Preparation method of chlorpheniramine maleate intermediate

Abstract

The invention belongs to the field of organic medicine synthesis, and particularly relates to a preparation method of a chlorpheniramine maleate intermediate. The method comprises the following steps: reacting chlorobenzyl cyanide with 2-halogen pyridine under the action of sodium amide to obtain a 2-(4-chlorphenyl)-2-(pyridine-2-yl)acetonitrile crude product; The main improvement point is as follows: the 2-(4-chlorphenyl)-2-(pyridine-2-yl)acetonitrile crude product reacts with an ethyl acetate solution of hydrogen chloride to obtain 2-(4-chlorphenyl)-2-(pyridine-2-yl)acetonitrile hydrochloride precipitate. The method disclosed by the invention is simple in operation steps, is relatively low in equipment requirement, can obtain good-state hydrochloride, is easy to purify, is relatively high in product purity and is suitable for industrial scale-up production.

Description

technical field

[0001] The invention belongs to the field of organic drug synthesis, in particular to a preparation method of a chlorpheniramine maleate intermediate. Background technique

[0002] Chlorpheniramine maleate is chlorpheniramine, an antihistamine drug that plays an anti-allergic effect by antagonizing the H1 receptor, and is suitable for skin allergies: urticaria, eczema, dermatitis, drug eruption, pruritus, Neurodermatitis, insect bites, solar dermatitis, allergic rhinitis, drug and food allergies. It can also be used for allergic rhinitis, vasomotor rhinitis, drug and food allergies. As a histamine H1 receptor antagonist, it can resist telangiectasia caused by allergic reactions, reduce capillary permeability, and relieve wheezing caused by bronchial smooth muscle contraction. The antihistamine effect is long-lasting and has obvious central inhibition. It can increase the effects of anesthetics, analgesics, hypnotics and local anesthetics, and is mainly meta...

Examples

Embodiment 1

[0043] This embodiment relates to a preparation method of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile, comprising the following steps:

[0044] 1) Add p-chlorophenylacetonitrile (90.95g, 1.0eq) into a 1L three-necked flask, add toluene (455mL, 5V), and then NaNH 2 (51.49g, 2.2eq) was added to the three-necked flask, and the reaction was stirred at 25-30°C for 30 minutes, then 2-bromopyridine (104.28g, 1.1eq) was added dropwise to the reaction, and the temperature was controlled below 25-30°C , After the dropwise addition, react at room temperature (25-30° C.), and monitor the reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, quenched by adding water (180mL, 2V) and stirred for 30 minutes;

[0045] 2) Add ethyl acetate (270mL*2, 3V*2), separate the liquid, and concentrate the organic phase;

[0046] 3) adding ethyl acetate (15V) to the organic phase;

[0047] 4) Stir in an ice-water bath, add hydrogen chloride ethyl ac...

Embodiment 2

[0050] This embodiment relates to a preparation method of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile, comprising the following steps:

[0051] 1) Add p-chlorophenylacetonitrile (90.95g, 1.0eq) into a 1L three-necked flask, add toluene (455mL, 5V), and then NaNH 2 (51.49g, 2.2eq) was added to the three-necked flask, and the reaction was stirred at 25-30°C for 30 minutes, then 2-bromopyridine (104.28g, 1.1eq) was added dropwise to the reaction, and the temperature was controlled below 30-40°C , After the dropwise addition, react at room temperature (25-30° C.), and monitor the reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, quenched by adding water (180mL, 2V) and stirred for 30 minutes;

[0052] 2) Add ethyl acetate (270mL*2, 3V*2), separate the liquid, and concentrate the organic phase;

[0053] 3) adding ethyl acetate (15V) to the organic phase;

[0054] 4) Stir in an ice-water bath, add hydrogen chloride ethyl ac...

