139755-83-2

Sildenafil 1 (Viagra(TM)), a well known and commercially important pharmaceutical drug, has been prepared using polymer-supported reagents in a multi-step, convergent process resulting in a clean and efficient preparation without the need for conventional purification methods. (C) 2000 Elsevier Science Ltd.

Sildenafil citrate monohydrate, well known as Viagra , is a drug for the treatment of erectile dysfunction. Here we present the X-ray crystal structure of the sildenafil base, C22H30N 6O4S. The compound crystallizes in the monoclinic system, space group P21/c with the unit cell parameters a = 17:273(1), b=17:0710(8), c=8:3171(4) A° , β =99:326(2), Z = 4, V = 2420:0(3) A°3. A comparison with the known crystal structures of sildenafil citrate monohydrate and sildenafil saccharinate is also presented.

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.

The invention discloses a preparation method of sildenafil. The method comprises the following steps: activating an intermediate compound B in an aprotic solvent by using thionyl chloride, reducing with 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-formamide in a zinc powder-ammonium chloride system in the presence of an acid-binding agent to obtain an intermediate compound E, and condensing to obtain an intermediate compound C; and cyclizing the intermediate compound C in an alcohol solvent under an alkaline condition to prepare sildenafil. The preparation method disclosed by the invention is short in reaction time, greatly shortens the production period so as to reduce the production cost, and is simple in operation and suitable for large-scale production.

Sulphonated graphene oxide was used for cascade condensation and cyclization reactions towards accessing substituted pyrazolo pyrimidinones. Further, sulphonation and amination reactions were integrated through continuous flow chemistry to access PDE-5 inhibitors. Herein, we report a simple continuous synthetic platform that reduce tedious manual operations and accelerate the synthesis of several potent inhibitors of phosphodiesterase type-5. The developed platform enabled us to perform one-flow multi-step, multi-operational process to synthesize the PDE-5 inhibitors such as sildenafil and its analogues in 32.3 min of the reaction time, with minimal human intervention and single solvent.

A general and efficient method for the synthesis of quinazolinones, quinoxalinones, benzooxazinones, and benzothiazoles from the reactions of α-keto acids with 2-aminobenzamides, benzene-1,2-diamines, 2-aminophenols, and 2-aminobenzenethiols, respectively, is described. The reactions were conducted under catalyst-free conditions, using water as the sole solvent with no additive required, and successfully applied to the synthesis of sildenafil. More importantly, these reactions can be conducted on a mass scale, and the products can be easily purified through filtration and washing with ethanol (or crystallized).

An improved, gram-scale synthesis of the blockbuster drug sildenafil, used for the treatment of male erectile dysfunction, has been developed. Unlike the previous literature, the current method demonstrates the use of arylacetic acid as an acyl source, a cheap oxidant K2S2O8, and water as the reaction medium in the key step of pyrrazolo[4,3-d]pyrimidin-7-one ring formation. As well as being a green and benign approach, the current method reduces the cost by half compared to our previous strategy. In addition, the general relevance of the method has been demonstrated in the synthesis of a variety of quinazolinone and benzothiazole derivatives with excellent functional group tolerance.

A facile access to fused pyrimidin-4(3H)-one derivatives has been established by using the metal-free ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines. The utilization of two readily available amines allowed a direct coupling strategy to quinazolinone natural product, bouchardatine, as well as sildenafil (Viagra) in a highly convergent manner. This journal is

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.

A simple and practical protocol was developed for the synthesis of sulfonamides by reacting organometallic reagents with SO2 gas generated on demand. SO2 was generated from readily available reagents safely in a highly contained and controlled fashion. The protocol allows the synthesis of sulfonamides without using either atom-inefficient SO2 surrogates or a SO2 cylinder that requires stringent storage regulations in the laboratory. The protocol was successfully applied to the synthesis of sildenafil.

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.

The invention sildenafil citrate intermediate sildenafil intermediate is represented by the formula (I) with a compound of the structure shown in the N - methyl piperazine reaction obtained, of formula (I) compound as, N - methyl piperazine or a salt thereof after being mixed, in order to water as a solvent for the reaction, of formula (II) compound of the structure shown. The present invention water is used as the solvent, can be directly filtered after the reaction formula (II) compound as, high purity of the product. (by machine translation)

The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.

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.

