- Production and preparation method of roflumilast crystalline powder bulk drug
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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 is stable, the yield is high, and industrial production is easy.
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Paragraph 0013; 0016-0025
(2021/03/06)
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- A preparation method of roflumilast
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The invention discloses a method for preparation of roflumilast, comprises the following steps: 4 - (methoxy) benzoic acid chlorization reaction to obtain 4 - (methoxy) benzoyl chloride; with 3, 5 - dichloro - 4 - aminopyridine by amidation reaction to obtain N - (3, 5 - dichloro - 4 - pyridyl) - 4 - (methoxy) benzamide; then by Vismeier reaction to obtain N - (3, 5 - dichloro - 4 - pyridyl) - 4 - (methoxy) - 3 - formyl-benzoyl; through the Baeyer - villiger - hydrolysis reaction to obtain N - (3, 5 - dichloro - 4 - pyridyl) - 4 - (methoxy) - 3 - hydroxy benzoyl; then with the [...] yl cyclopropane ether to obtain roflumilast. The invention starting raw material is cheap, the reaction conditions are mild and controllable, synthetic route green environmental protection, high yield, the prepared Roflumilast purity is good.
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- Preparation methods of anti-inflammatory agent roflumilast for inhibiting PDE4 enzymatic activity and intermediate of roflumilast
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The invention discloses preparation methods of an anti-inflammatory agent roflumilast for inhibiting the PDE4 enzymatic activity and an intermediate of the roflumilast. A chemical name of the anti-inflammatory agent roflumilast for inhibiting the PDE4 enzymatic activity is 3-(cyclopropyl methoxy)-N-(3,3-dichloropyridine-4-yl)-4-(difluoromethoxy) benzamide, the chemical formula of the roflumilast is C17H14C12F2N2O3, and the structural formula of the roflumilast is described as follow: (the structural formula is shown in the description). The preparation methods are concise in preparation technological process, available in raw material, simple in synthetic condition and high in yield and purity of a product, is environmentally friendly, is beneficial to realizing industrialization, lowers the production cost and is suitable for mass production; and the searched novel preparation methods of the roflumilast and the intermediate thereof have great significance on economical technology of the roflumilast.
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- A method for preparing raw material for roflumilast and detection method
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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.
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- Synthesis method of roflumilast
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The invention provides a synthetic method for roflumilast. The method comprises the following steps: (a), in an organic solvent, producing an exchange reaction of a compound (I) and magnesium or a Grignard reagent under the backflow condition to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 0-50 DEG C to obtain a compound (II); or in the organic solvent, reacting the compound (I) with n-butyl lithium at 90 DEG C below zero to 70 DEG C below zero to generate an intermediate, and producing a carbonyl insertion reaction of the intermediate and carbon dioxide at 90 DEG C below zero to 70 DEG C below zero to obtain a compound (II); (b) in the organic solvent, reacting the compound (II) obtained in the step (a) with pivaloyl chloride or sulfonyl chloride at 0-50 DEG C in the presence of alkali to generate a mixed anhydride intermediate, and reacting the mixed anhydride intermediate with 3,5-dichloro-4-aminopyridine at 0-70 DEG C to obtain a compound (III) which is roflumilast. The method is short in process route, low in raw material and reagent costs, high in total yield, mild in reaction condition and suitable for industrialized production. The synthetic route of the method is as shown in the descriptions.
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Paragraph 0044; 0045; 0046; 0047; 0048; 0049; 0050-0059
(2017/07/26)
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- Preparation method for high-purity roflumilast
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The invention belongs to the technical field of medicine, and particularly relates to a preparation method for high-purity roflumilast and an intermediate 3-hydroxy-4-diflouromethylbenzaldehyde of the roflumilast. The preparation method comprises the steps that the 3-hydroxy-4-diflouromethylbenzaldehyde is firstly obtained by taking 3-hydroxy-4-dihydroxybenzaldehyde as raw materails at higher yield and purity and then synthesized into 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde, the 3-cyclopropylmethoxy-4-diflouromethylbenzaldehyde is oxidized to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid, and finally the 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid reacts with 4-amino-3,5-dichloropyridine to obtain the roflumilast. Due to the fact that the 3-hydroxy-4-diflouromethylbenzaldehyde with the higher yield and purity is obtained, the total yield of the roflumilast is increased, and many by-products which are difficult to separate cannot be generated.
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- A process for the preparation of roflumilast
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The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of roflumilast. The preparation method comprises the following steps: (1) dissolving an activating reagent into a solvent, adding 3-cyclopropylmethoxyl-4-difluoromethoxylbenzoic acid into the solvent to carry out reactions in the presence of an alkali; (2) adding 3,5-dichloro-4-aminopyridine into the solution obtained in the step (1) to carry out reactions so as to obtain the roflumilast. The 2,4-dimethoxyl-6-chloro-1,3-5-s-triazine and other reagents used in the preparation method are conventional reagents in production, and are easily available. Moreover, the production conditions are simple. Sulfoxide chloride, which has high requirements on production conditions and severely pollutes the environment, is replaced; and conditions that are not suitable for industrialization such as high temperature reduced pressure distillation, and the like are avoided at the same time, so the preparation method is a novel synthesis method suitable for industrial operation. Because the synthesis route is reasonably designed, and the reaction activity is high, the reaction yield is prominently improved, and can reach 86-95%.
