Take tadalafil and remove the methyl group from the nitrogen of its piperazinedione ring. What remains is nortadalafil, and what that removal exposes is a free N-H position. Analytical laboratories have since reported at least eight distinct compounds that differ only in the group sitting on that one nitrogen.
That is the reason this compound matters as a reference material. It is not one analog among many. It is the common core the others decorate. That makes it the anchor point for any method meant to separate them.
Kimera supplies nortadalafil as an analytical reference standard and for structure-activity relationship work. It is research material, not a pharmaceutical, not a generic, and not a substitute for any approved product. Tadalafil itself is an approved pharmaceutical and is not in this catalogue.
All information here describes laboratory research findings. This material is supplied for research use only and is not for human or veterinary use.
What nortadalafil is
The “nor” prefix is standard chemical notation for the loss of a methyl group from a parent structure. Applied here it gives a compound one CH2 unit lighter than tadalafil, 375.4 against 389.4.
Identity and physical data
| Property | Value |
|---|---|
| Compound | Nortadalafil |
| Synonyms | Demethyltadalafil, desmethyl-tadalafil |
| PubChem CID | 9820973 |
| CAS number | 171596-36-4 |
| Molecular formula | C21H17N3O4 |
| Molecular weight | 375.4 g/mol |
| InChIKey | XHDLVMPUSXRZOS-FOIQADDNSA-N |
| Configuration | (6R,12aR) |
| Chemical class | Tetracyclic pyrazino-pyrido-indole |
The stereo block is defined, and that matters
The InChIKey ends FOIQADDNSA rather than UHFFFAOYSA. A defined block means the record describes a specific stereoisomer, not a mixture. The scaffold carries two stereocentres, at positions 6 and 12a, so four stereoisomers are possible in principle.
The catalogue material is the (6R,12aR) form, which is also the configuration reported for the compound when isolated from real samples. A 2021 study measured circular dichroism on material isolated from three products bought online: a honey preparation, a tablet and a candy [1]. Every spectrum aligned with the 6R,12aR standard.
The nitrogen that names the family
Reading the analytical literature in date order shows a pattern that is hard to miss. Each new report isolates a compound from a supplement, elucidates it by NMR and mass spectrometry, and names it for whatever sits on that nitrogen.
Eight substituents, one position
| Reported analog | Substituent on the nitrogen | First report |
|---|---|---|
| Tadalafil (reference parent) | methyl | approved drug |
| Nortadalafil | hydrogen | [1] |
| N-cyclopentyl nortadalafil | cyclopentyl | 2015 [2] |
| N-phenylpropenyltadalafil | phenylallylidene-amino | 2015 [3] |
| Isopropylnortadalafil | isopropyl | 2016 [4] |
| Bisprenortadalafil | tadalafil precursor moiety | 2016 [5] |
| N-3-hydroxypropylnortadalafil | 3-hydroxypropyl | 2018 [6] |
| N-benzyl tadalafil | benzyl | 2020 [7] |
| N-cyclohexyl nortadalafil | cyclohexyl | 2022 [8] |
Several of those names carry “nortadalafil” inside them, which is the naming convention acknowledging the core. Where a report uses “tadalafil” in the name instead, the compound is the same scaffold with a different group at the same position.
Why that makes it a reference anchor
A laboratory building a screening method for this family needs the unsubstituted core as well as the substituted examples. The core defines the fragment ions and the chromophore the whole family shares, and it establishes the retention behaviour that substitution shifts. Without it, a method calibrates against derivatives with no fixed point between them.
One of these has since become catalogue material in its own right. Isopropylnortadalafil, first reported in a supplement in 2016 [4], is the compound sold as N-Isopropyl Tadalafil for reference use.
Why routine detection struggles
This is the practical problem the reference standards exist to solve, and two independent groups have stated it plainly.
The ultraviolet spectrum is nearly useless here
A 2020 report isolating N-benzyl tadalafil from a coffee-based product noted that the ultraviolet absorption spectrum of the unknown was almost identical to that of tadalafil [7]. A 2022 report on N-cyclohexyl nortadalafil said the same, and added that the tandem mass spectrum was highly similar to tadalafil below 300 m/z [8].
