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Synthetic method of epinastine hydrochloride

A technology of epilastine hydrochloride and a synthesis method, applied in the field of synthesizing epilastine hydrochloride, can solve the problem that 2-chloro-2-phenylethylamine is difficult to obtain, cannot meet the needs of mass production, and has many side reactions. problems, to achieve the effects of cheap raw materials, avoiding the use of azide compounds, and mild reaction conditions

Inactive Publication Date: 2020-12-04
NANJING YUANSHU MEDICAL TECH CO LTD
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Problems solved by technology

[0005] Chinese patent CN107141297B adopts the reaction of 2-benzylaniline and N-substituent glycine as the starting material, and the position of the amino group contained in the raw material N-substituent glycine is exactly the position of the amino group that needs to be introduced later, avoiding the introduction of amine in one step However, the reaction conditions required for the reaction of 2-benzylaniline and N-substituent glycine are more difficult than the original amine and acid chloride reaction, and the yield is low, and the amine needs deprotection to carry out subsequent reactions
The process route is relatively short and the reaction conditions are relatively mild, but the starting material 2-chloro-2-phenylethylamine is not easy to obtain, the reaction side reactions are many, and the reaction yield is low, which cannot meet the needs of industrialized mass production

Method used

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  • Synthetic method of epinastine hydrochloride
  • Synthetic method of epinastine hydrochloride
  • Synthetic method of epinastine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1: the preparation of compound 1

[0060]

[0061] Add phthalic anhydride (50g, 0.337mol) and 100g benzene into a 250ml flat-bottomed flask. Let off heat slowly. After the addition was complete, stir for 1h. After suction filtration, the filter cake was slurried with 50 ml of ethyl acetate, and dried in vacuo at 50°C for 8 hours to obtain 74.52 g of white powder of compound 1 with a yield of 91.50% and a purity of 98.79% by HPLC.

[0062] 1 H NMR ( DMSO-d6 , 400 MHz ) δ( d, J = 8.0 HZ , 2H ) ; δ( t , J = 6.0HZ , 2H ) ; δ( m , 4H ) ; δ( S , 2H ) ; 13 C NMR (400 MHz, DMSO) Δ167.89, 148.80, 140.02, 139.37, 132.17, 130.42, 129.91, 129.08, 128.24, 123.78, 119.31, 114.48, MS M / Z: 242.0 {M + H]. +}.

Embodiment 2

[0063] Embodiment 2: the preparation of compound 2

[0064]

[0065] Add 200g of polyphosphoric acid into a 500ml flat-bottomed flask, heat to 90°C, the polyphosphoric acid is in a fluid state, stir with a constant temperature heating stirrer, add compound 1 (50g, 0.207mol), and continue the reaction for 3h. After the reaction, slowly pour the reaction solution into 500ml of ice water, stir, and a large amount of white solids precipitate, filter with suction, wash the filter cake once with 50ml of water, beat the filter cake with 200ml of 5% sodium hydroxide aqueous solution for 1 hour, filter with suction, and filter the cake Wash twice with 50ml of water, and dry in vacuum at 60°C for 12h to obtain 43.14g of white powder of compound 2, with a yield of 93.24% and a purity of 96.42% by HPLC.

[0066] 1 H NMR ( 400 MHz , DMSO-d6 ) δ 9.49 ( s , 1H ) , 7.97 – 7.88 ( m , 1H ) , 7.71 – 7.56 ( m , 5H ) , 7.55 – 7.51 ( m , 1H ) , 7.47 – 7.42 ( m , 1H ). 13 C NMR (400 MHz, DMSO)...

Embodiment 3

[0067] Embodiment 3: the preparation of compound 3

[0068]

[0069] Add compound 2 (20g, 89mmol), 150ml acetic acid, and 1g of 5%Pd / C in a 250ml autoclave, replace the autoclave with nitrogen three times, stir, heat to 50°C, and introduce 0.7MPa hydrogen to react 12h. After the reaction, the hydrogen in the autoclave was replaced with nitrogen. Remove Pd / C by suction filtration, add 300g of water to the filtrate, a large amount of solids are precipitated, filter with suction, wash the filter cake twice with 50ml of water, beat the filter cake with 100ml of 5% sodium bicarbonate aqueous solution for 0.5h, filter with suction, and filter the cake Wash once with 50 ml of water, and dry in vacuum at 60°C for 12 hours to obtain 17.7 g of light gray powder compound (3), with a yield of 94.45% and an HPLC purity of 98.74%.

[0070] 1 H NMR ( 400 MHz , DMSO-d6 ) δ 10.45 ( s , 1H ) , 7.73 ( dd , J =7.7, 1.1 Hz , 1H ) , 7.73 ( dd, J = 7.7, 1.1 Hz , 1H ) , 7.47 ( td , J = 7.5, 1....

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Abstract

The invention relates to a synthesis method of epinastine hydrochloride. The method comprises the following steps: reacting phthalic anhydride with aniline to obtain a compound 1, reacting the compound 1 with polyphosphoric acid under certain conditions to perform cyclization to obtain a compound 2, reducing carbonyl of the compound 2 under certain conditions to obtain a compound 3, and carrying out chlorination reaction on the compound 3 to obtain a compound 4, carrying out cyano substitution reaction on the compound 4 to obtain a compound 5, reducing the compound 5 by using a carbon-nitrogenunsaturated bond to obtain a compound 6, reacting the compound 6 with cyanogen bromide, and forming hydrochloride by using hydrochloric acid to obtain a compound 7; according to the method, the epinastine hydrochloride is prepared from bulk chemical products, is extremely low in price and mild in reaction condition, avoids the use of azide compounds, and the method is suitable for large-scale industrial production. The prepared epinastine hydrochloride is high in purity and low in cost, and has higher market competitiveness.

Description

technical field [0001] The invention belongs to the technical field of synthesis, in particular to a new method for synthesizing epinastine hydrochloride. Background technique [0002] In recent years, with the growth of the population base and the increasing incidence of allergic reactions, the market demand for antihistamines has also shown an upward trend year by year. Epinastine hydrochloride, as the second-generation H1 antihistamine drug, was launched in Japan in 1994, and later in South Korea, Germany and other countries. In 2004, some Chinese pharmaceutical companies were approved for production. Epinastine hydrochloride has a wide range of indications and has a good curative effect in the treatment of eczema, urticaria, allergic bronchial asthma, and allergic rhinitis. Epinastine hydrochloride has high selectivity and specific affinity for H1 receptors, and can quickly and completely eliminate allergic symptoms. It will not penetrate the blood-brain barrier, so it...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王凯周太勇王显康
Owner NANJING YUANSHU MEDICAL TECH CO LTD
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