The invention relates to an improved sildenafil preparation method, characterized in that sildenafil is represented by the formula IV compound in the alkaline aqueous solution under the conditions of the cyclization reaction preparation, formula IV compound is represented by the formula I compound with a chloro formate form the active mixed anhydride (II), its without separation and purification directly reacted with compound III. The method for preparing sildenafil yield and high purity, low cost, and easy industrial production: . (by machine translation)

The invention discloses a preparation method of sildenafil and relates to the technical filed of chemical medicine synthesis. The method includes following steps: (1) carrying out a reaction between 2-ethyoxyl-5-(4-methylpiperazine-1-ylsulfonyl)benzoic acid with thionyl chloride in the presence of a catalyst to prepare an intermediate I; (2) carrying out a reaction between the intermediate I with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-methanamide in the presence of an acid-binding agent to prepare an intermediate II; (3) carrying out a cyclization reaction to the intermediate II in the presence of a specific alkali to obtain a crude product of sildenafil; and (4) performing recrystallization to obtain a pure product of sildenafil. In the invention, reduced pressure distillation for removing exceeded thionyl chloride is unnecessary so that pollution is avoided. Meanwhile, the preparation method can reduce device investment, can simplify technology and can increase efficiency.

The invention relates to an improved synthesis process for sildenafil which is a raw medical material for treating male erectile dysfunction (ED). The improved synthesis process is characterized by using different synthetic routes, a compound (I) is subjected to N-methyl piperazine reaction in water, crystallization is directly realized through adjustment of the pH value to obtain a compound (IV), the reaction is rapid, and no by-product is generated; the compound (IV) is subjected to reaction with a water-mixed solvent under the alkaline condition, and after the reaction is finished, crystallization is directly realized through adjustment of the pH value by addition of diluted hydrochloric acid, so as to obtain the pure sildenafil. The synthesis process for the prepared sildenafil is simple and convenient in operation, mild in reaction condition, high in yield and purity, and suitable for industrial production.

A unified approach to the tandem preparation of diverse nitrogen heterocycles via decarboxylative acylation of ortho-substituted amines with α-oxocarboxylic acids and subsequent intramolecular cyclizations has been developed. The key features of this work include: the first example of transition-metal-free decarboxylative amidation of α-oxocarboxylic acids with ortho-substituted amines, realization of intramolecular cyclization of amides employing nucleophiles that have previously been unexplored, mechanistic investigation of an unprecedented K2S2O8 promoted amide formation and its subsequent intramolecular cyclizations, and application to the synthesis of a best-selling marketed drug.

A novel palladium-catalyzed sulfination of aryl and heteroaryl halides is described. This reaction operates under mild conditions and provides access to a wide range of aryl and heteroaryl sulfinates, a useful and versatile class of synthetic intermediates. Capitalizing on this sulfination reaction, one-pot protocols allowing direct access to sulfones and sulfonamides have also been developed. The practicality of these transformations is illustrated with the parallel synthesis of analogues of the drug Viagra.

The pyrazolo pyrimidinone was prepared by treatment of 4-amino-5-pyrazole carboxamide with 2-ethoxy benzoic acid and the product characterized using NMR, high resolution mass spectrometry and X-ray crystallography. In the crystal, the hydrogen bonds and intermolecular interactions join the bridge between O26 of one molecule and C10-H10A of another. The molecule (C22H 30N6O4S) crystallized in the monoclinic P2(1)/c space group. Unit cell parameters for 5-(2-ethoxy-5-(4-methyl-piperazine-1- sulfonyl)-phenyl)-1-methyl-3-propyl-1,6-dihydro-pyrazolo(4,3-d)pyrimidin-7-one: a = 17.2898(4), b = 6.9755(3), c = 8.0757(2)?, β = 100.0710(10) and Z = 4.

A method for increasing blood flow to vital organs during cardiopulmonary resuscitation of a person experiencing a cardiac arrest may include performing standard or active compression decompression cardiopulmonary resuscitation on a person to create artificial circulation by repetitively compressing the person's chest such that the person's chest is subject to a compression phase and a relaxation or decompression phase. The method may also include administering one or more vasodilator drugs to the person to improve the artificial circulation created by the cardiopulmonary resuscitation. The method may also include binding at least a portion of the person's abdomen, either manually or with an abdominal compression device. Performing cardiopulmonary resuscitation on a person may include ventilating the person with either an impedance threshold device or a intrathoracic pressure regulator.

