Synthesis method of propranolol hydrochloride

Abstract

The invention discloses a synthesis method of propranolol hydrochloride. The synthesis method of propranolol hydrochloride comprises the following steps: by taking menaphthol and epoxy chloropropane as raw materials, carrying out etherification reaction under an alkaline condition and under the action of a phase transfer catalyst to obtain a key intermediate 3-(1-naphthoxy)-1, 2-epoxypropane; carrying out ring-opening reaction and salifying reaction on the 3-(1-naphthoxy)-1, 2-epoxypropane and isopropylamine under the catalytic action of alkali to obtain a crude propranolol hydrochloride product; and finally refining the crude propranolol hydrochloride product to obtain propranolol hydrochloride with the purity of 99.8% or above. The synthesis method is a preparation method which is shortin synthesis route, simple to operate and suitable for industrial production.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and relates to a synthetic method of propranolol hydrochloride. Specifically, the method uses methyl naphthol and epichlorohydrin as raw materials to obtain the key intermediate 3-(1-naphthyloxy) through etherification reaction Base)-1,2-epoxypropane, then with isopropylamine through alkali-catalyzed ring-opening reaction, salt-forming reaction to obtain the crude product of propranolol hydrochloride, and finally obtain pure propranolol hydrochloride through refining, which is a short synthetic route, The preparation method is simple in operation and suitable for industrial production. Background technique

[0002] Propranolol hydrochloride (Propranolol hydrochloride), chemical name is 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride, its chemical structure is as follows:

[0003]

[0004] Propranolol hydrochloride is the first beta-receptor blocker invented by scienti...

Examples

Embodiment 1-1

[0026] Example 1-1 Synthesis of 3-(1-naphthyloxy)-1,2-propylene oxide

[0027] Weigh methylnaphthol (144.1g, 1.0mol, 1.0eq), benzyltriethylammonium chloride (13.9g, 0.05mol, 0.05eq), epichlorohydrin (277.5g, 3.0mol, 3.0eq) and add Put it into a 1L four-neck flask, stir and raise the temperature to 50°C to dissolve and clarify, then add dropwise 30% NaOH aqueous solution (200g, 1.5mol, 1.5eq) for 1h, then control the temperature at 50°C for 6h, and monitor the disappearance of the raw material (V PE / EA＝ 5:1), stop the reaction, cool to room temperature, stand to separate the organic layer, wash once with water, and then concentrate the organic layer to dryness under reduced pressure at 50°C to obtain reddish-brown oil 3-(1-naphthyloxy)- 188.4 g of 1,2-propylene oxide, and the molar yield was 94.1%.

Embodiment 1-2

[0028] Example 1-2 Synthesis of 3-(1-naphthyloxy)-1,2-propylene oxide

[0029] Weigh methyl naphthol (216.2g, 1.5mol, 1.0eq), polyethylene glycol 6000 (18.0g, 0.03mol, 0.02eq), epichlorohydrin (347g, 3.75mol, 2.5eq) and join in 2L In an open flask, stir and heat up to 65°C to dissolve and clarify, then add dropwise 30% NaOH aqueous solution (320g, 2.4mol, 1.6eq) for 1h, then keep the temperature at 65°C for 4h, and TLC monitors that the raw material disappears (V PE / EA＝ 5:1), stop the reaction, cool to room temperature, stand to separate the organic layer, wash once with water, and then concentrate the organic layer to dryness under reduced pressure at 50°C to obtain reddish-brown oil 3-(1-naphthyloxy)- 286.5 g of 1,2-propylene oxide, and the molar yield was 95.4%.

