- Improved synthesis process of sildenafil
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The invention discloses an improved synthesis process of sildenafil, belonging to the technical field of preparation of drug intermediates. In the process, high-concentration chlorosulfonic acid is prevented from being used as a reaction solvent and reagent, and 3-5 equivalent chlorosulfonic acid is used as a reaction reagent. Compared with the prior art, the process has the characteristics of economical performance, environmental protection, safety and the like, for example, equipment cannot be corroded, the post-treatment of reaction becomes simpler, the solvent is single and can be reused, product purity is high, and the like.
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Paragraph 0039-0045
(2021/06/21)
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- Method for preparing sildenafil citrate
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The invention discloses a method for preparing sildenafil citrate. The preparation method comprises the following steps: (a) adding a compound II into chlorosulfonic acid for a reaction to generate anintermediate III; (b) reacting the intermediate III with N-methyl piperazine to generate a crude sildenafil product; (c) recrystallizing the crude sildenafil product to obtain a pure sildenafil product; and (d) carrying out a salifying reaction on the pure sildenafil product to obtain sildenafil citrate. The method is beneficial for industrial production.
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Paragraph 0094-0098
(2020/05/30)
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- Preparation method of sildenafil
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The invention provides a preparation method of sildenafil. The preparation method comprises the following steps: dissolving a compound III in an organic solvent I, adding a compound II for amidation reaction, washing and drying to obtain a compound IV; directly adding the solution obtained in the step S1 into a chlorosulfonic acid-thionyl chloride mixture for chlorosulfonation reaction without separation and purification, pouring ice water after the reaction is finished, layering, taking an organic phase, washing and drying to obtain a compound V; adding the compound V obtained in the S2 intoN-methyl piperazine, carrying out N-sulfonation reaction for 0-4 hours, concentrating, adding alkali and an organic solvent II, heating to carry out cyclization reaction for 2-6 hours, adding water for cooling, adding hydrochloric acid for acidification, and filtering to obtain a target compound I. A continuous method is adopted for synthesis, and the production efficiency is improved.
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Paragraph 0038-0040; 0043-0045; 0048-0050; 0053-0055; 0058
(2020/10/04)
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- Sildenafil intermediate synthesis method
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Sildenafil has a good effect of treating male erectile dysfunction (ED) in clinic. Many preparation methods of sildenafil have been already reported and mostly belong to two-step synthesis. The two-step post-treatment operation is relatively tedious, and yield is low. The invention provides a synthesis method of a sildenafil intermediate, comprising the following steps: dissolving a compound II inan organic aprotic solvent, and adding a compound I to carry out a condensation reaction; adding alkali to carry out a cyclization reaction after it is monitored that the compound II is completely reacted so as to obtain a compound IV. By ''one-pot'' synthesis, generation of ''three wastes (waste gas, waste water and industrial residue)'' is reduced, reaction time is greatly shortened, reaction yield is raised, and stability is good.
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Paragraph 0030; 0033-0046
(2018/10/19)
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- Preparation method of sildenafil citrate
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The invention belongs to the field of chemical drugs, and in particular relates to a preparation method of sildenafil citrate. The invention provides the preparation method of sildenafil citrate. Thepreparation method comprises the following steps: a) adding a compound of a structure as shown in a formula (I) and thionyl chloride into chlorosulfonic acid, and carrying out a sulfonation reaction to generate a compound of a structure as shown in a formula (II); b) dissolving the compound of the structure as shown in the formula (II) in dichloromethane and adding N-methyl piperazine to carry outa substitution reaction at 20-30 DEG C to obtain sildenafil; and c) adding citric acid into a sildenafil aqueous solution to adjust the pH value for a salt forming reaction so as to obtain the sildenafil citrate. Experimental results verify that the sildenafil citrate prepared by the preparation method is high in yield and high in purity.
