Preparation method of Nedocromil sodium

Abstract

The invention discloses a preparation method of 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] quinoline-2,8-sodium dicarboxylic acid (Nedocromil sodium). A raw material of m-anisidine (a compound A ) is treated with a condensation reaction to generate a compound B; the compound B is treated with a first Friedel-Crafts acylation to obtain a compound C1 and a compound C2; the compound C1 and the compound C2 are treated with demethylation, and isomer C2 is separated out to obtain a compound D; the compound D is treated with a second Friedel-Crafts acylation to obtain a diacetyl compound E; and the compound E is treated with a substitution reaction, ether formation, rearrangement, reduction, ring formation, hydrolysis and salt forming reaction to obtain the Nedocromil sodium (a compound L). The method of the invention increase synthesis yield of Nedocromil sodium.

Description

technical field [0001] The invention relates to a preparation method for preparing nedocromil sodium, an anti-allergic inflammation drug, from m-aminoanisole. Background technique [0002] Sodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (Chinese Name: Nedocromil sodium, English name: Nedocromil sodium) is an anti-allergic inflammatory drug successfully developed by the British Fison Pharmaceutical Company in the late 1980s. This drug is currently the non-steroidal anti-inflammatory anti-asthma drug with the strongest anti-inflammatory effect, and is currently the most attention-grabbing anti-allergic inflammation drug in the world. Nedocromil sodium is recommended as a "first-line drug" in the asthma prevention and control standards formulated by the U.S. Department of Health and Human Health and European and American countries. This variety has not been declared and produced in China at present. [0003] For the synthesis of ned...

AI Technical Summary

Problems solved by technology

The method of document 1 has many steps, and the intermediates are mostly oily, and its process is not conducive to product quality control and is not suitable for industrial production

The method step listed in document 2 is relatively short, but the process of synthesizing 3-acetamido-4,6-diacetylphenol (compound E) from 3-methoxyacetanilide (compound B) in its method is in Carry out two Friedel-Crafts acylation reactions on the same benzene ring simultaneously, and there is also an incomplete problem of ether bond cleavage, so the key intermediate compound E in the synthetic process of nedocromil sodium has a low purity, and the actual yield is very low. only about 15%

[0004] In foreign documents, EP0030423 (hereinafter referred to as document 3) also discloses a synthetic method of nedocromil sodium, the process of which is generally consistent with the method of document 2, although it is also mentioned that diacetylation is completed by a two-step reaction, However, the isomer compound C2 produced by the first acetylation was not separated, and the ether bond was not completely broken, and there were also the shortcomings of Document 2.

[0005] EP0052280 (hereinafter referred to as document 4) conducted a special study on the re-acetylation reaction of benzene ring, pointed out that the reaction of preparing diacetyl compound is a relatively difficult chemical reaction, and clearly showed that the similar compound I produced by the first acetylation The compound of compound II can produce diacetyl compound under certain conditions, but it is difficult to realize the second acetylation reaction of the compound similar to compound II to produce diacetyl compound

Images