Embodiment 2-1

[0030] Embodiment 2-1 propranolol is synthesized

[0031] Dissolve 3-(1-naphthyloxy)-1,2-epoxypropane (160g, 0.8mol, 1.0eq), isopropylamine (108g, 1.6mol, 2.0eq) in 300mL of toluene, and then add N , N-diisopropylethylamine (25.9g, 0.2mol, 0.25eq), added dropwise for 30min, after the dropwise completion, the temperature was raised to 45°C, and the reaction was kept for 4h, and the raw material disappeared under TLC monitoring (V CHCl3 / MeOH =20:1), stop the reaction, cool to 5°C, precipitate solid, filter and dry to obtain 189.4g of propranolol crude product, the yield is 91.3%, and the HPLC purity is 99.1%.

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and relates to a synthetic method of propranolol hydrochloride. Specifically, the method uses methyl naphthol and epichlorohydrin as raw materials to obtain the key intermediate 3-(1-naphthyloxy) through etherification reaction Base)-1,2-epoxypropane, then with isopropylamine through alkali-catalyzed ring-opening reaction, salt-forming reaction to obtain the crude product of propranolol hydrochloride, and finally obtain pure propranolol hydrochloride through refining, which is a short synthetic route, The preparation method is simple in operation and suitable for industrial production. Background technique

[0002] Propranolol hydrochloride (Propranolol hydrochloride), chemical name is 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride, its chemical structure is as follows:

[0003]

[0004] Propranolol hydrochloride is the first beta-receptor blocker invented by scienti...

Examples

Embodiment 1-1

[0026] Example 1-1 Synthesis of 3-(1-naphthyloxy)-1,2-propylene oxide

[0027] Weigh methylnaphthol (144.1g, 1.0mol, 1.0eq), benzyltriethylammonium chloride (13.9g, 0.05mol, 0.05eq), epichlorohydrin (277.5g, 3.0mol, 3.0eq) and add Put it into a 1L four-neck flask, stir and raise the temperature to 50°C to dissolve and clarify, then add dropwise 30% NaOH aqueous solution (200g, 1.5mol, 1.5eq) for 1h, then control the temperature at 50°C for 6h, and monitor the disappearance of the raw material (V PE / EA＝ 5:1), stop the reaction, cool to room temperature, stand to separate the organic layer, wash once with water, and then concentrate the organic layer to dryness under reduced pressure at 50°C to obtain reddish-brown oil 3-(1-naphthyloxy)- 188.4 g of 1,2-propylene oxide, and the molar yield was 94.1%.

Embodiment 1-2

[0028] Example 1-2 Synthesis of 3-(1-naphthyloxy)-1,2-propylene oxide

[0029] Weigh methyl naphthol (216.2g, 1.5mol, 1.0eq), polyethylene glycol 6000 (18.0g, 0.03mol, 0.02eq), epichlorohydrin (347g, 3.75mol, 2.5eq) and join in 2L In an open flask, stir and heat up to 65°C to dissolve and clarify, then add dropwise 30% NaOH aqueous solution (320g, 2.4mol, 1.6eq) for 1h, then keep the temperature at 65°C for 4h, and TLC monitors that the raw material disappears (V PE / EA＝ 5:1), stop the reaction, cool to room temperature, stand to separate the organic layer, wash once with water, and then concentrate the organic layer to dryness under reduced pressure at 50°C to obtain reddish-brown oil 3-(1-naphthyloxy)- 286.5 g of 1,2-propylene oxide, and the molar yield was 95.4%.

Embodiment 2-1

[0030] Embodiment 2-1 propranolol is synthesized

[0031] Dissolve 3-(1-naphthyloxy)-1,2-epoxypropane (160g, 0.8mol, 1.0eq), isopropylamine (108g, 1.6mol, 2.0eq) in 300mL of toluene, and then add N , N-diisopropylethylamine (25.9g, 0.2mol, 0.25eq), added dropwise for 30min, after the dropwise completion, the temperature was raised to 45°C, and the reaction was kept for 4h, and the raw material disappeared under TLC monitoring (V CHCl3 / MeOH =20:1), stop the reaction, cool to 5°C, precipitate solid, filter and dry to obtain 189.4g of propranolol crude product, the yield is 91.3%, and the HPLC purity is 99.1%.

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