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Paragraph 0031; 0032
(2018/06/16)
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- Sedinafine derivatives of the microwave-assisted method for preparing
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The invention discloses a microwave-assisted synthesis method of sildenafil derivatives, which mainly comprises the following steps: by using 2-alkoxybenzoic acid and 4-amino-1-methyl-3-n-propyl-1H-pyrazolyl-5-formamide as initial raw materials, carrying out amidation, cyclization, mononitration, nitro reduction, guanidylation and the like to obtain the sildenafil derivatives. The method greatly shortens the reaction time, enhances the reaction efficiency, has the advantages of high yield and high purity, is simple to operate and easy to control, and is beneficial to industrial production of sildenafil analogs.
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- Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs
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Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this Letter we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.
- Wang, Cuihua,Ashton, Trent D.,Gustafson, Alden,Bland, Nicholas D.,Ochiana, Stefan O.,Campbell, Robert K.,Pollastri, Michael P.
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p. 2579 - 2581
(2012/05/05)
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- Liquid-chromatography determination of impurities in sildenafil citrate
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A simple, economic and time-efficient stability-indicating, reversed phase liquid chromatographic (RP-LC) method has been developed for the analysis of sildenafil citrate in the presence of both process related impurities and degradation products generated by decomposition. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. Considerable degradation was found to occur in alkali and oxidative stress conditions. The drug was found to be stable to other stress conditions attempted. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 99.6 %. The method was validated with respect to specificity, linearity, accuracy, precision, robustness, limit of detection and quantification. The method is simple, rapid, selective, accurate and stability indicating, useful in the quality control of bulk manufacturing of sildenafil.
- Kumar, A.Phani,Ganesh,Prasad, K. Hari,Hariharakrishnan,Dubey,Rao, B. Venugopala
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experimental part
p. 1219 - 1222
(2012/01/05)
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- PROCESS FOR THE PREPARATION OF SILDENAFIL AND INTERMEDIATES THEREOF
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The present invention discloses a process for preparing sildenafil and its intermediates having the structures outlined below: In particular, the present invention provides a process for preparing the compound of formula (I) and its intermediates, i.e. the compounds of formula (I), (II), (III) and (IV). The compound of formula (I) is obtained from the compound of formula (II); the compound (II) is obtained from the compound of formula (III) and methylpiperazine; the compound (III) is obtained by treating the compound of formula (IV) with chlorosulfonic acid; the compound (IV) is obtained though treating the compound of formula (V) in the presence of at least one selected from POX3, PX3, PX5 and their mixtures in any ratio. The process for preparing the compound of formula (I) according to the present invention reduces the side reactions in the processes of the prior art. These improvements lead to higher yields and a better industrial applicability with easier controlling of the reaction.
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Page/Page column 7
(2010/03/31)
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- PROCESS FOR THE PREPARATION OF SILDENAFIL
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The present invention is directed to a process for the preparation of the compound of Formula (I) : comprising the step of converting a compound selected from the group consisting of the compounds of formulae (II), (III) and (IV) : wherein X is halogen, in one or more steps to give the compound of formula (I). The invention is also directed to a process for the preparation of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Moreover, the invention relates to intermediates suitable for use in the above processes as well as processes for their preparation.
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Page/Page column 18; 14
(2008/12/06)
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- Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction
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The 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3- propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, sildenafil, is a cGMP-specific phosphodiesterase-5 (PDE5) inhibitor used for penile erectile dysfunction. In the search for more potent and selective PDE5 inhibitors, new sildenafil analogues (6a-v), characterized by the presence on the sulfonyl group in the 5′ position of novel N-4-substituted piperazines or ethylenediamine moiety, were prepared by traditional and microwave-assisted synthesis and tested in rabbit isolated aorta and corpus cavernosum. Similarly to sildenafil, several analogues showed IC50 values in the nanomolar range. In the in vitro studies, all the tested compounds caused concentration-dependent relaxations in both rabbit isolated aorta and corpus cavernosum. All sildenafil analogues potentiated the nitric oxide-dependent vasodilation in endothelium-intact rabbit aorta. Compound 6f exhibited great pEC50 value in corpus cavernosum, and compounds 6r and 6u in isolated aorta were found as potent as sildenafil for inhibiting PDE5. Because several analogues were significantly more lipophilic than sildenafil, these compounds may offer a new lead for development of new sildenafil analogues.