Both observations follow from the chemistry. The chromophore is the benzodioxole and indole system, which substitution at that distant nitrogen barely perturbs. Diode array detection therefore sees one compound where there may be several.
Fragmentation shares a common core
The same logic applies to mass spectrometry below the mass of the substituent. Fragments generated from the shared tetracyclic core are common to the family, so a spectral library match on those ions confirms the scaffold rather than the compound. Precursor mass separates the analogs, and precursor mass alone does not distinguish isomers of equal formula.
Stereochemistry is not settled by mass
A 2019 study makes the sharpest available case for why chiroptical methods belong in this work [9].
What high resolution mass spectrometry could not do
Investigators isolated a dipropylaminopretadalafil stereoisomer from a health supplement. High resolution mass spectrometry gave the same precursor ion at m/z 492 within 2 ppm as the two trans analogs. Retention times sat very close. The tandem fragmentation pattern matched closely too. On that evidence the compound looked like a trans isomer.
What resolved it
Enantioselective separation on a chiral column distinguished it from both trans isomers. Ellipticity and optical rotation were then compared against homologous compounds lacking the diketopiperazine ring. One-dimensional NMR and nuclear Overhauser effect spectroscopy supported the result. Together they established the cis-(6R,12aR) configuration [9].
The identification took three orthogonal techniques. Mass spectrometry was not among them. For any question about which stereoisomer is present, the method has to be chiral or chiroptical.
How often it turns up
Survey work gives the base rates, and they are the reason regulators fund this analysis.
Screening surveys
A 2018 survey of Chinese tonic liquors screened for 86 phosphodiesterase type 5 inhibitors by liquid chromatography with quadrupole time of flight mass spectrometry [10]. Four of 28 samples, 14.3 percent, carried undeclared compounds, among them sildenafil, tadalafil, vardenafil and nortadalafil.
A 2023 study paired high performance thin layer chromatography with high resolution tandem mass spectrometry [11]. It found sildenafil, tadalafil or both in 73.3 percent of the products tested. Every one of those products carried a natural label. Quantities matched or exceeded those in approved medicinal products.
Where the first report sits
The earliest paper in this line dates to 2006 [12]. It isolated a tadalafil analog alongside hydroxyhomosildenafil from a herbal product, and argued the compound belonged on screening target lists. A 2014 report from Argentina identified aminotadalafil in a supplement and described itself as the first such report in Latin America [13].
Eighteen years separate that first paper from the most recent analog in the table above, and the list has not stopped growing.
Methods that separate the family
Immunoassay for group screening
A 2022 study designed haptens computationally, selecting for frontier molecular orbital softness while preserving three-dimensional structure, and raised an antiserum against the best candidate [14]. The resulting indirect competitive ELISA detected five compounds at once, including nortadalafil. Limits of detection ran from 0.004 to 0.396 ng/mL, over a working range of 0.094 to 16.71 ng/mL.
Correlation against HPLC-MS/MS on real samples reached R of 0.9955. An assay of that kind screens groups quickly and cheaply, then hands positives to a confirmatory method.
Confirmatory chromatography
Ultra high performance liquid chromatography with high resolution mass spectrometry is the confirmatory standard across these papers, usually with an Orbitrap or time of flight analyser. Purification for structure elucidation runs through semi-preparative HPLC, with NMR and infrared closing the identification [2][8].
The metabolite complication
A 2025 forensic method quantified four inhibitors and twelve metabolites in rat plasma [15]. Desmethyltadalafil and methyl-desmethyltadalafil were not detected in plasma at all. Their glucuronide conjugates appeared instead, and tandem mass spectrometry characterised them.
Anyone designing a detection method for biological matrix rather than for product powder should note that the parent may be absent while a conjugate carries the signal.
Physicochemical properties and handling
| Parameter | Detail |
|---|---|
| Solubility | Soluble in DMSO and DMF; poorly soluble in water |
| Storage | Sealed, dry, protected from light |
| Stability | Stable as a dry solid at ambient conditions |
| Stock solutions | Prepare in DMSO; aliquot to avoid freeze-thaw |
The tetracyclic core is rigid and planar over much of its area, which makes the solid poorly soluble in aqueous buffer. Prepare concentrated stocks in DMSO and dilute immediately before use.
