cas 171596-29-5, Tadalafil | Articles data

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Preparation method of tadalafil
The invention discloses a preparation method of tadalafil. According to the method, a compound I is adopted as a starting material, the tadalafil is obtained through condensation, Fisher indole synthesis reaction, Pictet-Spengler reaction, acylation and ring closing in sequence, and dangerous reagents (n-butyllithium and the like) are not used during ring closing. The reaction route is simple, the reaction condition is mild, the purity is high, the cost is relatively low, the operation is simple and convenient, and industrial production is easy.
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(2022/03/27)

Preparation method of tadalafil
The invention provides a preparation method of tadalafil, and relates to the technical field of medicines. The preparation method comprises the steps of taking D-cis-carboline hydrochloride as an initial raw material, carrying out acylating chlorination reaction on the D-cis-carboline hydrochloride and chloroacetyl chloride under the action of an acid-binding agent, carrying out primary refining on an obtained chloroacetylate intermediate crude product, carrying out aminolysis cyclization reaction on the obtained high-purity chloroacetylate intermediate and methylamine, adding a pulping solvent into the obtained tadalafil crude product for pulping, carrying out solid-liquid separation, washing the obtained solid product, and drying to obtain the high-purity tadalafil. Moreover, the D-cis-carline hydrochloride raw material is cheap, easy to obtain and stable in quality, the D-cis-carline hydrochloride raw material is used as a starting raw material, the production period of tadalafil is short, and the production cost is low.
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Paragraph 0052-0054; 0056; 0059; 0061; 0064; 0066

(2022/01/12)

Preparation method of phosphodiesterase inhibitor
The invention discloses a preparation method of a phosphodiesterase inhibitor and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: starting the raw material 1 and methanol to prepare the intermediate I without adding organic solvent crystallization. After the series of centrifugation, washing and drying, the intermediate II is directly condensed and cyclized with piperonal, and a final product tadalafil is prepared by chloroacetylation, aminolysis and refining steps. The method improves the product yield and quality, greatly shortens the reaction period, reduces the operation steps and the production cost, and is suitable for industrial mass production.
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(2021/11/03)

Method for preparing Tadalafil by one-pot method
The invention discloses a method for preparing Tadalafil by a one-pot method. The method for preparing the Tadalafil by the one-pot method comprises the steps that D-Tryptophan methyl ester hydrochloride and piperonal are used as starting materials, and a single-configuration high-purity compound I hydrochloride is obtained through a Pictet-Spengler reaction; the compound I hydrochloride is subjected to an acylation reaction with chloroacetyl chloride in an organic base system of an aprotic solvent to obtain a mixed reaction solution; and the mixed reaction solution is directly added to a methylamine solution to undergo an aminolysis cyclization reaction without treatment, and the mixture is subjected to cooling crystallization to obtain the Tadalafil after the reaction. According to the method for preparing the Tadalafil by the one-pot method, the usage amount of the solvent is reduced, the amount of waste liquid discharge is effectively controlled, and environmental protection is facilitated; the production cycle is shortened, and the process efficiency is improved; and the yield is improved, and the cost is reduced. Compared with an existing process route, the method for preparing the Tadalafil by the one-pot method is more environmentally friendly, more efficient and lower in cost, and is more suitable for industrial production.
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Paragraph 0031; 0033; 0034; 0036; 0037; 0039; 0040; 0042

(2020/03/06)

Tadalafil preparation method
The invention belongs to the field of chemical synthesis, and particularly relates to a tadalafil preparation method. According to the method, easily-available piperonyloyl chloride and the like are used as raw materials; the prepared intermediate 1 and sarcosine are subjected to an amidation reaction; under specific reaction conditions, high-purity tadalafil can be prepared at a high yield; and the whole synthesis process is only divided into two steps, and the product can be prepared in a one-pot boiling mode. Compared with the method in the prior art, the method of the invention significantly reduces the complex reaction steps, is simple in operation, and is suitable for large-scale industrial production of tadalafil.
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Paragraph 0054-0055; 0058; 0068-0075

