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Preparation method of roflumilast

A technology of roflumilast and refined products, which is applied in the field of new special preparations, can solve problems such as high energy consumption, instability and easy hydrolysis of acyl chlorides, complicated operation steps, etc., and achieve simplified reaction steps, avoiding corrosion, and good product yield. The effect of rate and purity

Active Publication Date: 2013-02-27
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above-mentioned method is a classic synthetic route of roflumilast. However, this method needs to first carry out acyl chloride of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and then react with 3, The 5-dichloro-4-aminopyridine condensation reaction has complicated operation steps. At the same time, the acyl chloride reaction needs to be heated and the energy consumption is high, and the acyl chloride is unstable and easy to be hydrolyzed. It is prepared with a highly corrosive di Thionyl chloride has special requirements for reaction equipment, which is not conducive to the industrialized production of roflumilast
[0008] At present, there is no report of using DCC as a catalyst to directly synthesize roflumilast from 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid and 4-amino-3,5-dichloropyridine

Method used

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  • Preparation method of roflumilast
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  • Preparation method of roflumilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1 The preparation method of Roflumilast of the present invention

[0044]

[0045] (1) Add 47.4g of compound IV (4-amino-3,5-dichloropyridine) and 250ml of dry dichloromethane (DCM) into the reaction flask, stir to dissolve. Add 80g of N,N'-dicyclohexylcarbodiimide (DCC) in batches, and stir at room temperature for 40min. Then, 50 g of compound II (3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid) was dissolved in 250 ml of DCM, and the solution was added dropwise into the reaction flask, and the reaction was stirred at room temperature for 5 h after the addition.

[0046] (2) Filter out the white solid DCU (reaction by-product of DCC), then adjust the reaction solution to PH2~3 with 2mol / L HCl, filter out the solid, leave the solution to separate layers, and extract the aqueous layer with ethyl acetate for 2 Times (2*150ml). The combined organic layers were sequentially washed with saturated NaHCO 3Wash twice (2*150ml), wash twice with saturated NaCl...

Embodiment 2

[0050] Embodiment 2 The preparation method of Roflumilast of the present invention

[0051] (1) Add 4.74g of compound IV (4-amino-3,5-dichloropyridine) and 30ml of dry N,N-dimethylformamide (DMF) into the reaction flask, stir to dissolve. Add 8.0g of N,N'-dicyclohexylcarbodiimide (DCC) in batches, and stir at room temperature for 40min. Then, 5.0 g of compound II (3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid) dissolved in 30 ml of dry DMF was added dropwise to the reaction flask, and the reaction was stirred at room temperature for 5 h after the addition.

[0052] (2) Use 2mol / L HCl to adjust the reaction solution to PH2~3, filter out the solids, evaporate most of the DMF under reduced pressure, add 50ml of dichloromethane, stir for 30min and then a small amount of DCU solid precipitates, filter, and remove the dichloromethane from the mother liquor Add 30ml H after methane 2 O and 50ml of ethyl acetate, the solution was left to stand and the layers were separated, and...

Embodiment 3

[0053] Embodiment 3 The preparation method of Roflumilast of the present invention

[0054] (1) Add 4.74g of compound IV (4-amino-3,5-dichloropyridine) and 30ml of dry DMF into the reaction flask, stir to dissolve. Add 8.0g of N,N'-dicyclohexylcarbodiimide (DCC) in batches, and stir at room temperature for 40min. Then, 5.0 g of compound II (3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid) dissolved in 30 ml of dry DMF was added dropwise to the reaction flask, and the reaction was stirred at room temperature for 5 h after the addition.

[0055] (2) Adjust the reaction solution to pH 2~3 with 2mol / L HCl, filter off the solid, distill off most of the DMF under reduced pressure, add 30ml of HCl 2 O and 50ml of ethyl acetate, the solution was left to stand and the layers were separated, and the aqueous layer was extracted twice with ethyl acetate (2*30ml). The combined organic layers were sequentially washed with saturated NaHCO 3 Wash 2 times (2*30ml), wash 2 times with satu...

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Abstract

The invention provides a preparation method of roflumilast. The preparation method of roflumilast comprises the following steps of : (1) taking 3-cyclopropyl methoxy group-4-difluoro methoxy group benzoic acid and 4-amino-3, 5-dichloropyridine, and adopting N, N'-dicyclohexylcarbodiimide as the catalytic agent to perform amide reaction, wherein mole dosage ratio of 4-amino-3, 5-dichloropyridine and 3-cyclopropyl methoxy group-4-difluoro methoxy group benzoic acid is equal or greater than 1; mole dosage ratio of N'-dicyclohexylcarbodiimide and 4-amino-3, 5-dichloropyridine is equal or greater than 1, and solvent used by the amide reaction is aprotic polar solvent; and (2) after the reaction is finished, adding poor solvent of N, N'-dicyclohexylurea to perform purification, and accordingly roflumilast refined products are obtained. The preparation method of roflumilast adopts DCC (N, N'-dicyclohexylcarbodiimide) as the catalytic agent, guarantees good product yield and purity, can directly perform amidate condensation reaction without performing acylating chlorination reaction on intermediates, simplifies reaction steps, simultaneously avoids corrosivity from acylating chlorination solvent thionyl chloride to equipment, and is more suitable for industrialized mass production.

Description

technical field [0001] The invention relates to a new special preparation method of roflumilast. Background technique [0002] Roflumilast (Roflumi last), chemical name: 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzyl Amide, its CAS number is: 162401-32-3, the structural formula is as follows: [0003] [0004] Roflumilast is used to treat chronic obstructive pulmonary disease (COPD), reduce the frequency of acute exacerbation (exacerbation) of severe COPD, relieve the exacerbation of lung and airway inflammation; it is a phosphodiesterase 4 (PDE4) inhibitor, mainly expressed Inflammatory cells associated with asthma, including eosinophils, neutrophils, and mast cells; the drug can specifically act on proteases involved in smooth muscle contraction, prevent cAMP degradation, thereby blocking pro-inflammatory response signaling, thus It has anti-inflammatory activity and has achieved good curative effect in the clinical treatment of asthma a...

Claims

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Application Information

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IPC IPC(8): C07D213/75
Inventor 王朝阳马静君郭培良黄耀宗王利春沈芃梁隆程志鹏
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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