A kind of preparation method of roflumilast intermediate

Abstract

The invention discloses a preparation method for roflumilast intermediates. The preparation method includes: 1), adding 3, 4-dihydroxybenzaldehyde and methyl bromodifluoroacetate into acetonitrile for contact reaction at the temperature of 30-45 DEG C in the presence of hydroxylamine, adding water after reaction completion, extracting and concentrating dichloromethane, and performing petroleum ether recrystallization to obtain 3-hydroxy-4-diflouromethylbenzaldehyde; 2), adding the 3-hydroxy-4-diflouromethylbenzaldehyde and bromomethyl cyclopropane into the acetonitrile for hybrid reaction in the presence of N-methylmorpholine and zinc salt at the temperature of 55-60 DEG C to obtain 3-cyclopropylmethoxy-4-(difluoromethoxy) benzaldehyde; 3), subjecting the 3-cyclopropylmethoxy-4-(difluoromethoxy) benzaldehyde and oxidizing agent comprising MnO2 and HClO to oxidation reaction at the temperature of 45-50 DEG C to obtain 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid. The preparation method has the advantages that selectivity is high and yield is increased; conditions are milder, influences on other groups are avoided and by-products are fewer.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a roflumilast intermediate. Background technique

[0002] Roflumilast (roflumilast) is a selective phosphodiesterase 4 (PDE4) inhibitor, by inhibiting the activity of phosphodiesterase 4, blocking the pulmonary inflammatory process that leads to COPD, thereby reducing the symptoms of patients and preventing the disease deterioration. Due to the high morbidity and mortality of COPD in the world, it has broad application prospects as a therapeutic drug for COPD. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide. Sturt conducted extensive research.

[0003] In the method for preparing roflumilast, such as WO2005026095, etc., all use 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as an intermediate, and then acid chloride, and 3,5-dichloro-4 - Condensation of aminop...

Examples

Embodiment 1

[0030] A preparation method of roflumilast intermediate, the preparation method comprising:

[0031] 1) Add hydroxylamine (50wt% aqueous solution) (16.5g), 3,4-dihydroxybenzaldehyde (60.8g, 500mmol), methyl difluorobromoacetate (106.6g, 525mmol) into acetonitrile at 45°C for contact After the reaction, the reaction solution was added with water, extracted with dichloromethane, concentrated, and recrystallized from petroleum ether to obtain 84.9 g of 3-hydroxy-4-difluoromethoxybenzaldehyde, with a yield of 90.3% and a purity of 98.66%.

[0032] 2) 3-hydroxy-4-difluoromethoxybenzaldehyde (37.6g, 200mmol), bromomethylcyclopropane (29.7g, 220mmol) and N-methylmorpholine (28.3g, 280mmol) and zinc nitrate (22.7g, 120mol) in acetonitrile for a mixed reaction, the temperature of the mixed reaction is 55 ° C, after the reaction, the reaction solution is added with water, dichloromethane extraction, concentration, methanol recrystallization to obtain 3-cyclopropane 42.5 g of methoxy-4-...

Embodiment 2

[0035] A preparation method of roflumilast intermediate, the preparation method comprising:

[0036] 1) Add hydroxylamine (50wt% aqueous solution) (13.2g), 3,4-dihydroxybenzaldehyde (60.8g, 500mmol), methyl difluorobromoacetate (106.6g, 525mmol) into acetonitrile at 45°C for contact After the reaction, the reaction solution was added with water, extracted with dichloromethane, concentrated, and recrystallized from petroleum ether to obtain 84.4 g of 3-hydroxy-4-difluoromethoxybenzaldehyde, with a yield of 89.7% and a purity of 99.23%.

[0037]2) 3-hydroxy-4-difluoromethoxybenzaldehyde (37.6g, 200mmol), bromomethylcyclopropane (29.7g, 220mmol) and N-methylmorpholine (26.3g, 260mmol) and zinc nitrate (30.3g, 160mol) in acetonitrile for mixed reaction, the temperature of the mixed reaction is 60 ° C, after the reaction, the reaction solution is added with water, dichloromethane extraction, concentration, methanol recrystallization to obtain 3-cyclopropane 42.9 g of methoxy-4-dif...

Embodiment 3

[0040] A preparation method of roflumilast intermediate, the preparation method comprising:

[0041] 1) Add hydroxylamine (50wt% aqueous solution) (19.8g), 3,4-dihydroxybenzaldehyde (60.8g, 500mmol), methyl difluorobromoacetate (111.6g, 550mmol) into acetonitrile at 45°C for contact After the reaction, the reaction solution was added with water, extracted with dichloromethane, concentrated, and recrystallized from petroleum ether to obtain 84.2 g of 3-hydroxy-4-difluoromethoxybenzaldehyde, with a yield of 89.5% and a purity of 99.08%.

