8-phenylmenthol, lengthy reaction steps, etc.

Inactive Publication Date: 2008-12-31
京山瑞生制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method (-)-8-phenylmenthol consumption is relatively large and the reaction steps are lengthy, and the productive rate is low

Method used

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  • Asymmetric synthesis for chiral huperzine A
  • Asymmetric synthesis for chiral huperzine A
  • Asymmetric synthesis for chiral huperzine A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1. Synthesis of intermediate β-ketoesters

[0017] Step 1, synthetic pyridone (2)

[0018] To a solution of 300 g (1.9 mol) of 1,4-dihydrospiro[4,5]-8-decanone dissolved in 6 L of ammonia-saturated methanol was added 320 g (3.8 mol) of methyl propiolate. The reaction mixture was heated to reflux at 100 °C for 10 h, and the internal pressure of the material reached a maximum of 200 psi. After cooling, the solvent was removed under reduced pressure to obtain 294 g of crude pyridone (2), a pale yellow solid. mp about 250°C.

[0019] Step 2, Synthesis of 7,8-dihydro-2-methoxyspiro[1,3-dioxolane-2,6(5H)-quinazoline (3)

[0020] At room temperature, under dark, crude product (2) and Ag 2 CO 3 867g (3.14mol) and 980ml (15.7mol) of methyl iodide dissolved in 20L of chloroform were mixed and stirred overnight. Filtration, concentration, and purification by dynamic axial compression chromatography (DAC) (40% ethyl acetate / hexanes) afforded ketal (3) 257 g (74%). m...

Embodiment 2

[0023] The synthesis of embodiment 2.(-)-huperzine A

[0024] Step 1, Synthesis of methyl 7,8,9,10-tetrahydro-8-hydroxyl-2-methoxy-7-methyl-11-oxo-5,9-methylene ring aryl octapyridine-5 (6H)-Carboxylate (5)

[0025] At -10°C, under nitrogen protection, 88 μl (1.0 mmol) of methacrolein (1.0 mmol) and ( -)-cinchonidine 31.0 mg (0.10 mmol). The mixture was stirred at -10°C for 253h. After concentration under reduced pressure, the residue was purified by dynamic axial compression chromatography (DAC) (hexane / ethyl acetate, 3 / 2) to give (5) 14.6 mg (45%), a colorless oil (containing at least 3 diastereoisomers in a ratio of 10:7:1).

[0026] Step 2, synthesis of methyl 7,8,9,10-tetrahydro-8-methanesulfonyloxy-2-methoxy-7-methyl-11-oxo-5,9-methylenecycloaryl octane Pyridine-5(6hydro)-carboxylate (6)

[0027] At 0°C, under nitrogen protection, add 70 μl (0.50 mmol) of triethylamine (0.50 mmol) and 5.0 mg (41 μmol) of DMAP and 15 μl (0.19 mmol) of methanesulfonyl chloride (5) in...

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Abstract

Disclosed is an asymmetric total-synthesis method for chiral huperzine a. The method takes 1,4-dihydro-spiro (4,5) -8 -decanone as starting material to get benzoate through hydroxymethylation and the treatment of benzoyl chloride and K2CO3; the benzoate is reacted with hydrogen sulfate O-methyl iso urea to get quinazoline; after the ketal is eliminated, Mander reagent is used for methyl esterification reaction so as to obtain beta-keto ester. Chiral ammonia, such as cinchona alkaloid, is used to promote the tandem asymmetric Michael addition/aldol condensation reaction of beta-keto esters and methyl acrolein. The compound carboxylate of diastereoisomer is reacted with MsCl, triethylamine and DMAP to get transformed. Through TMSI and MeOH processing, the protective group is removed so as to obtain optically pure-chiral huperzine a.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis of natural products, in particular to a production method of (-)-huperzine A. Background of the invention [0002] Huperzine A [(-)-Huperzine A, 1] is an alkaloid with a new structure isolated from the phenolic part of the Lycopodium plant Melaleuca [Huperzia serrata (Thunb) Trev.], which is a powerful , Specific, reversible and highly selective inhibitor of acetylcholinesterase (AchE). It is mainly used clinically for the treatment of myasthenia gravis, which can improve senile memory loss, and can significantly improve the memory, cognitive and behavioral functions of patients with Alzheimer's disease (AD), and no obvious adverse effects have been found reaction. Pharmacological experiments show that the inhibitory effect of huperzine A on acetylcholinesterase in vitro is 3 times that of physostigmine and 30 times that of galantamine. [0003] The present invention relates to a kind...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/22C07B53/00
CPCY02P20/55
Inventor 阎家麒
Owner 京山瑞生制药有限公司
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