Synthetic method of formoterol fumarate important intermediate benzyl ether compound

Abstract

The invention discloses a synthetic method of a formoterol fumarate important intermediate benzyl ether compound. The synthetic method comprises the following steps: enabling a compound I to react with a compound II in an organic solvent at 100-120 DEG C for 4-6 hours under the concerted catalysis of a catalyst (I) and a catalyst (II); and by using an inorganic alkaline substance as an acid-binding agent in the reaction process, after the reaction ends, adding water to perform cooling and crystallization, and filtering to obtain the benzyl ether compound. The synthetic steps disclosed by the invention perform concerted catalysis on benzyl etherification reaction between a substitute and benzyl chloride by adopting the two catalysts at the same time, and can be used for increasing the reaction speed, shortening the reaction time, shortening the total reaction time to 4 hours from 48 hours, and greatly improving the production efficiency; and after the reaction ends, the qualified benzyl ether compound (of which the content is more than 98%) can be obtained without refining; the synthetic method disclosed by the invention is more suitable for the large-scale industrial production of formoterol fumarate.

Description

technical field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation method of an important intermediate of medicine, more specifically, an important intermediate of formoterol fumarate: 4-benzyloxy-3-nitroacetophenone (abbreviated as " Synthetic method of benzyl etherate"). Background technique

[0002] Formoterol fumarate is a β2 sympathomimetic drug, which has the typical basic structure of all sympathomimetic drugs, and is an epinephrine derivative. This product has a high degree of β2 receptor selectivity, which is due to the substituents on the amino nitrogen. Substitution of cresylamine groups on the phenolic hydroxyl groups present in many other beta2 sympathomimetic drugs (fenoterol, terbutaline, albuterol, salmeterol). Its four notable features are: long-acting, high selectivity, strong anti-inflammatory effect, and mild side effects. Pharmacological and clinical studies have shown that formoterol...

Examples

Embodiment 1

[0034] This embodiment is a comparative example using a single catalyst

[0035] Add 18.1g (0.1mol) of the substituent, 0.4g of Tween 80, and 54g of N,N'-dimethylformamide to the reaction flask, stir and dissolve, then add 12.7g of anhydrous sodium carbonate, and add 20.2g of chlorine Benzyl (0.16mol), heat up to 115-120°C, react for 18 hours (TLC detects that the reaction is complete), cool down, add 90ml of water, crystallize, filter to obtain "benzyl ether compound" 21.7g, yield 80.1%, content 95.7 %.

Embodiment 2

[0037] This embodiment is a comparative example using a single catalyst

[0038] Add 18.1g (0.1mol) of the substituent, 0.4g of benzyltriethylammonium chloride, and 54g of N,N'-dimethylformamide to the reaction flask, stir and dissolve, then add 12.7g of anhydrous sodium carbonate , add 20.2g of benzyl chloride (0.16mol), raise the temperature to 115-120°C, react for 30 hours (TLC detects that the reaction is complete), cool down, add 90ml of water, crystallize, and filter to obtain "benzyl ether compound" 20.8g, yield 76.8 %, the content is 93.9%.

Embodiment 3

[0040] Add 18.1g (0.1mol) of the substituent, 0.2g of Tween 80, 0.2g of benzyltriethylammonium chloride, 54g of N,N'-dimethylformamide into the reaction flask, stir and dissolve, then add Add 20.2g (0.16mol) of benzyl chloride to 12.7g of anhydrous sodium carbonate, heat up to 115-120°C, react for 4 hours, cool down, add 90ml of water, crystallize, and filter to obtain 24.4g of "benzyl ether compound", yield 90.0 %, the content is 98.2%.

technical field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation method of an important intermediate of medicine, more specifically, an important intermediate of formoterol fumarate: 4-benzyloxy-3-nitroacetophenone (abbreviated as " Synthetic method of benzyl etherate"). Background technique

[0002] Formoterol fumarate is a β2 sympathomimetic drug, which has the typical basic structure of all sympathomimetic drugs, and is an epinephrine derivative. This product has a high degree of β2 receptor selectivity, which is due to the substituents on the amino nitrogen. Substitution of cresylamine groups on the phenolic hydroxyl groups present in many other beta2 sympathomimetic drugs (fenoterol, terbutaline, albuterol, salmeterol). Its four notable features are: long-acting, high selectivity, strong anti-inflammatory effect, and mild side effects. Pharmacological and clinical studies have shown that formoterol...

Examples

Embodiment 1

[0034] This embodiment is a comparative example using a single catalyst

[0035] Add 18.1g (0.1mol) of the substituent, 0.4g of Tween 80, and 54g of N,N'-dimethylformamide to the reaction flask, stir and dissolve, then add 12.7g of anhydrous sodium carbonate, and add 20.2g of chlorine Benzyl (0.16mol), heat up to 115-120°C, react for 18 hours (TLC detects that the reaction is complete), cool down, add 90ml of water, crystallize, filter to obtain "benzyl ether compound" 21.7g, yield 80.1%, content 95.7 %.

Embodiment 2

[0037] This embodiment is a comparative example using a single catalyst

[0038] Add 18.1g (0.1mol) of the substituent, 0.4g of benzyltriethylammonium chloride, and 54g of N,N'-dimethylformamide to the reaction flask, stir and dissolve, then add 12.7g of anhydrous sodium carbonate , add 20.2g of benzyl chloride (0.16mol), raise the temperature to 115-120°C, react for 30 hours (TLC detects that the reaction is complete), cool down, add 90ml of water, crystallize, and filter to obtain "benzyl ether compound" 20.8g, yield 76.8 %, the content is 93.9%.

Embodiment 3

[0040] Add 18.1g (0.1mol) of the substituent, 0.2g of Tween 80, 0.2g of benzyltriethylammonium chloride, 54g of N,N'-dimethylformamide into the reaction flask, stir and dissolve, then add Add 20.2g (0.16mol) of benzyl chloride to 12.7g of anhydrous sodium carbonate, heat up to 115-120°C, react for 4 hours, cool down, add 90ml of water, crystallize, and filter to obtain 24.4g of "benzyl ether compound", yield 90.0 %, the content is 98.2%.

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