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Synthetic method of formoterol fumarate important intermediate benzyl ether compound

A technology for the synthesis of formoterol fumarate, applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid amide optical isomers, etc., can solve the problems of increased difficulty, high cost, shortened reaction time, etc. problem, to achieve the effect of speeding up the reaction speed, improving production efficiency and shortening the reaction time

Active Publication Date: 2014-10-08
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned synthesis method has the following disadvantages: (1) The reaction time is long, requiring reflux for 48 hours (2) Potassium iodide is expensive and the cost is high
(3) The yield of this method is only about 75%, and the impurity content is relatively high. The product contains unconverted raw materials—substitutes, which need to be refined to obtain qualified benzyl ether compounds, which will seriously affect the rich Intrinsic quality control of formoterol maleate products and unsuitability for large-scale industrial production
It is found through experimental research that the application of the above method in the reaction of formoterol benzyl etherate fumarate fails to significantly shorten the reaction time and improve the yield and quality. Our analysis has something to do with the molecular structure of the reactant and the reaction solvent system. Great relationship, the ortho nitro group in the molecular structure of compound I increases the difficulty of benzyl etherification

Method used

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  • Synthetic method of formoterol fumarate important intermediate benzyl ether compound
  • Synthetic method of formoterol fumarate important intermediate benzyl ether compound

Examples

Experimental program
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Effect test

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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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C205/45C07C201/12C07C233/43C07C231/20C07C57/15C07C51/41
Inventor 姜根华霍志甲王丽红张瑜
Owner TIANJIN LISHENG PHARM CO LTD