- Flores Toque, Haroldo A.,Priviero, Fernanda B. M.,Teixeira, Cleber E.,Perissutti, Elisa,Fiorino, Ferdinando,Severino, Beatrice,Frecentese, Francesco,Lorenzetti, Raquel,Baracat, Juliana S.,Santagada, Vincenzo,Caliendo, Giuseppe,Antunes, Edson,De Nucci, Gilberto
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p. 2807 - 2815
(2008/12/22)
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- Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors
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Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
- Haning, Helmut,Niewoehner, Ulrich,Schenke, Thomas,Lampe, Thomas,Hillisch, Alexander,Bischoff, Erwin
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p. 3900 - 3907
(2007/10/03)
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- A modified, economical and efficient synthesis of variably substituted pyrazolo[4,3-d]pyrimidin-7-ones
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1-Methyl-3-propyl-1H-pyrazole-5-carboxylic acid (3) was exclusively brominated at the 4-position by bromine in the dark. Brominated product 8 was then converted into 1-methyl-3-propyl-1H-pyrazole-5-carboxamide 9 by successive treatment with thionyl chloride and ammonium hydroxide. Carboxamide 9 was treated with various aroyl amides under microwave (MW) irradiation to afford 4-aroylamino-1-methyl-3-propyl-1H-pyrazole-5-carboxamides 10-22 and 5-aryl-1-methyl-3-propyl-1,6-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-ones 23-35. The 1H-pyrazole-5-carboxamides 10-22 were also converted to pyrimidinones 23-35 either by conventional heating or by MW irradiation. However, MW irradiation method gives excellent yields in very short time.
- Khan, Khalid Mohammed,Maharvi, Ghulam Murtaza,Choudhary, Muhammad Iqbal,Atta-Ur-Rahman,Perveen, Shahnaz
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p. 1085 - 1093
(2007/10/03)
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- Method of treating a patient having precancerous lesions with phenyl purinone derivatives
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Derivatives of Phenyl Purinone are useful for the treatment of patients having precancerous lesions. These compounds are also useful to inhibit growth of neoplastic cells.
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- An improved process for preparing a pyrazolopyrimidinone derivative
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An improved process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n.propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, which allows to obtain the desired product in good yield and high purity degree, is described.
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- An improved process for preparing a therapeutically active pyrazolopyrimidinone derivative
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An improved process which allows to obtain 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n.propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known with the generic name sildenafil, in pure form and very good yield and further demontrated to be economically advantageous when compared to the known processes.
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- Sildenafil (Viagra(TM)), a potent and selective inhibitor of type 5 CGMP phosphodiesterase with utility for the treatment of male erectile dysfunction
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5-(2'-Alkoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-ones, and in particular our preferred compound, sildenafil (VIAGRA(TM)), discovered through a rational drug design programme, are potent and selective inhibitors of the type 5 cGMP phosphodiesterase from both rabbit platelets and human corpus cavernosum. Sildenafil is currently in the clinic for the oral treatment of male erectile dysfunction.
- Terrett, Nicholas K.,Bell, Andrew S.,Brown, David,Ellis, Peter
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p. 1819 - 1824
(2007/10/03)
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- Pyrazolopyrimidinone antianginal agents
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Compounds of the formula STR1 and pharmaceutically acceptable salts thereof are selective cGMP PDE inhibitors which are useful in the treatment of such diseases and adverse conditions as angina, hypertension, congestive heart failure, reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disorders of gut motility.
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- PYRAZOLOPYRIMIDINONE ANTIANGINAL AGENTS
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Compounds of the formula:wherein R1 is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R2 is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl; R3 is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or (C3 -C6 cycloalkyl)C1-C6 alkyl; R4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R6)-piperazinyl group; R5 is H, C1-C4 alkyl, C1-C3 alkoxy, NR7 R8, or CONR7 R8 ; R6 is H, C1-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (R7 R8 N)C2 -C6 alkyl, (R7 R8 NCO)C1-C6 alkyl, CONR7 R8, CSNR7 R8 or C(NH)NR7 R8 ; R7 and R8 are each independently H, C1-C4 alkyl, (C1-C3 alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl; and pharmaceutically acceptable salts thereof, are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis
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