Embodiment 3

[0057] This embodiment relates to a preparation method of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile, comprising the following steps:

[0058] 1) Add p-chlorophenylacetonitrile (90.95g, 1.0eq) into a 1L three-necked flask, add toluene (455mL, 5V), and then NaNH 2 (51.49g, 2.2eq) was added to the three-necked flask, and the reaction was stirred at 25-30°C for 30 minutes, then 2-bromopyridine (104.28g, 1.1eq) was added dropwise to the reaction, and the temperature was controlled below 50-60°C , After the dropwise addition, react at room temperature (85-90° C.), and monitor the reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, quenched by adding water (180mL, 2V) and stirred for 30 minutes;

[0059] 2) Add ethyl acetate (270mL*2, 3V*2), separate the liquid, and concentrate the organic phase;

[0060] 3) adding ethyl acetate (15V) to the organic phase;

[0061] 4) Stir in an ice-water bath, add hydrogen chloride ethyl ac...

technical field

[0001] The invention belongs to the field of organic drug synthesis, in particular to a preparation method of a chlorpheniramine maleate intermediate. Background technique

[0002] Chlorpheniramine maleate is chlorpheniramine, an antihistamine drug that plays an anti-allergic effect by antagonizing the H1 receptor, and is suitable for skin allergies: urticaria, eczema, dermatitis, drug eruption, pruritus, Neurodermatitis, insect bites, solar dermatitis, allergic rhinitis, drug and food allergies. It can also be used for allergic rhinitis, vasomotor rhinitis, drug and food allergies. As a histamine H1 receptor antagonist, it can resist telangiectasia caused by allergic reactions, reduce capillary permeability, and relieve wheezing caused by bronchial smooth muscle contraction. The antihistamine effect is long-lasting and has obvious central inhibition. It can increase the effects of anesthetics, analgesics, hypnotics and local anesthetics, and is mainly meta...

Examples

Embodiment 1

[0043] This embodiment relates to a preparation method of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile, comprising the following steps:

[0044] 1) Add p-chlorophenylacetonitrile (90.95g, 1.0eq) into a 1L three-necked flask, add toluene (455mL, 5V), and then NaNH 2 (51.49g, 2.2eq) was added to the three-necked flask, and the reaction was stirred at 25-30°C for 30 minutes, then 2-bromopyridine (104.28g, 1.1eq) was added dropwise to the reaction, and the temperature was controlled below 25-30°C , After the dropwise addition, react at room temperature (25-30° C.), and monitor the reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, quenched by adding water (180mL, 2V) and stirred for 30 minutes;

[0045] 2) Add ethyl acetate (270mL*2, 3V*2), separate the liquid, and concentrate the organic phase;

[0046] 3) adding ethyl acetate (15V) to the organic phase;

[0047] 4) Stir in an ice-water bath, add hydrogen chloride ethyl ac...

Embodiment 2

[0050] This embodiment relates to a preparation method of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile, comprising the following steps:

[0051] 1) Add p-chlorophenylacetonitrile (90.95g, 1.0eq) into a 1L three-necked flask, add toluene (455mL, 5V), and then NaNH 2 (51.49g, 2.2eq) was added to the three-necked flask, and the reaction was stirred at 25-30°C for 30 minutes, then 2-bromopyridine (104.28g, 1.1eq) was added dropwise to the reaction, and the temperature was controlled below 30-40°C , After the dropwise addition, react at room temperature (25-30° C.), and monitor the reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, quenched by adding water (180mL, 2V) and stirred for 30 minutes;

[0052] 2) Add ethyl acetate (270mL*2, 3V*2), separate the liquid, and concentrate the organic phase;

[0053] 3) adding ethyl acetate (15V) to the organic phase;

[0054] 4) Stir in an ice-water bath, add hydrogen chloride ethyl ac...

Embodiment 3

[0057] This embodiment relates to a preparation method of 2-(4-chlorophenyl)-2-(pyridin-2-yl)acetonitrile, comprising the following steps:

[0058] 1) Add p-chlorophenylacetonitrile (90.95g, 1.0eq) into a 1L three-necked flask, add toluene (455mL, 5V), and then NaNH 2 (51.49g, 2.2eq) was added to the three-necked flask, and the reaction was stirred at 25-30°C for 30 minutes, then 2-bromopyridine (104.28g, 1.1eq) was added dropwise to the reaction, and the temperature was controlled below 50-60°C , After the dropwise addition, react at room temperature (85-90° C.), and monitor the reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, quenched by adding water (180mL, 2V) and stirred for 30 minutes;

[0059] 2) Add ethyl acetate (270mL*2, 3V*2), separate the liquid, and concentrate the organic phase;

[0060] 3) adding ethyl acetate (15V) to the organic phase;

[0061] 4) Stir in an ice-water bath, add hydrogen chloride ethyl ac...

Images