Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine

A technology of ester physostigmine and oxygen physostigmine, which is applied in the field of synthesis of natural drug physostigmine and its derivative anicarbamate physostigmine for anti-senile dementia, can solve the problem of bioavailability Low, narrow therapeutic window, short action time of physostigmine, etc.

Inactive Publication Date: 2008-02-13
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it has been found in clinical studies that physostigmine has a short duration of action, low bioavailability, and a narrow therapeutic window (Al-Jafari, A.; Kamal, M.A.; Greig, N.H.; Alhomida, A.S.; Perry, E.R. Biochem. Biophys. Res.Commun.1998, 248, 180), which greatly limits the clinical use of physostigmine

Method used

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  • Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine
  • Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine
  • Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Implementation Example 1 Preparation of Compound 5

[0019]

[0020] Add metal Na (3.5g, 0.15mol) into 150mL liquid ammonia, stir at -60°C until the metal Na completely disappears, add L-tryptophan 3 (20.4g, 0.1mol), stir at -60°C After 15 minutes, MeI (14.2 g, 0.1 mol) was slowly added dropwise, and after stirring at -60° C. for 2 h, the reaction solution was naturally warmed to room temperature. 100 mL of water was added to dissolve the reaction solution, and the pH was adjusted to 5 with glacial acetic acid. A large amount of white solids were precipitated, and the solids were filtered to obtain 20.1 g of crude compound 4. The crude product was dissolved in 150 mL of dry THF, and LiAlH was slowly added in batches under ice-water bath conditions. 4 (5.2g, 0.14mol), after the addition was complete, the reaction solution was stirred at room temperature for 0.5h. Add saturated Na 2 SO 4 solution until the white precipitate no longer increases. Remove the precipit...

Embodiment 2

[0021] Implementation Example 2 Preparation of Compound 6

[0022]

[0023] Compounds 6a and 6b were prepared by using compound 5 as a raw material according to the literature method, through intermolecular asymmetric cyclopropanation-ring-opening-ring and three-step one-pot waterfall reaction, and reacting with diazoacetate to prepare (Qin, Y.et al. Org. Lett. 2006, 8, 2187). 6a: [α] 20 D =-175° (c1.0, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ7.15(td, J=7.6, 1.2Hz, 1H), 7.08(dd, J=7.6, 0.8Hz, 1H), 6.69(td, J=7.6, 0.8Hz, 1H), 6.42(d, J =8.0Hz, 1H), 5.38(s, 1H), 4.40(t, J=8.0Hz, 1H), 4.09-4.19(m, 3H), 3.74-3.77(m, 1H), 2.92(s, 3H) , 2.80(d, J=16.0Hz, 1H), 2.74(d, J=15.6Hz, 1H), 2.56(dd, J=12.0, 5.2Hz, 1H), 2.05(t, J=6.8Hz, 1H) , 1.21(t, J=7.6Hz, 3H)ppm.

[0024] 6b: [α] 20 D =-150°(c1.0, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ7.16(td, J=7.6, 1.2Hz, 1H), 7.10(dd, J=7.2, 0.8Hz, 1H), 6.70(td, J=7.6, 1.2Hz, 1H), 6.43(d, J =7.6Hz, 1H), 5.41(s, 1H), 4.41(t, J=8.0Hz, 1H), 4.1...

Embodiment 3

[0025] Implementation Example 3 Preparation of Compound 7

[0026]

[0027] 6a: R=Et7

[0028] 6b: R = t Bu

[0029] LiAlH 4 (2.5g, 64mmol) was added to 50mL of dry ethylene glycol dimethyl ether solution, and after refluxing for 5 minutes, compound 6a (5.0g, 16mmol) or 6b (5.7g, 16mmol) was dissolved in 100mL of ethylene glycol dimethyl ether The solution was slowly added dropwise into the reaction solution, and after the dropwise addition was completed, it was refluxed for 10 minutes. After the reaction solution was cooled to room temperature, saturated Na 2 SO 4 solution until the white precipitate no longer increases. Remove the precipitate by filtration, wash the filter cake with 200 mL of ethyl acetate, combine the filtrate, separate the organic layer, extract the aqueous phase with ethyl acetate (3 × 100 mL), combine the organic phase, anhydrous Na 2 SO 4 Dry, filter, evaporate the solvent under reduced pressure, and the crude product is separated and purified...

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Abstract

The invention belongs to the field of drug synthesis, and relates to a new method for synthesizing physostigmine, a natural drug against senile dementia, and its derivative, anilinoformate, phenserine. The present invention uses L-tryptophan 3 as raw material, firstly prepares chiral oxazolone intermediate 5, and then through intermolecular asymmetric cyclopropionation-ring-opening-ring and three-step one-pot waterfall reaction, and diazonium Acetate reaction was prepared to obtain optically pure 3-substituted tetrahydropyrroloindole skeleton 6, which was reduced by lithium aluminum hydride to obtain diol-substituted intermediate 7, and intermediate 7 was treated with Raney nickel (Raney-Ni ) after removing the hydroxymethylene group to obtain the intermediate 8 deoxy physostigmine (desoxyeseroline), and the intermediate 8 is obtained by electrophilic bromination reaction, methyl etherification, demethylation and carbonamidation four-step reaction with high yield. Completed the synthesis of physostigmine and its derivative, anilinoformate, physostigmine, a natural drug against Alzheimer's disease. The method has the advantages of high key reaction yield, simple operation, short reaction steps, etc., and has the advantages of solving the problem of raw material source of the marketed drug physostigmine and its derivative anilinoformate phenserine. important practical significance.

Description

technical field [0001] Due to the limited sources of natural medicines, their prices are often high and the work of using them as parent compounds for drug substitution and transformation is limited. Therefore, how to economically and effectively synthesize natural medicines with limited sources has always been one of the important areas of medicinal chemistry research. one. Most of the indole alkaloids with tetrahydropyrroloindole skeletons have important physiological activities, and some of them have been successfully used in clinical treatment. How to synthesize such alkaloids and their analogs economically and effectively is crucial for the development of them Potential medicinal value, especially the source of raw materials for drugs that have been marketed and drugs that are about to be marketed, has important practical significance. The invention relates to a novel method for synthesizing the natural drug physostigmine and its derivative anicarbamate physostigmine wit...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 秦勇宋颢王浩蔚何彬
Owner SICHUAN UNIV
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