Synthesis method for preparing huperzine A intermediate

A synthesis method and technology of huperzine A are applied in the field of intermediate synthesis, can solve the problems of large amount of methyl propiolate, harsh synthesis method conditions, and high synthesis reaction cost, and achieve convenient purification, few reaction steps, and memory. Barrier improvement effect

Active Publication Date: 2014-11-19
ZHEJIANG WANBANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthetic method of this technique is that yield is higher in all known routes, and the synthetic method of reaction condition is relatively gentle. But still there are following disadvantages: the second step prepares compound 5, and the methyl propiolate consumption is too large, and the cost is high and highly allergic
[0013] The conditions of the synthetic method of the above-mentioned process are harsh, the cost of the synthetic reaction is high, the yield is low, and the environmental pollution is serious

Method used

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  • Synthesis method for preparing huperzine A intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation process of 7-((dimethylamino)methenyl)-1,4-cyclohexanedione monoethylene glycol ketal is:

[0025] Add the compound 1,4-cyclohexanedione monoethylene ketal (15.6 g, 0.1 mol) and N,N-dimethylformamide dimethyl acetal (50 mL, 0.38 mol) to the In a 100ml three-necked bottle. The reaction solution was stirred at 100°C for 24 hours. The reaction liquid was directly spin-dried to obtain compound 7-((dimethylamino)methenyl)-1,4-cyclohexanedione monoethylene glycol ketal (20 g, yield 95%) as a brown liquid, Used directly in the next step.

[0026] The reaction equation is: .

[0027] 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (s, 1H), 4.03 – 4.01 (m, 4H), 3.09 (s, 6H), 2.94 (s, 2H), 2.55-2.51 (t, J = 7.0 Hz, 2H), 1.99-1.95 ( t, J = 7.0 Hz, 2H).

Embodiment 2

[0029] The preparation process of 2-carbonyl-6-ethylene ketal-5,7,8-dihydro-3-quinolinecarboxylic acid methyl ester is:

[0030] Mix 7-((dimethylamino)methenyl)-1,4-cyclohexanedione monoethylene glycol ketal (10.6 g, 0.05 mol) and methyl cyanoacetate (24.8 g, 0.25 mol) at room temperature , Methanol (80 mL) was added to a 250-mL three-necked flask, protected by nitrogen. The reaction solution was stirred for 24 hours under reflux conditions. Rotate directly to dry, pass through the column (dichloromethane (v) / methanol (v) = 15:1) to obtain the compound 2-carbonyl-6-ethylene ketal-5,7,8-dihydro-3-quinoline Yellow solid of methyl carboxylate (12 g, 91% yield).

[0031] The reaction equation is: .

[0032] m / z: 266 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 4.05-4.04 (m, 4H), 3.92 (s, 3H), 3.02-2.99 (t, J = 6.6 Hz, 2H), 2.81 (s, 2H), 2.00-1.97 ( t, J = 6.6 Hz, 2H).

Embodiment 3

[0034] The preparation method of 2-carbonyl-6-ethylene ketal-5,7,8-dihydro-quinoline:

[0035] Combine 2-carbonyl-6-ethylene ketal-5,7,8-dihydro-3-quinolinecarboxylic acid methyl ester (5 g, 0.019 mol) and potassium hydroxide (3.2 g, 0.057 mol) at room temperature , Dioxane (50 mL) and water (10 mL) were added to a 100 mL three-necked flask, protected by nitrogen. The reaction solution was stirred for 24 hours under reflux conditions. After cooling, ethyl acetate (40 mL) was added to the reaction system. The organic phase was dried with anhydrous sodium sulfate, spin-dried, and passed through a column (dichloromethane (v) / methanol (v) = 15:1) to obtain the compound 2-carbonyl-6-ethylene ketal-5,7,8 -Dihydro-quinoline (3 g, 77% yield) as a white solid.

[0036] The reaction equation is: .

[0037] m / z: 208 (M+H) + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.42 (brs, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.12 (d, J = 9.2 Hz, 1H), 3.92-3.91 (m, 4H), 2.62-2.57 (m, 4H) , 1.82-1.79 (t, J = 6.6 Hz, ...

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Abstract

The invention discloses a synthesis method for preparing a huperzine A intermediate, which comprises the following steps: carrying out substitution at the alpha site of the carbonylic group by using 1,4-cyclohexyl diketone ethylene glycol and N,N-dimethylformamide dimethyl acetal as raw materials to obtain a substitution product, cyclizing the substitution product under the action of methyl cyanoacetate to obtain a cyclization product, and decarboxylating the cyclization product under the action of a strong base to obtain 2-carbonyl-6-ethylene ketal-5,7,8-dihydro-quinoline. The method has the advantages of fewer synthesis reaction steps, mild reaction conditions, low requirements for operating personnel and low environmental pollution, greatly lowers the raw material cost, and is simple to operate and convenient for refinement; and the obtained 2-carbonyl-6-ethylene ketal-5,7,8-dihydro-quinoline has high quality and high yield.

Description

Technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a method for synthesizing an intermediate for preparing Huperzine A. Background technique [0002] Huperzine A, the trade name is Haberin or Shuangyiping, is an alkaloid isolated from the Lycopodium plant Melaleuca, first discovered by Chinese scientists in the 1980s. It is a highly effective reversible acetylcholinesterase inhibitor with high selectivity, high fat solubility, long action time, easy passage through the blood-brain barrier, high oral bioavailability and few adverse reactions. By selectively inhibiting the activity of acetylcholinesterase and reducing the decomposition of acetylcholine, it can compensate for the acetylcholine neurotransmitter defect in the brain of Alzheimer's disease (AD) patients, thereby improving the memory, cognitive and behavioral functions of the patients, and enhancing learning Memory function and improvement of spatial memory disorde...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/113
CPCC07D491/113
Inventor 张凯
Owner ZHEJIANG WANBANG PHARMA
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