- 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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Read Online
- ANTI-INFLAMMATORY COMPOUND, AND PREPARATION AND USE THEREOF
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The present invention provides an anti-inflammatory compound, which is a compound having a structure (I) as shown below: The compound is a target that is important for autoimmune activation, and that has strong inhibitory effect on PDE4 and penetrates the skin easily, and is a new type anti-inflammatory compound that is easily degraded.
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Paragraph 0387-0391
(2020/12/13)
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- Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors
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Metal-mediated C-H functionalization of cyclic N-oxides was exploited to access a series of new difluoromethylated analogs of imidazolidinone-based PDE4 inhibitor CMPI in a diastereoselective manner. Among the products synthesized, compounds with fine-tuned activity/selectivity profiles compared to both CMPI and the clinically applied apremilast were identified. From these studies, an unusual fused 1,2-oxazinoimidazolidinone heterocyclic system was suggested as a novel scaffold for the design of potent and selective PDE4 inhibitors. Computational studies suggest that the oxygen atom in the imidazolidinone unit can bind to the metal ion center (most likely Mg2+). DFT calculations of the relative interaction energies of inhibitors with Mg2+ and Zn2+ ions were performed on a model of the bimetal active site of PDE4.
- Dorokhov, Valentin S.,Golovanov, Ivan S.,Tartakovsky, Vladimir A.,Sukhorukov, Alexey Yu.,Ioffe, Sema L.
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supporting information
p. 6900 - 6908
(2018/10/20)
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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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Paragraph 0020-0021; 0277; 0279
(2018/05/16)
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- Synthesis method of roflumilast key intermediate
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The invention discloses a synthesis method of a roflumilast key intermediate. Specifically speaking, the synthesis method comprises the following steps: (1) preparing 3-methoxy-4-difluoro methoxybenzaldehyde; (2) preparing 3-hydroxy-4-difluoro methoxybenzaldehyde; (3) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzaldehyde; (4) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzoic acid. Compared with the existing synthesis method, the synthesis method disclosed in the invention has the advantages that low-price raw materials are adopted, thereby greatly reducing the production cost; vanillin serves as a starting material, thereby avoiding generation of similar impurities; column chromatography is replaced with recrystallization which serves as a purification way, thereby facilitating large-scale production application, and the yield and the purity are higher.
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Paragraph 0038; 0046-0048
(2017/07/21)
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- Roflumilast intermediate 3-cyclopropanecarboxylic methoxy-4-difluoro methoxylphenylboronic preparation of formic acid
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The invention mainly aims to provide a simple method for preparing a roflumilast key intermediate 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid. In the process, 3-floro-4-hydroxy benzaldehyde is taken as a raw material and undergoes etherification reaction to obtain 4-difluoromethoxy-3-fluorobenzaldehyde, then 4-difluoromethoxy-3-fluorobenzaldehyde undergoes electrophilic substitution by using alkoxy phenylcyclofluorine to obtain 3-cyclopropyl methoxy-4-difluoromethoxy benzaldehyde and finally 3-cyclopropyl methoxy-4-difluoromethoxy benzaldehyde is oxidized by sodium chlorite to obtain 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid. The method has the beneficial effects that during the first-step reaction, the problem of selective etherification does not exist as hydroxy in the raw material substrate is single; the product is single; the yield and purity of the product are highe so that purification through column chromatography is not needed; poisons and hazardous materials are not used in the three reaction processes; the reaction conditions are mild; and the method is simple and convenient to operate, is simple in aftertreatment and is very suitable for industrial mass production; therefore the method is a low-cost and environment-friendly synthesis process.
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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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Paragraph 0041; 0042
(2016/10/10)
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- Preparation method for roflumilast intermediates
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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.