Synthesis of Sildenafil by the O-alkylation of 5-[2-hydroxy-5-(4- methylpiperazin-1-ylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H- pyrazolo-[4,3-d]pyrimidin-7-one 8 proved difficult because concomitant alkylation of the pyrimidine moity also occurred. The selective O-alkylation was carried by DCC assisted decarboxilative etherification of the carbonate 9.

Boronic compounds of formula II and the process for their preparation, wherein Y1 and Y2 are selected from hydroxyl, (C1-C4)alcoxyl and phenoxyl optionally substituted with one or two radicals independently selected from (C1-C4)alkyl and (C1-C4)alcoxyl; or alternatively Y1 and Y2 together with the boron atom can form a cyclic system. Process for the preparation of Sildenafil by reaction of a intermediate of formula II with a intermediate of formula III, wherein X3 is a leaving group and R1 is selected from H and (C1-C4)alkyl.

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.

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.

Disclosed herein the process for producing 5-[2-ethoxy-5-(4-methyl)piperazine-l-yl- sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or its salt thereof employing novel intermediate.

The present invention provides compositions and delivery methods to enhance treatment for sexual dysfunction or hypofunction through the delivery of phosphodiesterase 5 inhibitors to a mammal. Phosphodiesterase inhibitors are one example of a compound class used for this indication. Examples of compounds in this class include taldalafil and vardenafil and sildenafil. Furthermore, the present invention provides compositions and delivery methods to enhance the sildenafil concentration in solution, suspension and gel formulations and methods of parenteral, intradermal, sublingual, intranasal, and buccal sildenafil delivery.

Provided are processes for the preparation of sildenafil base and the citrate salt sildenafil. Also provided are sildenafil citrate water adduct and a method of preparing pharmaceutical compositions comprising combining the sildenafil citrate and/or sildenafil citrate water adduct with at least one pharmaceutically-acceptable excipient.

The instant invention relates to a combination of an alpha-2-delta ligand and a PDEV inhibitor for use in therapy, particularly in the curative, prophylactic or palliative treatment of pain, particularly neuropathic pain. Particularly preferred alpha-2-delta ligands are gabapentin and pregabalin. Particularly preferred PDEV inhibitors are sildenafil, vardenafil and tadalafil.

This invention is directed to the use phosphodiesterase type 5 (PDE5) inhibitors in the treatment of selective serotonin reuptake inhibitor (SSRI) induced sexual dysfunction. Specifically, this invention is directed to a method for treating an animal to cure; prevent or ameliorate SSRI induced sexual dysfunction which comprises administering to the animal an effective amount of the inhibitor. The animal may be a male or a female human. The invention also includes the use of such inhibitors in the manufacture of a medicament to prevent; cure or ameliorate SSRI induced sexual dysfunction. Moreover, the invention includes a kit comprising a SSRI, such as sertraline, fluoxetine, paroxetine, and a PDE5 inhibitor, such as sildenafil citrate, for the treatment or prevention of serotonergic associated disorders such as depression, obsessive compulsive disorder or panic disorder, while reducing or preventing sexual dysfunction.

The present invention relates to kits, and aspects thereof, for reducing or eliminating the aching associated with the administration of multiple doses of a PDE5 inhibitor, the kits comprising a plurality of pharmaceutical compositions for sequential administration over a period of time which compositions comprise increasing amounts of PDE5 inhibitor starting with an amount which gives a sub-optimal response and ending with an amount which gives an optimal response.

There is provided a process for the production a compound of general formula I: wherein A, R1, R2, R3 and R4 have meanings given in the description, which process comprises the reaction of a compound of formula II, wherein Rx is a group substitutable by an aminopyrazole, with a compound of general formula III

There is provided a process for the production a compound of general formula I: 1wherein A, R1, R2, R3 and R4 have meanings given in the description, which process comprises the dehydrogenation of a compound of general formula II, 2

A “one-pot” process is described herein for the production of pyrazole compounds of general formula (II) comprising the steps of reacting a compound of general formula (III) with an acylating agent in the presence of a base and an optional activating agent followed by the addition of a hydrazine compound in situ.