(2020/02/10)

Production process of tadalafil bulk drug
The invention belongs to the technical field of medicines, and particularly relates to a production process of a tadalafil bulk drug. The production process of the tadalafil bulk drug comprises the following steps: A1, carrying out an esterification reaction on methanol and D-tryptophan to obtain an intermediate I; A2, performing a condensation reaction on the intermediate I and heliotropin to obtain an intermediate II; A3, performing an acylation reaction on the intermediate II and chloroacetyl chloride to obtain an intermediate III; and A4, carrying out a cyclization reaction on the intermediate III and monomethylamine to obtain the tadalafil bulk drug. According to the method, a reaction path is reasonably selected, and meanwhile, the process details of each reaction step are deeply optimized, so high purity and yield of a product of each step of reaction can be obtained, the prepared tadalafil bulk drug is low in cost and good in stability, the economical efficiency of the whole reaction path is improved, and production cost is reduced.
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(2020/07/02)

TADALAFIL SYNTHESIS METHOD
?The invention relates to a new one-pot continuous method for the synthesis of tadalafil from methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate and methylamine in aprotic solvent. The method allows to obtain high-quality tadalafil (I) with the high yield at low temperature in a short time.
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Page/Page column 11-22

(2020/11/03)

Method for synthesizing tadalafil
The invention discloses a method for synthesizing tadalafil. Tadalafil is synthesized from D-tryptophan and a compound of formula 1. The method for preparing tadalafil of the invention can effectivelyprepare tadalafil. In addition, the starting material piperonyl dimethyl acetal of the preparation method is easy to obtain as a non-controlled material, the procurement and management are not restricted, the use of the controlled material piperonyl is effectively avoided, the management and procurement are convenient, the process steps are short, the production cost is greatly reduced, and the preparation method is more suitable for large-scale and industrial production of tadalafil.
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(2019/10/02)

Preparation method of tadalafil and intermediate of tadalafil
The invention relates to a preparation method of a selective and reversible inhibitor tadalafil of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5). The method comprises the following steps: carrying out an esterification reaction on D-tryptophan as an initial raw material and methanol under catalysis of sulfuric acid to generate D-tryptophan methyl ester (an intermediate1); carrying out a Pictet-Spengler (P-S) reaction on the D-tryptophan methyl ester and heliotropin to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (an intermediate 2); carrying out an amidation reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride and chloroacetyl chloride to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (an intermediate 3); andfinally carrying out a cyclization reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester and a methylamine alcohol solution to obtain the tadalafil. The method provided by the invention has the advantages of easily available raw materials, simple operation, greenness, environmental protection and low costs, andis suitable for industrial production.
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(2019/11/20)

Preparation method of tadalafil
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tadalafil. The preparation method comprises the following steps: subjecting (1R,3R)-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-methylenedioxy phenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (compound A) and a methylamine aqueous solution to a temperature controlled reaction inthionyl chloride, adding purified water for crystallization, and then performing centrifugation to obtain tadalafil. Organic solvent residues meet pharmacopeia standards without the need of recrystallization. According to the method, the yield of tadalafil is greatly increased, the operation is simplified, the dosage of an organic solvent is reduced, the purification operation is reduced, and themethod is suitable for industrial production.
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Paragraph 0010; 0011; 0012

(2019/08/12)

Synthesis preparation method of Tadalafil
The invention discloses a synthesis preparation method of Tadalafil. According to the method, Tadalafil is synthesized by taking compounds shown in the formula II and the formula III (please see the formulas in the description) as start materials. The synthesis preparation method of Tadalafil shown in the formula I (please see the formula in the description) has the advantages of being mild in reaction condition, easy and convenient to operate in process, high in yield, good in stability and controllability, friendly to environment and the like and is suitable for industrialized production.
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Paragraph 0043; 0044; 0047; 0048; 0049; 0051; 0052

(2017/08/25)

The method of synthesis for preparing compound
A synthesis method of a compound shown as a formula I is provided. The method includes (1) bringing a compound shown as a formula 1 into contact with BOC anhydride to produce a compound shown as a formula 2; (2) bringing the compound shown as the formula 2 into contact with a compound shown as a formula 3 to produce a compound shown as a formula 4; (3) subjecting the compound shown as the formula 4 to amino deprotection to produce a compound shown as a formula 5; and (4) bringing the compound shown as the formula 5 into contact with a compound shown as a formula 6 to produce the compound shown as the formula I that is Tadalafil. The method prepares the Tadalafil through four steps of reactions. The total yield reaches 36.1%. Process steps of the method are simple. Initial raw materials are cheap and easily available. All the intermediates are easy to purify. After-treatment operation is simple. The content of impurities in a finished product is low. The target product is high in purity. Compared with other Tadalafil preparing processes at present, the method obviously reduces environment pollution and benefits industrial production.
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Paragraph 0054; 0073-0074

(2017/09/01)

Preparation method of Tadalafil compounds
The invention discloses a preparation method of Tadalafil compounds. In the synthetic method, the compound IV is obtained by two-step acylation reaction of a starting material D-tryptophan methyl ester hydrochloride with chloroacetyl chloride and 3,4-dyhydroxy-benzoyl chloride, the compound is obtained by cyclization reaction of the compound IV with phosphorus acyl halide, the compound VI is generated from the compound V via asymmetric hydride reaction and is then reacted with methylamine, and the final Tadalafil compounds are obtained through cyclization reaction of dibromomethane. With the method, use of heliotropin of state controlled chemicals is avoided, cis-type carbine intermediate is obtained by adopting asymmetric hydrogenation, and ee value is above 99%; the preparation method is simple in operation and synthetic reaction, moderate in reaction condition, high in purity and yield, and suitable for industrialized production.
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(2017/08/15)

Key intermediate and synthesis method thereof, and application of key intermediate in preparing tadalafil
The invention discloses a key intermediate and a synthesis method thereof, and application of the key intermediate in preparing tadalafil. The synthesis method comprises the following steps: by using D-tryptophan methyl ester hydrochloride and 3,4-dihydroxybenzaldehyde as raw materials, carrying out condensation cyclization, chloracetylation and aminolysis cyclization to generate the key intermediate for preparing tadalafil. The method has the advantage of accessible raw materials, and overcomes the technical defects due to the use of the police-controlled precursor chemical heliotropin as the raw material in the prior art. The method has the advantages of no need of any catalyst and high yield in the preparation process. The obtained key intermediate can be used for preparing tadalafil. Thus, the synthesis method is simple and easy to implement, has the advantages of stable technique and low cost, and is suitable for industrial large-scale production. The structural formula of the key intermediate is disclosed as Formula (III).
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(2016/10/08)

Compound acyl intermediate as well as synthetic method thereof and application thereof in preparing tadalafil
The invention discloses a compound acyl intermediate as well as a synthetic method and application thereof in preparing tadalafil. The synthetic method comprises the following steps: preparing (1R, 3R)-methyl-1-(3,4-dihydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyridino[3,4-b]indol-3-carboxylic acid (compound I) by taking D-tryptophan methyl ester hydrochloride and 3,4-dihydroxy benzaldehyde as raw materials, and allowing the compound I to have chloroacetylation with chloroacetyl chloride to generate the compound acyl intermediate. By adopting the method, raw materials are easy to get, so that the technical weakness caused by using the poisonable chemical heliotropin controlled by the public security department in the prior art as a raw material is overcome. The preparation process requires no catalyst, and the yield is high. The obtained compound acyl intermediate can be used for preparing the tadalafil, and is simple and easy, stable in process, low in cost, and suitable for industrialized mass production. The structural formula of the compound acyl intermediate is shown as formula (II): (see the description) (II).
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(2016/11/14)

Cis-tetrahydrocarboline intermediate and synthesis method thereof, and application of cis-tetrahydrocarboline intermediate in preparing tadalafil
The invention discloses a cis-tetrahydrocarboline intermediate and a synthesis method thereof, and application of the cis-tetrahydrocarboline intermediate in preparing tadalafil. D-tryptophan methyl ester hydrochloride and 3,4-dihydroxybenzaldehyde are used as raw materials to prepare the cis-tetrahydrocarboline intermediate, so that the raw materials are accessible, thereby overcoming the technical defects when the police-controlled precursor chemical heliotropin is used as the raw material in the prior art. The preparation method does not need any catalyst, and can be used for directly preparing the cis-tetrahydrocarboline intermediate by using lower alcohols, nitriles or nitroparaffins as a solvent; and after the reaction finishes, simple cooling and filtration are performed to obtain the product, wherein the mole yield is 90-97%. The cis-tetrahydrocarboline intermediate can be used for preparing tadalafil; and the synthesis method is simple and easy to implement, has the advantages of stable technique and high yield, and is suitable for industrial large-scale production. The structural formula of the cis-tetrahydrocarboline intermediate is disclosed as (I).
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(2016/10/08)

Novel synthetic method for tadalafil
The invention relates to a synthetic method for a compound in the technical field of medicine and chemical engineering, and particularly relates to a novel synthetic method for tadalafil. The synthetic method comprises the steps of: 1) condensing an initial raw material which is D-tryptophan (I) and methylamino acetonitrile (II) or salt thereof to obtain a compound as shown in a formula III; 2) carrying out Pictet-Spengler cyclization reaction on the compound as shown in the formula III and heliotropin and carrying out crystallization to obtain a compound as shown in a formula V; and 3) hydrolyzing the compound V under an acidic or alkaline condition by cyano and then condensing the compound to obtain the target product tadalafil (VI). The formula is shown in the description. In the synthetic method provided by the invention, chemical raw materials which are great in toxicity, severe in environmental pollution and flammable and combustible such as thionyl chloride, chloroacetyl chloride, methylamine and the like. The novel synthetic method for tadalafil provided by the invention is simple in reaction method, convenient to operate and high in yield.
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Paragraph 0044; 0045

(2016/10/07)

A PROCESS FOR THE PREPARATION OF CGMP-PHOSPHODIESTERASE INHIBITOR AND ORAL PHARMACEUTICAL FORMULATION COMPRISING TADALAFIL CO-PRECIPITATES
The present Invention relates to an improved process for preparation of tadalafil and crystallization and/or purification thereof, wherein the processes are conducted at increased pressure. The invention relates also to a process for preparation of tadalafil co-precipitates and to a solid pharmaceutical composition comprising tadalafil co-precipitates and at least one water soluble diluent and/or water insoluble non-swellable diluent, wherein the composition is substantially free of water insoluble swellable diluents.
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(2016/02/26)

Tadanafil preparation intermediate high purity crystal and preparation method thereof
The present invention belongs to the technical field of the preparation of crystals, and specifically discloses a tadanafil preparation intermediate high purity crystal and a preparation method thereof. The preparation method is as follows: a (1R, 3R)-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyridino [3,4-b] indole-3-carboxylate crude product is added into acetonitrile, after heating and clear dissolving, charcoal is used for decolorizing, the solution is filtered when the solution is hot, clear filtrate is cooled and stirred for uniformly precipitating crystals, and the precipitated crystals are collected by filtration, and dried for solvent removal to obtain the crystals. The prepared tadanafil intermediate crystal (1R, 3R)-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4 methylenedioxyphenyl)-9H-pyridino [3,4-b] indole-3-carboxylate is high in purity, and the preparation method is easy, easy in operation and suitable for industrial production.
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(2016/11/28)

Phosphodiesterase 5 inhibitors Tadalafei preparation method
The invention relates to a preparing method of a phosphodiesterase 5 inhibitor tadalafil. D-methyl tryptophanate hydrochloride is adopted as an initial raw material, and is subjected to cyclization with heliotropin, N-acylation, aminolysis-cyclization, and other reactions to obtain a tadalafil crude product. The tadalafil crude product is recrystallized to obtain a tadalafil finished product. The method has characteristics of mild reaction conditions, short reaction time, high yield, good product stability and convenience for industrial production.
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(2018/02/04)

Improved synthesis of tadalafil using dimethyl carbonate and ionic liquids
An improved synthesis of tadalafil, a drug for the treatment of male erectile dysfunction, involves the use of safer solvents and reagents as well as a reduced number of steps.
Earle, Martyn J.,Noe, Marco,Perosa, Alvise,Seddon, Kenneth R.
p. 1204 - 1211
(2014/01/06)

PROCESS FOR OBTAINING COMPOUNDS DERIVED FROM TETRAHYDRO-beta-CARBOLINE
The invention relates to a process for obtaining compounds derived from tetrahydro-β-carboline, specifically tadalafil and intermediate products from the synthesis, comprising the reaction between piperonal and an alkyl ester of D-tryptophan as a salt, and in the absence of any other component, followed by haloacetylation and a final cyclization with methylamine.
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(2014/01/07)

First highly stereocontrolled synthesis of tetrahydro trans-β- carboline derivatives by exploiting the influence of a cyclic amide
Stereocontrolled synthesis of trans-β-carboline derivatives by employing amidation strategy is presented. ARKAT-USA, Inc.
Vedantham, Ravindra,Shanmugam, Sakthivel,Vetukuri, Prasadaraju Vnkv,Khagga, Mukkanti,Bandichhor, Rakeshwar
p. 22 - 32
(2013/01/15)

PROCESS FOR OBTAINING COMPOUNDS DERIVED FROM TETRAHYDRO-BETA-CARBOLINE
The invention relates to a process for obtaining compounds derived from tetrahydro-beta-carboline, specifically tadalafil and intermediate products from the synthesis, comprising the reaction between piperonal and an alkyl ester of D-tryptophan as a salt, and in the absence of any other component, followed by haloacetylation and a final cyclization with methylamine.
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(2012/08/28)

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs
In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.
Ochiana, Stefan O.,Gustafson, Alden,Bland, Nicholas D.,Wang, Cuihua,Russo, Michael J.,Campbell, Robert K.,Pollastri, Michael P.
scheme or table
p. 2582 - 2584
(2012/05/05)

VASODILATOR-ENHANCED CARDIOPULMONARY RESUSCITATION
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.
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(2012/08/27)

A PROCESS FOR THE PREPARATION OF TADALAFIL.
The present invention relates to a process for the preparation of Tadalafil, to intermediates for the synthesis thereof, and to a process for their preparation.
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Page/Page column 13; 14

(2010/05/14)

Active pharmaceutical ingredient adsorbed on solid support
Dosage forms comprising tadalafil adsorbed on a particulate carrier. Furthermore it is disclosed an adsorbate comprising tadalafil adsorbed on a particulate carrier. The present invention also refers to a process for the preparation of the adsorbate comprising the steps of (a) providing an API being practically insoluble in water; (b) providing solid support carrier particles; (c) placing the API and the carrier particles into a predetermined solvent which, allows adsorption of the API on the surface of carrier particles but gives substantially no precipitate, and (d) removing the solvent to form an API-carrier adsorbate. Furthermore the invention relates to a process for the preparation of the dosage form, as well as to the use of the adsorbate for the preparation of the dosage form. Moreover it relates to the dosage form for use in the treatment of erectile dysfunction, hypercholesterolemia, human immunodeficiency virus (HIV) infections and/or Acquired Immune Deficiency Syndrome (AIDS).
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(2010/11/03)

Microwave-assisted synthesis of tetracyclic 2,5-diketopiperazines on a soluble polymer support: A structural analogue of tadalafil
Structural analogues of tadalafil that contain two diversity points have been synthesized from a soluble polymer support employing a PictetSpengler reaction using focussed microwave irradiation. Polymer-bound deprotected tryptophan reacts with various ald
Chang, Wong-Jin,Chanda, Kaushik,Sun, Chung-Ming
experimental part
p. 42 - 50
(2009/07/25)

Synthesis of tadalafil (Cialis) from l-tryptophan
The first synthesis of tadalafil 1 (Cialis) from l-tryptophan is described. The title compound 1 was synthesized via seven steps from l-tryptophan methyl ester hydrochloride in 42.3% overall yield. Two characteristic steps involved in this synthesis are t
Xiao, Sen,Shi, Xiao-Xin,Xing, Jing,Yan, Jing-Jing,Liu, Shi-Ling,Lu, Wei-Dong
scheme or table
p. 2090 - 2096
(2010/03/04)

A PROCESS FOR THE PREPARATION OF INTERMEDIATES OF TETRACYCLIC COMPOUNDS
The present invention relates to a process for the preparation of cis-intermediates of Formula II, (Formula II) wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl, and X represents a leaving group, which are useful synthetic intermediates in the preparation of tetracyclic compounds having phosphodiesterase inhibitory activity.
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Page/Page column 9

(2009/03/07)

Conversion of tryptophan into ?-carboline derivatives
The invention belongs in the field of organic chemistry and relates to a new shortened Pictet-Spengler type reaction for preparing isomerically pure β-carboline compounds useful for the synthesis of tadalafil.
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Page/Page column 9

(2009/10/18)

PROCESS FOR PREPARATION OF TADALAFIL
It has been found that tadalafil can be obtained in high purity when (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyL-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate is reacted with methylamine in methanol in specific quantities for a specific reaction time. It has also been found that (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, the key intermediate in the preparation of tadalafil, may be obtained in higher yield from D-Tryptophan methyl ester without isolationg intermediate as solid.
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Page/Page column 5-6

(2009/12/27)

Alternative synthesis of tadalafil: PDE5 inhibitor
Two-step alternative synthesis of tadalafil (1) is described. The synthesis features Pictet-Spengeler type reaction and DCC (N,N′- dicyclohexylcarbodiimide)/HOBt (N-hydroxybenzotriazole)-mediated double amidation employing sarcosine ethyl ester hydrochlor
Anumula, Raghupathi Reddy,Madivada, Lokeswara Rao,Gilla, Goverdhan,Raju, V. V. N. K. Prasad,Kagga, Mukkanti,Reddy, Padi Pratap,Bhattacharya, Apurba,Bandichhor, Rakeshwar
experimental part
p. 4265 - 4271
(2009/04/11)

Highly stereoselective Pictet-Spengler reaction of d-tryptophan methyl ester with piperonal: convenient syntheses of Cialis (Tadalafil), 12a-epi-Cialis, and their deuterated analogues
The acid-catalyzed Pictet-Spengler reaction of d-tryptophan methyl ester with piperonal in acetic acid has been reported, the best stereoselectivity (cis/trans = 92:8) was obtained with benzoic acid as the catalyst. The Pictet-Spengler reaction of d-tryptophan methyl ester hydrochloride with piperonal in various solvents has been extensively studied, the solvent-dependence of stereoselectivities could be principally attributed to the solubility-difference between cis and trans products 5-HCl in the used solvent, the best stereoselectivity (cis/trans = 99:1) was obtained using nitromethane or acetonitrile as the solvent. A base-catalyzed epimerization at 12a-position of Cialis 1 (tadalafil) in a DMSO-containing solvent was also exploited. Cialis, 12a-epi-Cialis 2, deuterium-labeled 3,3,12a-d3-Cialis 3, and 3,3,12a-d3-12a-epi-Cialis 4 were efficiently synthesized from d-tryptophan methyl ester hydrochloride.
Shi, Xiao-Xin,Liu, Shi-Ling,Xu, Wei,Xu, Yu-Lan
p. 435 - 442
(2008/09/19)

PROCESS FOR THE PREPARATION OF TADALAFIL
The present invention provides novel intermediates of tadalafil and processes for their preparation. The present invention also provides for the preparation of tadalafil or a pharmaceutically acceptable salt or solvate thereof using the intermediates.
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Page/Page column 19

(2008/06/13)

AN IMPROVED PROCESS FOR PREPARING TADALAFIL AND ITS INTERMEDIATE
The present invention relates an improved process for the preparation of tetrahydro-?-carboline derivative of formula (V) which is useful as an intermediate for the preparation of Tadalafil of formula (I). Moreover, the present invention relates to the process for the preparation of Tadalafil of formula (I): Formula (V) and Formula (I).
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Page/Page column 11-12

(2008/06/13)

TADALAFIL HAVING A LARGE PARTICLE SIZE AND A PROCESS FOR PREPARATION THEREOF
The present invention provides particulate tadalafil having a particle size of about 200 to about 600 microns and a process for controlling the particle size of tadalafil.
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Page/Page column 11-12

(2008/06/13)

POLYMORPHIC FORMS OF TADALAFIL
Polymorphic forms of tadalafil, and processes for their preparation.
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Page/Page column 1; 17

(2008/06/13)

Process for preparing Tadalafil and its intermediate
The present invention relates an improved process for the preparation of tetrahydro-β-carboline derivative of formula (V) which is useful as an intermediate for the preparation of Tadalafil of formula (I). Moreover, the present invention relates to the process for the preparation of Tadalafil of formula (I)
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Page/Page column 3; 6

(2008/06/13)

Improved synthesis of tadalafil
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Zhang, Yunlong,He, Qian,Ding, Huasheng,Wu, Xihan,Xie, Yuyuan
p. 99 - 102
(2007/10/03)

PROCESS FOR PREPARING TADALAFIL AND ITS INTERMEDIATES
The present invention relates to two novel forms of Tadalafil which differ in their bulk densities. The invention also relates to an improved process for the preparation of Tadalafil and its intermediates.
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Page/Page column 7; 14; 16

(2008/06/13)

A PROCESS FOR THE PREPARATION OF TADALAFIL
The present invention discloses an optimized process for the preparation of Tadalafil starting from (6R, 12aR)-Methyl 1,2,3,4-tetrahydro - 2 - chloroacetyl-1-(3,4-methylenedioxy phenyl)- 9H -pyrido [3,4-b] indole-3-carboxylate (Chloro acetyl intermediate) without using large volumes of solvents, distillation, extraction, evaporation of solvents, Crude Tadalafil is isolated by cooling and recrystallizing from polar solvents such as DMF, 1,4-Dioxane, DMSO followed by addition of the reaction mass into water/water miscible solvent followed by cooling and maintaining at low temperature.
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Page/Page column 5

(2008/06/13)

Synergistic combinations
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.
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(2008/06/13)

Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors
The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is described. The PDE5 inhibitory activities of these compounds, their selectivities against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic assessments and the in vivo efficacy in increasing intracavernosal pressure are presented and discussed.
Jiang, Weiqin,Alford, Vernon C.,Qiu, Yuhong,Bhattacharjee, Sheela,John, T. Matthew,Haynes-Johnson, Donna,Kraft, Patricia J.,Lundeen, Scott G.,Sui, Zhihua
p. 1505 - 1515
(2007/10/03)

Two Concise syntheses of cialis via the N-acyliminium pictet-spengler reaction
The imine derived from piperonal and D-tryptophan methyl ester underwent N-acyliminium Pictet-Spengler reaction with either Fmoc-sarcosyl chloride or chloroacetyl chloride. The products were readily converted to the drug Cialis.
Revell, Jefferson D.,Srinivasan, Natarajan,Ganesan
p. 1428 - 1430
(2007/10/03)

The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1′,2′ :1,6]pyrido[3,4-b]indole-1,4-dione analogues
Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
Daugan, Alain,Grondin, Pascal,Ruault, Cécile,Le Monnier de Gouville, Anne-Charlotte,Coste, Hervé,Linget, Jean Michel,Kirilovsky, Jorge,Hyafil, Fran?ois,Labaudinièret, Richard
p. 4533 - 4542
(2007/10/03)

Method of treating nitrate-induced tolerance
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.
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(2008/06/13)