[0042] 2) 3-hydroxy-4-difluoromethoxybenzaldehyde (37.6g, 200mmol), bromomethylcyclopropane (28.4g, 210mmol) and N-methylmorpholine (30.3g, 300mmol) and zinc nitrate (26.5g, 140mol) in acetonitrile for mixed reaction, the temperature of the mixed reaction is 55 ° C, after the reaction, the reaction solution is added with water, dichloromethane extraction, concentration, methanol recrystallization to obtain 3-cyclopropane 41.5 g of methoxy-4-di...

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a roflumilast intermediate. Background technique

[0002] Roflumilast (roflumilast) is a selective phosphodiesterase 4 (PDE4) inhibitor, by inhibiting the activity of phosphodiesterase 4, blocking the pulmonary inflammatory process that leads to COPD, thereby reducing the symptoms of patients and preventing the disease deterioration. Due to the high morbidity and mortality of COPD in the world, it has broad application prospects as a therapeutic drug for COPD. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide. Sturt conducted extensive research.

[0003] In the method for preparing roflumilast, such as WO2005026095, etc., all use 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as an intermediate, and then acid chloride, and 3,5-dichloro-4 - Condensation of aminop...

Examples

Embodiment 1

[0030] A preparation method of roflumilast intermediate, the preparation method comprising:

[0031] 1) Add hydroxylamine (50wt% aqueous solution) (16.5g), 3,4-dihydroxybenzaldehyde (60.8g, 500mmol), methyl difluorobromoacetate (106.6g, 525mmol) into acetonitrile at 45°C for contact After the reaction, the reaction solution was added with water, extracted with dichloromethane, concentrated, and recrystallized from petroleum ether to obtain 84.9 g of 3-hydroxy-4-difluoromethoxybenzaldehyde, with a yield of 90.3% and a purity of 98.66%.

[0032] 2) 3-hydroxy-4-difluoromethoxybenzaldehyde (37.6g, 200mmol), bromomethylcyclopropane (29.7g, 220mmol) and N-methylmorpholine (28.3g, 280mmol) and zinc nitrate (22.7g, 120mol) in acetonitrile for a mixed reaction, the temperature of the mixed reaction is 55 ° C, after the reaction, the reaction solution is added with water, dichloromethane extraction, concentration, methanol recrystallization to obtain 3-cyclopropane 42.5 g of methoxy-4-...

Embodiment 2

[0035] A preparation method of roflumilast intermediate, the preparation method comprising:

[0036] 1) Add hydroxylamine (50wt% aqueous solution) (13.2g), 3,4-dihydroxybenzaldehyde (60.8g, 500mmol), methyl difluorobromoacetate (106.6g, 525mmol) into acetonitrile at 45°C for contact After the reaction, the reaction solution was added with water, extracted with dichloromethane, concentrated, and recrystallized from petroleum ether to obtain 84.4 g of 3-hydroxy-4-difluoromethoxybenzaldehyde, with a yield of 89.7% and a purity of 99.23%.

[0037]2) 3-hydroxy-4-difluoromethoxybenzaldehyde (37.6g, 200mmol), bromomethylcyclopropane (29.7g, 220mmol) and N-methylmorpholine (26.3g, 260mmol) and zinc nitrate (30.3g, 160mol) in acetonitrile for mixed reaction, the temperature of the mixed reaction is 60 ° C, after the reaction, the reaction solution is added with water, dichloromethane extraction, concentration, methanol recrystallization to obtain 3-cyclopropane 42.9 g of methoxy-4-dif...

Embodiment 3

[0040] A preparation method of roflumilast intermediate, the preparation method comprising:

[0041] 1) Add hydroxylamine (50wt% aqueous solution) (19.8g), 3,4-dihydroxybenzaldehyde (60.8g, 500mmol), methyl difluorobromoacetate (111.6g, 550mmol) into acetonitrile at 45°C for contact After the reaction, the reaction solution was added with water, extracted with dichloromethane, concentrated, and recrystallized from petroleum ether to obtain 84.2 g of 3-hydroxy-4-difluoromethoxybenzaldehyde, with a yield of 89.5% and a purity of 99.08%.

[0042] 2) 3-hydroxy-4-difluoromethoxybenzaldehyde (37.6g, 200mmol), bromomethylcyclopropane (28.4g, 210mmol) and N-methylmorpholine (30.3g, 300mmol) and zinc nitrate (26.5g, 140mol) in acetonitrile for mixed reaction, the temperature of the mixed reaction is 55 ° C, after the reaction, the reaction solution is added with water, dichloromethane extraction, concentration, methanol recrystallization to obtain 3-cyclopropane 41.5 g of methoxy-4-di...

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