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Paragraph 0050-0052
(2017/02/09)
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- PROCESS FOR PREPARATION OF ROFLUMILAST
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The present invention provides novel processes for the preparation of N-substituted benzamides having the formula (VIc). In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.
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- PROCESS FOR THE PREPARATION OF ROFLUMILAST
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The present invention relates to an improved process for the preparation of Roflumilast. The present invention also relates to crystalline Form-I of Roflumilast.
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- PROCESS FOR PREPARING ROFLUMILAST
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The invention relates to a process for the preparation of Roflumilast by reaction of an activated form of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid with an activating agent selected from (a) carbonyldiimidazole (CDI), (b) 1,1'-carbonyl-di-(1,2,4-triazol) (CDT), (c) 1,1'-carbonyl-bis-(2-methylimidazol), (d),1'-carbonyl-dipyperidin, (e) N,N'-dicyclohexylcarbodiimide (DCC), (f) N,N′-diisopropylcarbodiimide (DIC), (g) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and a combination of one of the previous (a)-(g) with (h) N-hydroxysuccinimide or (i) N-hydroxyphthalimide, and the subsequent reaction with 3,5-dichloropyridine-4-amine in the presence of an inorganic base. The invention also relates to the synthesis intermediates.
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Page/Page column 18-19
(2014/05/07)
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- PROCESS FOR PREPARATION OF ROFLUMILAST
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The present invention provides novel processes for the preparation of N-substituted benzamides having the formula (VIc). In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.
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- PREPARATION METHOD OF ROFLUMILAST
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The present invention provides novel processes for the preparation of N-substituted benzamides having the formula VIc: (formula) In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.
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Paragraph 0046; 0047
(2013/09/26)
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- A convenient method for the synthesis of roflumilast
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A convenient synthetic method has been developed for the synthesis of roflumilast from 4-difluoromethoxy-3-hydroxybenzaldehyde and bromomethyl cyclopropane via O-alkylation, oxidation and N-acylation. With sodium hydroxide as alkali in the last step, the total yield of roflumilast can be up to 68.3 % and the purity of the target product reached 99.2 %. It was obvious that sodium hydroxide showed more economic advantage for scale-up production than sodium hydride or potassium tert-butoxide.
- Lin, Yan,Huang, Peijun,Liu, Shuai,Sima, Lifeng,Chen, Ligong,Wang, Donghua
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p. 2107 - 2113
(2013/06/05)
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- A new route to Roflumilast via copper-catalyzed hydroxylation
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A new route to Roflumilast, a selective phosphodiesterase type 4 (PDE 4) inhibitor, is described. The synthetic procedure starts from 4-hydroxy-3-iodobenzoic acid to access the key intermediate 3- (cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid via copper-catalyzed hydroxylation and utilizes amide coupling to accomplish the synthesis of Roflumilast in 80% overall yield. Georg Thieme Verlag KG Stuttgart · New York.
- Ni, Feng,Li, Jianqi
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p. 3598 - 3602
(2013/02/22)
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- METHOD FOR THE TREATMENT OR PREVENTION OF RESPIRATORY INFLAMMATION WITH A CYCLOOXYGENASE-2 INHIBITOR IN COMBINATION WITH A PHOSPHODIESTERASE 4 INHIBITOR AND COMPOSITIONS THEREWITH
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A method is described for the prevention and/or treatment of respiratory inflammation, and in particular asthma and COPD, in a subject in need of such prevention or treatment, the method comprising administering to the subject a cycloogenase-2 inhibitor in combination with a phosphodiesterase 4 inhibitor. Also described are therapeutic and pharmaceutical compositions and kits that are useful in the present invention.
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Page/Page column 143-144
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ROFLUMILAST
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The present invention relates to a process for the preparation of 3-cyclopropylmethoxy-4-difluromethoxy benzoic acid of structural Formula I, and to the use of this compound as an intermediate for the preparation of roflumilast.
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Page/Page column 7
(2008/06/13)
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- NOVEL PROCESS FOR THE PREPARATION OF ROFLUMILAST
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The invention relates to novel processes for the preparation of high-purity roflumilast. The process involves reacting the anion of 4 - armino -3,5 dichloropyridine (I), with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (II), characterized in that the molar ratio of the employed anion of 4-amino-3,5 dichloropyridine to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is at least 1.5 and at most 3, preferably at least 1.8 and at most 2.7 particularly preferably at least 2 and at most 2.5 and very particularly preferably 2.2
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- FLUOROALKOXY-SUBSTITUTED BENZAMIDES AND THEIR USE AS CYCLIC NUCLEOTIDE PHOSPHODIESTERASE INHIBITORS
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Compounds of formula (I), in which one of the substituents R1 or R2 stands for hydrogen, 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or totally or partially fluorine-substituted 1-4C-alkoxy, and the other stands for totally or partially fluorine-substituted 1-4C-alkoxy, and R3 stands for phenyl, pyridyl, R31, R32 and R33-substituted phenyl or R34, R35, R36 and R37-substituted pyridyl, in which R31 stands for hydroxy, halogen, cyano, carboxyl, trifluoromethyl 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, amino, mono- or di-1-4C-atkylamino or 1-4C-alkylcarbonylamino; R32 stands for hydrogen, hydroxy, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy; R33 stands for hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy; R34 stands for hydroxy, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino; R35 stands for hydrogen, halogen, amino or 1-4C-alkyl; R36 stands for hydrogen or halogen; and R37 stands for hydrogen or halogen. These compounds constitute new effective bronchotherapeutic drugs
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