Chiral intermediate of rivastigmine, and preparation method thereof

A chiral reagent, ethyl technology, applied in the field of rivastigmine chiral intermediate and preparation thereof, can solve problems such as unfavorable industrial production, immature method, low total yield, etc. The effect of reducing the burden of three waste treatment and reducing the loss of splitting

Active Publication Date: 2014-11-19
DALIAN WONDERSUN BIOCHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Disadvantages: asymmetric synthesis requires the use of relatively expensive catalysts, the cost is high, the current method is immature, and the technical operation is complicated, which is not conducive to industrial production;
[0017] Disadvantages: deprotection reaction is required, and the raw material of m-methoxyacetophenone is not supplied in large quantities in the Chinese market, and the cost is relatively high;
[0020] Disadvantages: tertiary amines are obtained through three-step synthesis, but hydrogenation and pressurization equipment is required, the synthesis cycle is long, the cost is high, the selectivity is poor, and the total yield is low;

Method used

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  • Chiral intermediate of rivastigmine, and preparation method thereof
  • Chiral intermediate of rivastigmine, and preparation method thereof
  • Chiral intermediate of rivastigmine, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047]1) In a 500 mL three-neck flask equipped with a thermometer, add 50 g of 3-hydroxyacetophenone and 100 mL of methanol into the flask, add 44.7 g of methylamine aqueous solution (28%) dropwise, stir for 3 h, and filter to obtain a yellow Solid 3-(1-methylimino)ethyl)phenol 41.1 g, yield 75%;

[0048]

[0049] 2) Add 45 g of the above-mentioned 3-(1-methylimino)ethyl)phenol into 500 mL of absolute ethanol, add 8.1 g of potassium borohydride solid at room temperature, and stir at 30°C for 2 h, HPLC detects that the reaction of 3-(1-methylimino)ethyl)phenol is complete, add 500 mL of water, filter out inorganic salts, concentrate absolute ethanol, add about 500 mL of water, stir for 3 h, and filter to obtain white Solid, dried to obtain 3-(1-methylamino)ethyl)phenol 34.2 g, yield 75%;

[0050]

[0051] 3) Add 30 g of 3-(1-methylamino)ethyl)phenol and 46 g of D-camphorsulfonic acid into 250 mL of tetrahydrofuran (in, heat to reflux, completely dissolve, slo...

Embodiment 2

[0055] 1) In a 500 mL three-neck flask equipped with a thermometer, add 50 g of 3-hydroxyacetophenone and 50 mL of isopropanol into the flask, add 48.8 g of methylamine aqueous solution (28%) dropwise, stir for 6 h, and filter Obtained 46.6 g of yellow solid 3-(1-methylimino)ethyl)phenol, with a yield of 85%;

[0056] 2) Add 45 g of the above-mentioned 3-(1-methylimino)ethyl)phenol into 600 mL of anhydrous methanol, control the temperature at 40 °C, add 11.4 g of sodium borohydride solid, and Stir at low temperature for 2 h, HPLC detects that the reaction of 3-(1-methylimino)ethyl)phenol is complete, add 300 mL of water, filter off inorganic salts, concentrate anhydrous methanol, add about 500 mL of water, and stir for 8 h. A white solid was obtained by filtration and dried to obtain 31.9 g of 3-(1-methylamino)ethyl)phenol, with a yield of 70%;

[0057] 3) Add 30 g of 3-(1-methylamino)ethyl)phenol and 29.7 g of d-tartaric acid into 150 mL of isopropanol, heat to reflux, disso...

Embodiment 3

[0060] 1) In a 500 mL three-neck flask equipped with a thermometer, add 50 g of 3-hydroxyacetophenone and 200 mL of ethanol into the flask, add 52.8 g of methylamine aqueous solution (28%) dropwise, stir for 9 h, and filter to obtain a yellow Solid 3-(1-methylimino)ethyl)phenol 43.9 g, the yield is 80%;

[0061] 2) Add 45 g of the above-mentioned 3-(1-methylimino)ethyl)phenol into 600 mL of anhydrous isooctyl alcohol, control the temperature at 50 °C, and add 15.2 g of solid sodium cyanoborohydride , stirred at 50°C for 6 h, HPLC detected that the reaction of 3-(1-methylimino)ethyl)phenol was complete, added 300 mL of water, filtered off inorganic salts, concentrated anhydrous isooctyl alcohol, and added about 500 mL water, stirred for 4 h, filtered to obtain a white solid, and dried to obtain 36.5 g of 3-(1-methylamino)ethyl)phenol, with a yield of 80%;

[0062] 3) Add 30 g of 3-(1-methylamino)ethyl)phenol and 30.2 g of D-mandelic acid into 300 mL of ethanol, heat to reflux,...

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PUM

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Abstract

The invention discloses a chiral intermediate of rivastigmine, and a preparation method thereof. The preparation method comprises the steps of preparing 3-[1-(methyllamino)ethyl]phenol through reacting a raw material of 3-hydroxyacetophenone with an methylamine water solution to form an imine and reducing the imine; carrying out resolution by using a chiral reagent to obtain a novel intermediate of (s)-3-[1-(methyllamino)ethyl]phenol of rivastigmine; and further loading methyl on basis of the intermediate to obtain an important intermediate of (S)-3-[1-(dimethyllamino)ethyl]phenol. Compared with a conventional synthetic method of (s)-rivastigmine, the preparation method provided by the invention has high resolution rate, low cost and small load for treatment of three wastes, has little pollution to an environment, and is beneficial to large-scale production.

Description

technical field [0001] The invention relates to a rivastigmine chiral intermediate and a preparation method thereof. Background technique [0002] Alzheimer's disease (AD), also known as senile dementia, is a complex degenerative disease of the central nervous system. Tangle, its clinical symptoms are mainly manifested in varying degrees of loss of memory and cognitive ability of patients, and disturbance of behavioral activities. Using acetylcholinesterase inhibitors to increase the choline content in the brain and strengthen the central choline function is the only effective way to treat AD. [0003] Rivastigmine has a carbamate structure and can be covalently combined with the active site of cholinesterase (AChE). It is a cholinesterase inhibitor and was officially approved by the US FDA in April 2000. It is used in the treatment of moderate and mild Alzheimer's disease, and (S)-rivastigmine has better activity and selectivity than the racemate. [0004] (S)- Structur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/50C07C213/10C07C213/02
Inventor 曾伟方典军李涛李珊珊
Owner DALIAN WONDERSUN BIOCHEM TECH
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