Synthesis method of epinastine

A synthesis method and the technology of Epilastine, applied in the field of medicinal chemistry, can solve the problems of high equipment requirements, unfavorable industrialization and the like

Pending Publication Date: 2022-08-02
重庆恩联生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This reduction method adopts hydrogenation reduction, which has high requirements on equipment and is a dangerous process, which is not conducive to industrialization.

Method used

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  • Synthesis method of epinastine
  • Synthesis method of epinastine
  • Synthesis method of epinastine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Step 1: Synthesis of (2-aminophenyl) (phenyl) methanol (compound II)

[0104] Add 60g of compound I 2-aminobenzophenone and 300g of 95% ethanol solution into the clean and anhydrous first reaction flask, then slowly add 6g of sodium borohydride into the first reaction flask, and add the solution in the first reaction flask to the first reaction flask. The temperature of the first reaction flask was slowly raised to 75~80℃ for 2.0h, and the temperature of the solution in the first reaction flask was 75~80℃ and the air pressure was -0.09MPa, which was concentrated to 95% ethanol in the solution in the first reaction flask. The solution was removed, 300 g of water was added to the concentrated first reaction flask while it was still hot, stirred for 1 h to reduce the temperature of the solution in the first reaction flask to 10-15 °C, suction filtration, and drying to obtain compound II. In one step, the molar yield of compound II was 99.81%, and the HPLC purity was 99.867...

Embodiment 2

[0120] Step 1: Synthesis of (2-aminophenyl) (phenyl) methanol (compound II)

[0121] The air pressure was -0.05MPa, and the rest was the same as that of step 1 in Example 1. The molar yield of compound II was 99.65%, and the HPLC purity was 99.923%.

[0122] Step 2: Synthesis of 2-benzylaniline (compound III)

[0123] The air pressure is -0.05MPa, and the rest are the same as the second step of the first embodiment.

[0124] Step 3: Synthesis of N-[2-(phenylmethyl)phenyl]-2-chloroacetamide (Compound IV)

[0125] The air pressure was -0.05MPa, and the rest were the same as in step 3 of Example 1. The molar yield of compound IV was 90.27%, and the HPLC purity was 99.176%.

[0126] Step 4: Synthesis of 6-Chloromethyl Morphenidine (Compound V)

[0127] The air pressure is -0.05MPa, and the rest are the same as in Step 4 of Example 1.

[0128] Step 5: Synthesis of 6-(phthalimidomethyl)-6,11-dihydro-dibenzo-[b,e]azepine (Compound VI)

[0129] Add 140g DMF, 63.8g potassium carbo...

Embodiment 3

[0136] Step 1: Synthesis of (2-aminophenyl) (phenyl) methanol (compound II)

[0137] The air pressure was -0.07MPa, and the rest was the same as that of step 1 in Example 1. The molar yield of compound II was 97.83%, and the HPLC purity was 99.785%.

[0138] Step 2: Synthesis of 2-benzylaniline (compound III)

[0139] Add 59.3g of compound II and 240g of tetrahydrofuran to the clean and anhydrous second reaction flask, control the temperature of the solution in the second reaction flask at 0-10°C and add 72.28g of aluminum trichloride, 8.5 g of aluminum trichloride to the second reaction flask in turn. g sodium borohydride, and then the temperature of the solution in the second reaction flask was raised to 60-70 °C, and the reaction was refluxed for 12.0 h, under the conditions that the temperature of the solution in the second reaction flask was 60-70 °C and the air pressure was -0.07MPa Concentrate until the tetrahydrofuran in the solution in the second reaction bottle is r...

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Abstract

The invention discloses a synthesis method of epinastine, which comprises the following steps: taking cheap and easily available 2-aminobenzophenone as an initial raw material, reducing through hydroboron and lewis acid to obtain 2-benzylaniline, acylating with an acid-binding agent and chloroacetyl chloride to obtain N-[2-(phenylmethyl) phenyl]-2-chloroacetamide, cyclizing with a dehydrating agent to obtain 6-chloromethylmorphanthridine, and purifying to obtain the epinastine. The preparation method comprises the following steps: carrying out a condensation reaction on 2-(4-chlorophenyl)-6, 11-dibenzo-[b, e] azepine under the action of an acid-binding agent to obtain 6-(phthalimidomethyl)-6, 11-dihydro-dibenzo-[b, e] azepine, reducing carbon-carbon double bonds under the action of hydroboron to obtain 6-(phthalimidomethyl)-6, 11-dihydro-5H-dibenzo-[b, e] azepine, and carrying out a condensation reaction on the 6-(phthalimidomethyl)-6, 11-dihydro-5H-dibenzo-[b, e] azepine and the 6-(phthalimidomethyl)-6, 11-dihydro-dibenzo-[b, e] azepine. The preparation method comprises the following steps: firstly, preparing 6-aminomethyl-6, 11-dihydro-5H-dibenzo [b, e] azepine, hydrolyzing to obtain 6-aminomethyl-6, 11-dihydro-5H-dibenzo [b, e] azepine, and finally cyclizing with cyanogen bromide to obtain epinastine. According to the synthesis method disclosed by the invention, the use of an expensive silane reagent is avoided, the synthesis cost is greatly reduced, dangerous chemicals such as sodium azide and lithium aluminum hydride are not used, and the industrial operation is easy.

Description

technical field [0001] The invention discloses a method for synthesizing epilastine and belongs to the technical field of medicinal chemistry. Background technique [0002] Epis Epilastine is a histamine H1 receptor antagonist and an inhibitor of histamine release from mast cells. It has inhibitory effect on histamine, leukotriene C4, PAF, serotonin, and can inhibit the release of histamine, slow-reacting substance A (SRS-A) chemical mediator. Epinastine is difficult to pass through the blood-cerebrospinal fluid barrier, so its antagonism to H1 receptors in the central nervous system is weak. It is suitable for the prevention and treatment of allergic rhinitis, urticaria, eczema, dermatitis, pruritus, prurigo, psoriasis vulgaris with itching and allergic bronchial asthma in adults. [0003] The synthetic method of the Epilastine of present disclosed patent and literature report mainly contains following several: [0004] (1) CN103012408A discloses a method for synthesizin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D223/20C07C209/70C07C211/45C07D403/06
CPCC07D487/04C07D223/20C07C209/70C07D403/06C07C211/45
Inventor 杨杰陈顺祥付飞彭启灯
Owner 重庆恩联生物科技有限公司
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