Preparation method and detection method of roflumilast material
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A technology of roflumilast and a detection method, applied in the field of medicinal chemistry, can solve the problems of lack of a set of strict and reliable quality detection standards, difficult control and the like
Active Publication Date: 2013-03-13
GUIZHOU XINBANG PHARMACEUTICAL CO LTD
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During the experiment, it was found that when intermediate 2 was prepared with NaH as a base, a large amount of hydrogen gas was generated, which was difficult to control. At the same time, when the refined product was dissolved in a solvent, there was opalescence, which may be caused by impurities in NaH.
[0006] In addition, there is currently no set of strict and reliable quality testing standards for roflumilast raw materials
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Embodiment 1
[0277] Embodiment 1: the synthesis of compound SM-1
[0278] Step 1, 3,4-dihydroxybenzaldehyde, sodium chlorodifluoroacetate, H 2 O, NaOH, added to dimethylformamide for heating and stirring reaction, after the reaction, the reaction solution was cooled to room temperature, diluted with water, adjusted to acidity with HCL, then extracted with isopropyl ether, the organic layer was extracted with dilute NaOH, adjusted After the pH of the aqueous layer reaches 3, extract with isopropyl ether, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and recrystallize the residue with isopropyl ether to obtain 3-hydroxy-4-difluoromethoxybenzaldehyde M1 ;
[0279] Step 2, dissolve M1 in THF, add K 2 CO 3 , bromomethylcyclopropane, the reaction solution was heated to reflux for 14h, the reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure, and the residue was dissolved in dilute NaOH, and then...
Embodiment 2
[0281] Embodiment 2: the synthesis of compound SM-2
[0282] Dissolve 4-aminopyridine in dilute hydrochloric acid, add sodium hypochlorite aqueous solution dropwise under heating conditions, after the reaction, adjust the pH to alkaline with NaOH, solid precipitates, filter, wash the precipitate with water, and dry to obtain compound SM-2.
Embodiment 3
[0283] Embodiment 3: the synthesis of compound intermediate 1
[0284]Take 35g of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, 39mL of thionyl chloride, 1mL of dimethylformamide, and 350mL of toluene, add them to a 500mL three-necked flask, stir to dissolve the solid, and heat up to 80±5°C, then keep warm at 80±5°C for 3 hours, when the room temperature is naturally cooled to 50°C, transfer the reaction solution into a 500mL round bottom flask, and evaporate the solvent under vacuum to obtain 40g of intermediate 1, the yield range 90-110%, seal the round-bottom flask and set aside.
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Abstract
The invention discloses a preparation method and a detection method of a roflumilast material. The preparation method comprises the following steps: mixing 3-cyclopropyl methoxy group-4-difluoro methoxy group benzoic acid SM-1, thionyl chloride, dimethyl formamide with toluene, and carrying out an acylating chlorination reaction to obtain a midbody 1; mixing 3,5-dichloro-4-aminopyridine SM-2, tetrahydrofuran with potassium tert-butoxide and carrying out a salt forming reaction to obtain tetrahydrofuran solution of a midbody 2; and then mixing the midbody 1 and the midbody 2 with tetrahydrofuran, carrying out amidation to obtain a crude product of roflumilast, and refining the crude product of roflumilast to prepare the roflumilast material. Aiming to overcome the shortage of the prior art, the preparation process of the roflumilast material is optimized, so that the curative effect for treating diseases such as chronic obstructive pulmonary disease (COPD) is more remarkable; and besides, a systematic, complete and effective composition identifying and content measuring method is provided, so that the quality of the medicine can be effectively controlled, and the clinical effect is ensured.
Description
technical field [0001] The invention relates to a preparation method and detection method of roflumilast raw material, belonging to the technical field of medicinal chemistry. Background technique [0002] Chronic obstructive pulmonary disease (chronic obstructive puLmonary diseases referred to as COPD) is a preventable and treatable disease characterized by airflow limitation, which is not fully reversible and develops progressively. Abnormal inflammatory response to noxious particles. COPD mainly involves the lungs, but it can also cause systemic (or extrapulmonary) adverse effects. COPD is also often closely related to heart failure and metabolic syndrome, and the existence of these chronic comorbid diseases may further aggravate the clinical manifestations of COPD. As a chronic inflammatory disease of the airways and lungs, chronic obstructive pulmonary disease has become one of the leading causes of common diseases and deaths worldwide. [0003] Roflumilast is a phos...
Claims
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