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Synthesis method of epinastine

A synthetic method, the technology of epinastine, applied in the field of new chemical synthesis, can solve the problems of unsuitability for industrial production and low reaction yield, and achieve the effects of low cost, high product purity, and simple route process

Active Publication Date: 2013-04-03
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although this route avoids the use of metal cyanides and ammoniating reagents, the reaction yield is still not high and is not suitable for industrial production

Method used

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  • Synthesis method of epinastine
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  • Synthesis method of epinastine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The synthetic method of embodiment 1 epinastine

[0046] Include the following steps:

[0047] (1), 2-benzylaniline ( Synthesis of Intermediate 3)

[0048] Dissolve 2-aminobenzophenone I (6.0g, 30.45mmol, raw material 1) in 55mL of trifluoroacetic acid, slowly add triethylsilane (10.5g, 90.5mmol) dropwise at 0°C, and move to room temperature after 30min React for 8 hours until the reaction is complete. Thin-layer chromatography (TLC) detects the end point of the reaction, and the ratio shift value Rf=0.5 [developing solvent: V (petroleum ether) / V (ethyl acetate)=20 / 1]. Remove the solvent trifluoroacetic acid under reduced pressure, add saturated potassium carbonate aqueous solution and ethyl acetate to separate the liquid, and extract the aqueous phase with ethyl acetate, then combine the organic phase, wash the organic phase with water, dry, and concentrate to obtain 3.0 g of a light brown solid, which is Intermediate 3 is subject to the next reaction, and the yie...

Embodiment 2

[0068] The synthetic method of embodiment 2 epinastine

[0069] Include the following steps:

[0070] (1), (2-aminophenyl) (phenyl) methanol ( Synthesis of Intermediate 2)

[0071] Dissolve 2-aminobenzophenone I (6.0 g, 30.45 mmol, raw material 1) in 40 mL of ethanol, add sodium borohydride (2.31 g, 60.9 mmol) in portions at 0°C, and then move to room temperature for 3 h until The response is complete. The end point of the reaction was detected by thin-layer chromatography (TLC), and the ratio shift value Rf=0.3 [developing solvent: V (petroleum ether) / V (ethyl acetate)=10:1]. Add a small amount of water dropwise to remove the remaining sodium borohydride, spin off the solvent ethanol under reduced pressure, add water and ethyl acetate to separate the liquid, and extract the aqueous phase with ethyl acetate, then combine the organic phase, wash the organic phase with water, dry, and concentrate to obtain a light yellow 6.1 g of the solid is intermediate 2, and the next st...

Embodiment 3

[0088] The synthetic method of embodiment 3 epinastine

[0089] Include the following steps:

[0090] (1), 2-benzylaniline ( Synthesis of Intermediate 3)

[0091] Dissolve 2-aminobenzophenone I (6.0g, 30.45mmol, raw material 1) in 40mL of acetic acid, slowly add trimethylsilane (6.79g, 91.5mmol) dropwise at 0°C, and continue to react at 0°C for 30min Moved to 40 ° C conditions for 6h until the reaction is complete. Thin-layer chromatography (TLC) detects the end point of the reaction, and the ratio shift value Rf=0.5 [developing solvent: V (petroleum ether) / V (ethyl acetate)=20:1]. Spin off the solvent acetic acid under reduced pressure, add saturated potassium carbonate aqueous solution and ethyl acetate to separate the liquid, extract the aqueous phase with ethyl acetate, combine the organic phase, wash the organic phase with water, dry and concentrate to obtain 2.6 g of a light brown solid, which is the intermediate 3. The next reaction is to be carried out, and the yi...

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Abstract

The invention discloses a synthesis method of epinastine. The synthesis method is implemented by taking 2-aminobenzophenone as a raw material and comprises the following steps of: reacting the 2-aminobenzophenone with a silane agent to obtain 2-benzylaniline; then, carrying out acylation reaction on the 2-benzylaniline and 2-chloroacetyl chloride to obtain N-(2-benzyl phenyl)-2-chloroacetamide; carrying out acidamide dehydration and cyclization on the N-(2-benzyl phenyl)-2-chloroacetamide under the action of a dehydrating agent to obtain 6-(chloromethyl)-11H-dibenzo[b,e] azepine; carrying out azidation reaction on the 6-(chloromethyl)-11H-dibenzo[b,e] azepine to obtain 6-(azido-methytbiphenyl)-11H-dibenzo[b,e] azepine; carrying out reduction on the 6-(azido-methytbiphenyl)-11H-dibenzo[b,e] azepine to obtain 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e] azepine; and finally, carrying out cyclization on the 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e] azepine and cyanogen bromide to obtain the epinastine. The synthesis method disclosed by the invention avoids the application of expensive and flammable lithium aluminium hydride and aluminium hydride as well as hypertoxic sodium cyanide, so that the operation is safer in industrial production, and the cost is reduced. The method is simple in process and high in yield, requires mild conditions, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of compounds, more specifically, the invention relates to a new chemical synthesis method of epinastine. Background technique [0002] Epinastine, chemically known as 3-amino-9,13b-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine, is a potent antihistamine medicine. Epinastine is suitable for skin allergic reactions, and has good curative effect on allergic rhinitis and allergic bronchial asthma. Wide range of clinical application departments. It has high selectivity and affinity for H1 receptors, and its anti-allergic effect is stronger than that of traditional drugs. With multiple anti-allergic mechanisms, it can eliminate allergic symptoms more thoroughly, take effect more quickly, and quickly relieve the pain of patients. It is a drug that is widely used and has a very promising development prospect. [0003] The synthetic method of the epinastine of present disclosed patent and literature d...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 蔡倩刘建光
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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