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Synthetic method of rivastigmine and intermediates thereof

A technology of rivastigmine tartrate and compounds, which is applied in the field of anti-senile dementia drugs, can solve the problems of complex operation, low yield, and many by-products, and achieve the effects of simple and safe operation, simple process operation, and few reaction by-products

Active Publication Date: 2010-09-08
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method A needs to use hydrobromic acid or concentrated sulfuric acid for demethylation reaction, and hydrobromic acid or concentrated sulfuric acid is very corrosive, which is not conducive to industrial production; method B is synthesized by three-step reaction to obtain tertiary amine, which is complicated to operate and has a long synthesis cycle , high cost, poor selectivity, more by-products generated, so that the total yield is low, about 18%
Method C is relatively better, but there are still disadvantages that the product is not easy to purify and the yield is low
More importantly, the existing synthetic intermediate 3-(1-(dimethylamino) ethyl) phenol method all has the following defects: 3-(1-(dimethylamino) ethyl) phenol is Amphoteric compounds have a certain solubility in acidic or alkaline solutions, and the 3-(1-(dimethylamino) ethyl) phenol product obtained by the existing synthetic method needs to be released under acidic conditions. It is very difficult to adjust the equivalence point in production, so the operation is not easy to carry out, and the production efficiency is not high.
The second type of method, the asymmetric synthesis method, requires the use of relatively expensive catalysts, and these catalysts are also likely to cause the heavy metal content of the final product to exceed the standard

Method used

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  • Synthetic method of rivastigmine and intermediates thereof
  • Synthetic method of rivastigmine and intermediates thereof
  • Synthetic method of rivastigmine and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 Preparation of [1-(3-benzyloxy-phenyl)-ethyl]-dimethylamine (II)

[0033] (1) Preparation of 3-benzyloxyacetophenone (IV)

[0034] Add 3-hydroxyacetophenone (20g, 0.15mol) and 80ml of dimethylformamide into a 250ml reaction bottle, start stirring, after dissolving, add potassium carbonate (0.22mol), heat the oil bath to about 70°C, start Benzyl chloride (19.4g, 0.15mol) was added dropwise, and the temperature was controlled at 70-80°C during the dropwise addition. Acetone:cyclohexane=1:1 (v / v), ultraviolet color development), start to subtract the solvent, add 100ml water and 50ml ethyl acetate to the residual liquid, stir fully to separate the organic layer, and then use 50ml acetic acid to separate the water layer Extract once with ethyl ester, combine the organic layers, wash with 50ml of water × 3 times, add anhydrous magnesium sulfate to dry, evaporate the solvent to obtain the target product 3-benzyloxyacetophenone (30g), the yield is 93%. 1 H-NMR, MS ...

Embodiment 2

[0041] Example 2 Preparation of [1-(3-benzyloxy-phenyl)-ethyl]-dimethylamine (II)

[0042] (1) Preparation of 3-benzyloxyacetophenone (IV)

[0043] Add 3-hydroxyacetophenone (20g, 0.15mol) and 70ml of dichloroethane into a 250ml reaction bottle, start stirring, after dissolving, add potassium carbonate (0.22mol), heat the oil bath to about 50°C, and start dripping Add benzyl chloride (19.4g, 0.15mol), and control the temperature at 50-60°C during the dropwise addition process. After the dropwise addition, continue to keep warm at about 60°C for about 24 hours. : Cyclohexane=1:1 (v / v), ultraviolet color development), began to subtract the solvent, added 100ml water and 50ml ethyl acetate in the residual liquid, stirred fully to separate the organic layer, and then washed the water layer with 50ml ethyl acetate The ester was extracted once, the organic layers were combined, washed with 50ml of water × 3 times, dried by adding anhydrous magnesium sulfate, and the solvent was eva...

Embodiment 3

[0050] Example 3 Preparation of [1-(3-benzyloxy-phenyl)-ethyl]-dimethylamine (II)

[0051] (1) Preparation of 3-benzyloxyacetophenone (IV)

[0052] Add 3-hydroxyacetophenone (20g, 0.15mol) and 80ml toluene into a 250ml reaction bottle, start stirring, after dissolving, add sodium carbonate (36.3, 0.22mol), heat the oil bath to about 80°C, and start adding dropwise Benzyl chloride (19.4g, 0.15mol), the temperature is controlled at 80-90°C during the dropwise addition, and after the dropwise addition, continue to insulate and react at about 90°C for about 20 hours. Cyclohexane=1:1 (v / v), ultraviolet color development), start to subtract the solvent, add 100ml water and 50ml ethyl acetate to the residual liquid, stir fully to separate the organic layer, and then use 50ml ethyl acetate Extract once, combine the organic layers, wash with 50ml of water × 3 times, add anhydrous magnesium sulfate to dry, evaporate the solvent to obtain the target product 3-benzyloxyacetophenone (32.3...

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Abstract

The invention relates to a preparation method of rivastigmine tartrate and intermediates thereof, which comprises the steps of carrying out reductive amination on 3-benzyloxy acetophenone and dimethyl for obtaining a (1-(3-benzyloxy-phenyl)-ethyl)-dimethylamine (II) compound, removing benzyl with hydrogenated amine, obtaining 3-(1-(dimethylamino) ethyl) phenol (V), further carrying out condensation reaction with N-methyl-N-ethyl carbamoyl chloride, resolving a rivastigmine racemate with D-(+)-p-methyl dibenzoyl tartaric acid, and further salifying with L-(+)-tartaric acid for obtaining the rivastigmine tartrate (I). The method has the advantages of cheap price and easy obtainment of raw materials, short synthetic route, few reaction steps, mild reaction conditions and easy separation and purification of all the intermediates, thereby being applicable to industrial production.

Description

technical field [0001] The present invention relates to anti-senile dementia medicine rivastigmine tartrate (rivastigmine tartrate) and its intermediate preparation method and the intermediate. Background technique [0002] Rivastigmine tartrate, chemical name (S)-N-ethyl-N-methylcarbamate-3-[(1-dimethylamino)ethyl]phenyl tartrate, is an acetylcholinesterase inhibitor (AchEI), for the treatment of mild and moderate Alzheimer's disease, has been used clinically for many years at home and abroad. Rivastigmine tartrate structure is shown in formula (I): [0003] [0004] There are two types of synthesis techniques for existing rivastigmine tartrate: the first type is to first synthesize the rivastigmine racemate, and then chirally split to obtain the target object; the second type is asymmetric synthesis, that is, the intermediate is manually Sexual resolution, followed by asymmetric synthesis to obtain the target compound. The first type of synthetic method generally all...

Claims

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Application Information

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IPC IPC(8): C07C217/58C07C215/50C07C213/02C07C271/44C07C269/00C07C59/255A61P25/28
CPCC07C217/58A61P25/28
Inventor 朱永超张桂森马彦琴杨相平周英珍陈亮
Owner NHWA PHARMA CORPORATION
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