Formoterol, pharmaceutically acceptable salt thereof and preparation method of intermediate

Abstract

The invention relates to formoterol, a pharmaceutically acceptable salt thereof and a preparation method of an intermediate. The method for purifying the formoterol intermediate (a compound shown as aformula V) comprises the following steps of: I) performing a salt forming reaction of the crude compound shown as the formula V and fumaric acid in an organic solvent A to obtain fumarate of the compound shown as the formula V; II) performing a neutralization reaction of the fumarate of the compound of the formula V obtained in the step I) with the base in the organic solvent B to obtain a purified compound of the formula V; and III) crystallizing the purified compound shown as the formula V obtained in the step II) in an organic solvent C to obtain the formoterol intermediate.

Description

field of invention [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of formoterol, its pharmaceutically acceptable salt and its intermediate. Background technique [0002] The chemical name of the pharmaceutically acceptable salt (formula I) of formoterol is: {N-[2-hydroxyl-5-[(RS)-1-hydroxyl-2-[(RS)-2-(4-methyl Oxyphenyl)-1-methylethylamino]ethyl]phenyl]}formamide fumarate dihydrate is a β2 sympathomimetic drug with long-acting, high selectivity, strong anti-inflammatory effect, and It has the characteristics of fast effect and mild side effects; it has the typical basic structure of all sympathomimetic drugs, and the substituent on the amino nitrogen makes it highly selective for the β2 receptor. Pharmacological studies have shown that formoterol fumarate dihydrate exerts anti-inflammatory effects and inhibits pulmonary edema by inhibiting multiple links in the pathological process of asthma and t...

AI Technical Summary

Problems solved by technology

[0009] 1) Intermediates, final products and enantiomeric purity are not disclosed;

[0010] 2) Separation of undesired isomers (RS, SR) at the later stage of synthesis, and unrecyclable isomers are not recyclable, resulting in higher cost and increased pollution

[0014] 1) Harmful reagents such as hydrofluoric acid and crown ether and carcinogenic solvents such as benzene are used in the synthesis process, which are expensive and rare substances, and have serious health and environmental problems, so they are not suitable for scale-up operations

[0015] 2) Unpublished quality information about formoterol fumarate

[0019] 1) During the preparation process from the starting material to the compound of formula X, overnight grinding and repeated purification are required, and the operation is cumbersome

In addition, during the preparation and purification process of the compound of formula X, the adsorption effect of activated carbon is not significant, resulting in difficult crystallization and incomplete crystallization, which seriously affects the yield of the compound of formula X.

[0020] 2) In the preparation process of the compound of formula Ⅵ, the reaction rate of formic acid is slow, the reaction is incomplete, and the yield after purification is low. Using formic acid and acetic anhydride to react, acetic anhydride will react with the compound of formula Ⅴ to produce acetylated by-products ( Impurity C), not easy to remove, affects the purity and yield of the compound of formula VI

[0021] 3) Multiple crystallization is used in the whole preparation process of the final product formula I compound, high temperature conditions, cumbersome operation, and the formula I compound is extremely unstable when heated at high temperature in a solvent, especially in alcohol solvents, impurities will be produced A and impurity F, the purification effect is not significant, and the controllability of the scale-up production time is poor, and the ideal purification effect cannot be achieved.

[0022] 4) The final product formula I is vacuum-dried at a temperature of 60°C, and the temperature is relatively high, and there is a risk of losing crystal water

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