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Synthesis method of rivastigmine optical isomerization intermediate and (R)-rivastigmine

A technology of optical isomerization and synthesis method, which is applied in the field of chiral drug synthesis in pharmaceutical and chemical industry, which can solve the problems of long synthesis route, low total yield, unfriendliness, etc., and achieve the effect of short synthesis steps

Inactive Publication Date: 2020-01-10
SHANDONG NORMAL UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, even if the method of resolution can be used to obtain the rivastigmine of the R configuration, the reagents used are relatively cheap, but the highest yield is only 50%, so the yield will be low, thus increasing the cost of preparation, while not Future Development Needs for Atom Economy
[0009] In 2018, the chemical synthesis method of R-configuration rivastigmine was reported in the literature. The researchers obtained the chiral hydroxyl intermediate by-products that can synthesize S-configuration rivastigmine by enzyme-catalyzed resolution, and then obtained the R-configuration rivastigmine, but this synthetic route has a long synthetic route, and the total yield is low, and these reagents (Chemistry Select. 2018, 3, 1385)

Method used

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  • Synthesis method of rivastigmine optical isomerization intermediate and (R)-rivastigmine
  • Synthesis method of rivastigmine optical isomerization intermediate and (R)-rivastigmine
  • Synthesis method of rivastigmine optical isomerization intermediate and (R)-rivastigmine

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Embodiment approach

[0029] A typical embodiment of the present disclosure provides a method for synthesizing the optical isomerization intermediate of rivastigmine, which is catalyzed by 3-nitromethyl ethyl formate acetophenone and benzhydrylamine under the catalysis of Ir complex Obtained by asymmetric reductive amination reaction;

[0030] The chemical structural formula of 3-nitromethyl ethyl formate acetophenone (compound 1) is:

[0031] The chemical structural formula of rivastigmine optical isomerism intermediate (compound 2) is:

[0032] The chemical structural formula of the Ir complex is:

[0033]

[0034] The present disclosure finds through experiments that the optical isomerization intermediate of rivastigmine can be prepared by using the above-mentioned Ir complex, which has the advantages of high selectivity and high yield.

[0035] In one or more examples of this embodiment, the step of asymmetric reductive amination reaction is: adding organic acid, titanic acid to 3-nitr...

Embodiment 1

[0075] (1) Synthesis of N-methylethyl (3-acetylphenyl) carbamate (compound 1):

[0076] Add pretreated 100mL of anhydrous dichloromethane into a 250mL three-necked flask, add 10g of 3-hydroxyacetophenone and 15g of methyl ethyl carbamoyl chloride in turn under stirring, then add 10g of finely ground anhydrous sodium carbonate in batches, and finish adding Afterwards, the temperature was raised to 40°C until TLC showed that the 3-hydroxyacetophenone point basically disappeared (developing agent: PE / EA=4 / 1, and the reaction took about 8 hours). After removing the solvent, N-methylethyl(3-acetylphenyl)carbamate was obtained as light yellow oil (based on 3-hydroxyacetophenone, the yield was 99%).

[0077] (2) Synthesis of (R)-3-(1-(phenylamino)ethyl)phenylethyl (methyl)carbamate (compound 2):

[0078] Add 10mL of pre-anhydrous dichloromethane to the 25mL single-necked bottle, add 221mg N-methylethyl (3-acetylphenyl) carbamate and 240mg benzhydrylamine successively under stirring,...

Embodiment 2

[0084] (1) Synthesis of N-methylethyl (3-acetylphenyl) carbamate (compound 1):

[0085] Add 100mL of pretreated anhydrous toluene into a 250mL three-necked flask, add 10g of 3-hydroxyacetophenone and 15g of methyl ethyl carbamoyl chloride in turn under stirring, and then add 10g of finely ground anhydrous sodium bicarbonate in batches, after the addition Raise the temperature to 80°C and react until TLC shows that the 3-hydroxyacetophenone point basically disappears (developer: PE / EA=4 / 1, the reaction takes about 6 hours), the reaction solution is cooled to room temperature and filtered, and the filtrate is evaporated under reduced pressure After solvent, N-methylethyl (3-acetylphenyl) carbamate was obtained as light yellow oil (based on 3-hydroxyacetophenone, the yield was 98%).

[0086] (2) Synthesis of (R)-3-(1-(phenylamino)ethyl)phenylethyl(methyl)carbamate (compound 2)

[0087] Add 10mL of pre-anhydrous dichloromethane to the 25mL single-necked bottle, add 221mg N-methyl...

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Abstract

The invention provides a synthesis method of a rivastigmine optical isomerization intermediate and (R)-rivastigmine. The method comprises the following steps: carrying out an asymmetric reductive amination reaction on 3-nitromethyl ethyl formate acetophenone and diphenyl methylamine under the catalysis of an Ir complex to obtain the rivastigmine optical isomerization intermediate, carrying out a metal debenzylation catalysis reaction on the rivastigmine optical isomerization intermediate in a hydrogen atmosphere to obtain a compound 3, and carrying out an Eschweiler-Clarke methylation reactionon the compound 3 and formaldehyde to obtain the (R)-rivastigmine. The synthesis method of the (R)-rivastigmine has the advantages of short synthetic steps, high yield, high efficiency, economical property, practicability, environmental friendliness and good atom economy.

Description

technical field [0001] The disclosure belongs to the technical field of chiral drug synthesis in pharmaceutical chemical industry, and relates to a synthesis method of rivastigmine optical isomerization intermediates and (R)-rivastigmine. Background technique [0002] The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. [0003] Alzheimer's Disease (AD for short) is a degenerative disease of the central nervous system with a complex pathogenic mechanism. Personality abnormalities and marked deterioration of life skills occur. The pathological features are mainly changes of extracellular senile plaques (SP) and neurofibrillary tangles (NFT) in nerve cells, as well as neuron loss with glial cell proliferation. [0004] The new anti-senile dementia drug rivastigmine (Rivastigmine) developed by Swiss Novartis company, the chemical name is (S)-N-ethyl-3-[(1-dimethylamino)acetyl]-N-methylcarba...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/44
CPCC07B2200/07C07C269/06C07C271/44
Inventor 高国锐马瑜吕蒙蒙杨会乾杨帆李朝
Owner SHANDONG NORMAL UNIV
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