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Paragraph 0023; 0032
(2016/10/10)
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- Method for preparing caffeic acid derivative
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The invention discloses a method for preparing a caffeic acid derivative. A compound shown as the formula II serves as a raw material to be subjected to a substitution reaction with haloalkane to prepare a compound shown as the formula III, and the compound shown as the formula III and acetic anhydride are subjected to a Perkin reaction to prepare a compound shown as the formula I, namely, the target object caffeic acid derivative, wherein the structures of the compounds shown as the formula I, the formula II and the formula III are shown in the specification, wherein R represents methyl or cyclopropyl cyclopropyl. According to the method, the synthetic route is short, the product yield is high, adopted reagents are low in toxicity and safe, the production cost is low, and the method is suitable for large-scale industrial production.
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Paragraph 0018
(2017/04/27)
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- Novel 3-cyclopropylmethoxy-4-alkoxybenzamide PDE (phosphodiesterase) 4 inhibitors
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The invention discloses novel 3-cyclopropylmethoxy-4-alkoxybenzamide PDE (phosphodiesterase) 4 inhibitors. The inhibitors are compounds represented in a general formula I or a general formula II, prodrugs thereof, pharmaceutically usable salts thereof or solvates thereof, wherein R is independent methyl (Me-) or difluoromethyl (CF2H-); R is independent H, Me or Et; R is independent H, MeO or Cl; CnH(2n+2) is alkyl, and N is larger than or equal to 2; a substance shown in the specification is a substituted benzene ring or pyridine ring; X is C or N; Y is C or N. The novel 3-cyclopropylmethoxy-4-alkoxybenzamide PDE 4 inhibitors have the advantages of high in-vitro enzyme inhibition activity, capability of selective application to PDE4 and good anti-inflammation effect and anti-depression effect.
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Paragraph 0025; 0026
(2016/10/10)
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- Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships
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In this study, a series of catechol-based amides (8a-n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a-n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8j with a short amide linker (-CONHCH2-) displayed comparable PDE4CAT inhibitory activity (IC50 = 410 nM) with rolipram. More interestingly, compound 8g, a potent and selective PDE4D inhibitor (IC50 = 94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8g forms three extra H-bonds with the N-H of residue Asn487 and two water molecules.
- Zhou, Zhong-Zhen,Ge, Bing-Chen,Chen, Yu-Fang,Shi, Xiu-Dong,Yang, Xue-Mei,Xu, Jiang-Ping
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p. 7332 - 7339
(2015/11/16)
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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 15
(2014/05/07)
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- Novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases
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The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4- yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.
- Armani, Elisabetta,Amari, Gabriele,Rizzi, Andrea,Fanti, Renato De,Ghidini, Eleonora,Capaldi, Carmelida,Carzaniga, Laura,Caruso, Paola,Guala, Matilde,Peretto, Ilaria,La Porta, Elena,Bolzoni, Pier T.,Facchinetti, Fabrizio,Carnini, Chiara,Moretto, Nadia,Patacchini, Riccardo,Bassani, Franco,Cenacchi, Valentina,Volta, Roberta,Amadei, Francesco,Capacchi, Silvia,Delcanale, Maurizio,Puccini, Paola,Catinella, Silvia,Civelli, Maurizio,Villetti, Gino
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p. 793 - 816
(2014/03/21)
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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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Paragraph 0053
(2014/09/30)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Paragraph 0965
(2013/04/10)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 244
(2013/04/13)
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- Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridynyl alkylene alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 10
(2008/06/13)
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- Substituted pteridines for the treatment of inflammatory diseases
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The invention relates to new pteridines which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin or eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions which contain these compounds.
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Page/Page column 6
(2008/06/13)
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- NEW HETEROCYCLIC AMIDE COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The present invention relates to novel heterocyclic compounds that inhibit phosphodiesterase type 4 (PDE 4). The compounds are useful for treating inflammatory conditions, diseases of the central nervous systems and insulin resistant diabetes.
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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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- Compounds useful for treating allergic or inflammatory diseases
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Novel cyclohexanes of Formulas (I) and (II) STR1 are described herein. They inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production; these compounds are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase V.
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