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

A technology of phenol phenyl carbamate and physostigmine, which is applied in the field of synthesis of natural medicine physostigmine and its derivative anicarbamate physostigmine for anti-senile dementia, and can solve the problem of physostigmine Problems such as short action time, limited use of physostigmine, and low bioavailability

Inactive Publication Date: 2010-07-28
SICHUAN UNIV
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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

[0014] The preparation of embodiment 1 compound 5

[0015]

[0016] 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 precipitate by f...

Embodiment 2

[0017] The preparation of embodiment 2 compound 6

[0018]

[0019] 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° (c 1.0, 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.

[0020] 6b: [α] 20 D = -150° (c 1.0, 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), 4.18(dd,...

Embodiment 3

[0021] The preparation of implementation example 3 compound 7

[0022]

[0023] 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 by silica gel column (CH 2 Cl 2 :MeO...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention belongs to the field of the drug synthesis, relating to the novel synthesis method of the natural drug physostigmine preventing the disease of Alzheimer and the derivatives aniline formic ester phenserine. In the invention, the L-tryptophan 3 is used as the raw material; first the chiral oxazolone intermediate 5 is made; then through the three-step and one-pot chute-typed reaction between the molecules of the asymmetric cyproterone, opening of the ring and cyclization, the intermediate 5 reacts with the diazo acetate ester to prepare the optically pure 3-substituted tetrahydropyrrole indole skeleton 6; the skeleton is deoxidized by the tetra-lithium aluminum hydride to get the diol substituted intermediate 7; the intermediate 7 is doffed from the hydroxy-methyl by the Raney-Ni to get the intermediate 8 desoxyeseroline; the intermediate 8 finishes the synthesis of the physostigmine preventing the disease of Alzheimer and derivatives aniline formic ester phenserine, after the bromination, the methyl-etherification, the doffing of the methyl and the carbonylation reactions. The method has the advantages of the high collection rate of the key reactions, the simple operation, and the short reaction steps and so on; and the method has the important practical significance for the solution of the sources of the raw materials of the drug physostigmine and the derivatives aniline formic ester phenserine in the market.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 秦勇宋颢王浩蔚何彬
Owner SICHUAN UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap