171596-27-3

Basic information

• Product Name: cis-Tadalafil
• Synonyms: cis-Tadalafil;(6R,12aS)-;Tadalafil IMpurity: IMpurity H;Tadalafil EP IMpurity A (cis-tadalafil);6R,12S-Tadalafil;Pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3- benzodioxol-5-yl)-2,3,6,7,12, 12a-hexahydro-2-Methyl-,(6R, 12aS)-;(6R,12aS)-6-(1,3-benzodioxol-5-yl)-2-Methyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione;Tadanafil EP or USP impurity A
• CAS NO: 171596-27-3
• Molecular Formula: C₂₂H₁₉N₃O₄
• Molecular Weight: 388.39602
• Product Categories: Chiral Reagents;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 171596-27-3.mol
• Article Data: 5

Chemical Properties

• Melting Point: 285-287 °C(Solv: toluene (108-88-3))
• Boiling Point: 679.1±55.0 °C(Predicted)
• Appearance: /
• Density: 1.51±0.1 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly, Methanol (Slightly)
• PKA: 16.68±0.40(Predicted)
• CAS DataBase Reference: cis-Tadalafil(CAS DataBase Reference)
• NIST Chemistry Reference: cis-Tadalafil(171596-27-3)
• EPA Substance Registry System: cis-Tadalafil(171596-27-3)

Safety Data

• Hazardous Substances Data: 171596-27-3(Hazardous Substances Data)

Usage

Description

cis-Tadalafil, also known as (6R)-cis-enantiomer of Tadalafil (T004500), is a chemical compound with the molecular formula C22H19N3O4. It is a white solid and is an impurity of Tadalafil, which is a medication used to treat erectile dysfunction and pulmonary arterial hypertension. The cis-Tadalafil isomer has unique chemical properties that make it distinct from other forms of Tadalafil.

Uses

Used in Pharmaceutical Industry:
cis-Tadalafil is used as an impurity in the production of Tadalafil for the treatment of erectile dysfunction and pulmonary arterial hypertension. Its presence in the final product may affect the efficacy and safety of the medication, making it important to monitor and control its levels during the manufacturing process.
Used in Research and Development:
cis-Tadalafil is used as a research compound for studying the effects of Tadalafil and its various isomers on different physiological processes. This can help in understanding the mechanism of action, potential side effects, and the development of new drugs with improved properties.
Used in Quality Control:
cis-Tadalafil is used as a reference material in the quality control of Tadalafil products. It helps in the identification, quantification, and assessment of the purity of Tadalafil in pharmaceutical formulations, ensuring that the final product meets the required standards.
Used in Drug Regulatory Affairs:
cis-Tadalafil is used in drug regulatory affairs to establish guidelines and regulations for the approval and monitoring of Tadalafil-containing medications. This includes setting limits for the acceptable levels of impurities, such as cis-Tadalafil, in the final drug product to ensure patient safety and efficacy.

Upstream product

• 74-89-5 methylamine 
• 629652-44-4 (1R,3S)-1-benzo[1,3]dioxol-5-yl-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester 
• 171489-59-1 methyl (1R,3R)-1-(3,4-methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indol-3-carboxylate 
• 120-57-0 piperonal 
• 14907-27-8 (R)-(+)-tryptophan methyl ester hydrochloride 
• 171596-41-1 (1R,3R)-methyl 1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate 
• 4299-70-1 L-tryptophan methyl ester 
• 171596-44-4 (1R,3S)-1-(3,4-methylenedioxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester 
• 171596-29-5 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione 
• 50-00-0 formaldehyd 
• 13139-14-5 Boc-Trp-OH 

Downstream Products

• 531500-48-8 11-benzo[1,3]dioxol-5-yl-3-methyl-2,3,4a,11-tetrahydro-10H-3,10,11a-triaza-benzo[b]fluorene-1,4,5-trione 

Relevant articles and documents

Preparation method of tadalafil

The invention discloses a preparation method of tadalafil, starting material D-Tryptophan methyl ester hydrochloride is reacted with oxalyl chloride to obtain an intermediate III, and the final product tadalafil (I) is obtained through cyclization, Grignard reaction, asymmetric reduction, substitution and condensation reaction. The use of national control chemical piperonal is avoided, an intermediate VI can be highly-selectively obtained by the asymmetric reduction, and the method has the advantages of simple postprocessing, short synthesis steps and high product total yield, and is suitable for industrialized production.

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.

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).