Methods for the prevention and treatment of diseases and conditions of the eye including, but are not limited to: central retinal artery occlusion; central retinal vein occlusion; optic neuropathy including, but not limited to, anterior ischemic optic neuropathy and glaucomatous optic neuropathy; and macular (dry) degeneration are disclosed. These methods comprise administering to a patient a prophylactically or therapeutically effective amount of a cyclic guanosine 3′,5′-monophosphate phosphodiesterase type 5 inhibitor. Pharmaceutical compositions and dosage forms comprising cyclic guanosine 3′,5′-monophosphate phosphodiesterase type 5 inhibitors are also disclosed.

The use of a compound of formula (I) wherein R1is H; C1-C3alkyl; C1-C3perfluoroalkyl; or C3-C5cycloalkyl; R2is H; optionally substituted C1-C6alkyl; C1-C3perfluoroalkyl; or C3-C6cycloalkyl; R3is optionally substituted C1-C6alkyl; C1-C6perfluoroalkyl; C3-C5cycloalkyl; C3-C6alkenyl; or C3-C6alkynyl; R4is optionally substituted C1-C4alkyl, C2-C4alkenyl, C2-C4alkanoyl, (hydroxy)C2-C4alkyl or (C2-C3alkoxy)C1-C2alkyl; CONR5R6; CO2R7; halo; NR5R6; NHSO2NR5R6; NHSO2R8; SO2NR9R10; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R5and R6are each independently H or C1-C4alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino, 4-N(R11)-piperazinyl or imidazolyl group; R7is H or C1-C4 alkyl; R8is optionally substituted C1-C3alkyl; R9and R10together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinyl group; R11is H; optionally substituted C1-C3alkyl; (hydroxy)C2-C3alkyl; or C1-C4alkanoyl; R12is H; optionally substituted C1-C6alkyl; CONR13R14; CSNR13R14; or C(NH)NR13R14; and R?13? and R14are each independently H; C1-C4alkyl; or substituted C2-C4alkyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man; a pharmaceutical composition for said treatment; and a method of said treatment of said male animal with said pharmaceutical composition or with said either entity.

Sildenafil, a known pharmaceutical chemical useful in treatment of male sexual dysfunction, is prepared by processes in which the final chemical intermediate is of significantly lower basicity than sildenafil itself, so that sildenafil can be extracted in substantially pure form from the organic reaction mixture in which it is made by adding an aqueous medium of appropriately chosen acidic pH and causing phase shift of the sildenafil to occur selectively into the aqueous phase.

A process is provided for the preparation of a compound of formulae (IA) (sidenafil) and (IB) comprising reacting a compound of formula (IIA) and (IIB) respectively in the presence of—OR, wherein R in the case of formation of compound (IA) is CH2CH3and R in the case of formation of compound (IB) is CH2CH2CH3, where X is a leaving group:

Methods for the prevention and treatment of diseases and conditions of the eye including, but are not limited to: central retinal artery occlusion; central retinal vein occlusion; optic neuropathy including, but not limited to, anterior ischemic optic neuropathy and glaucomatous optic neuropathy; and macular (dry) degeneration are disclosed. These methods comprise administering to a patient a prophylactically or therapeutically effective amount of a cyclic guanosine 3',5'-monophosphate phosphodiesterase type 5 inhibitor. Pharmaceutical compositions and dosage forms comprising cyclic guanosine 3',5'-monophosphate phosphodiesterase type 5 inhibitors are also disclosed.

The present invention relates to methods for treating nitrate-induced tolerance in a mammal by administering a nitrate-induced tolerance treating amount of a compound of formulae (I), (II), (III) (IV), (V), (VI), (VII), (VIII), (IX), (XA) or (XB) as defined herein, or the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites or stereoisomers thereof. The invention also relates to pharmaceutical compositions for the treatment of nitrate-induced tolerance in a mammal comprising a nitrate-induced tolerance treating amount of a compound of formulae (I), (II), (III) (IV), (V), (VI), (VII), (VIII), (IX), (XA) or (XB) as defined herein, or the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites or stereoisomers thereof, and a pharmaceutically acceptable vehicle, diluent or carrier. The invention further relates to methods of preventing nitrate-induced tolerance in a mammal comprising administering a nitrate-induced tolerance preventing amount of a cGMP PDE inhibitor.

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.

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.

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