Production and preparation method of roflumilast crystalline powder bulk drug

The invention discloses a production and preparation method of a roflumilast crystalline powder bulk drug. The method comprises the following steps of: 1) acylation reaction: dropwise adding thionyl chloride into a toluene solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and heating t...

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Hauptverfasser: ZHOU FENG, ZHANG CUNGUO, SUN KAI
Format: Patent
Sprache:chi ; eng
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Beschreibung
Zusammenfassung:The invention discloses a production and preparation method of a roflumilast crystalline powder bulk drug. The method comprises the following steps of: 1) acylation reaction: dropwise adding thionyl chloride into a toluene solution of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and heating the reaction mixture to reflux, carrying out reaction for 2h, then conducting reduced pressure concentration to remove the solvent, dissolving the residue left by concentration in tetrahydrofuran, controlling the temperature of the solution at 15-20DEG C under stirring and dropwise adding the solution into a tetrahydrofuran solution of 4-amino-3, 5-dichloropyridine and sodium hydride; and 2) refining. The method has the beneficial effects that: a commercially available starting material of 1 (3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid) and a starting material of 2 (4-amino-3, 5-dichloropyridine) are selected as the starting materials, acylation and refining are carried out to obtain roflumilast, the process