Protect the stereocentres
Kimera ships a single defined stereoisomer, and that configuration is the property the material exists to provide. Avoid strongly basic conditions and prolonged heating in solution, since the position alpha to the ring carbonyl is where epimerisation would occur. Where configuration matters to the result, verify it rather than assuming the certificate still describes the aliquot after storage.
What a certificate should show
Purity by HPLC with the method stated, identity by mass spectrometry against 375.4, and structural confirmation by NMR. For this compound family, two further items are worth requesting explicitly.
Enantiomeric or diastereomeric purity
A routine achiral purity assay cannot report configuration, for the same reason set out in the 2019 chirality study [9]. Does the work depend on the compound being (6R,12aR)? Then ask for a chiral method with its chromatogram, or a circular dichroism spectrum against a standard [1].
Absence of the near neighbours
The near neighbours are the substituted analogs above, which share the chromophore and much of the fragmentation. A purity figure generated by a method that cannot resolve them is not evidence they are absent. Batch documentation for catalogue material sits in the certificate of analysis database.
Nortadalafil among the phosphodiesterase inhibitors
The catalogue holds six compounds in this category, split across two unrelated scaffolds.
| Compound | Scaffold | Stereocentres |
|---|---|---|
| Nortadalafil | tetracyclic tadalafil type | two |
| Aminotadalafil | tetracyclic tadalafil type | two |
| N-ethyl Tadalafil | tetracyclic tadalafil type | two |
| N-Isopropyl Tadalafil | tetracyclic tadalafil type | two |
| Mirodenafil | pyrazolopyrimidinone, sildenafil type | none |
| Acetildenafil | pyrazolopyrimidinone, sildenafil type | none |
The two scaffolds pose different analytical questions
That last column is the practical divide. The tadalafil-type compounds carry two stereocentres, so configuration stays a live question and may need a chiral method. The sildenafil-type compounds are achiral, so a single achiral method characterises them completely.
Grouping all six as one category is correct by target and misleading by method. Further reading sits in the PDE5 inhibitor research library, and the reference standard ships against batch documentation.
Open questions and how to read this literature
There is almost no pharmacology here
Nearly every paper naming this compound is an analytical or forensic one. Isolation, structure elucidation, method development, survey. That is unusual, and it means claims about what the compound does at its target rest on the parent scaffold rather than on work with the compound itself.
The 2021 configuration study spells out its own inference chain [1]. It cites a report that among tadalafil stereoisomers the 6R,12aR form carries the most potent inhibitory activity. From that it suggests a comparable strength for the 6R,12aR analogs. Suggests is the operative word. Read-across from a parent to an analog is a hypothesis, not a measurement.
New analogs arrive faster than standards
Eight substituted variants appear in the table above, several first reported within the last decade. Each surfaced because someone ran a screen and found a peak that did not match. Any library is therefore incomplete by construction, and a non-target high resolution approach is the only way to catch the next one.
Base rates come from convenience samples
The 14.3 percent and 73.3 percent figures above come from products someone already suspected [10][11]. Those are not population estimates and do not describe prevalence. They establish that the problem is common enough to fund the analysis.
What would help
Authentic standards for the substituted analogs are the practical bottleneck, since nobody can confirm a compound against a reference that does not exist. Published quantitative NMR data for each would partly close the gap.
Matrix is the other half of the problem
Read the isolation papers for what they were working with and a second difficulty appears. The compounds arrive in food.
The matrices are not powders
Across these reports the sample was a honey preparation, a tablet, a candy [1], a coffee-based product [7], a herbal capsule [12], and tonic liquor [10]. Each brings its own interference. Sugars suppress ionisation, lipids foul columns, and plant extracts contribute hundreds of coeluting species.
A method validated on a clean powder does not transfer to any of these without re-validation. Recovery is the figure to check first, because extraction from a sugar matrix behaves nothing like extraction from a capsule fill.
Sample preparation carries the risk
The tonic liquor survey used a QuEChERS preparation ahead of the chromatography (DOI). That choice matters more than the instrument. A quick, cheap cleanup that loses analyte gives a confident negative on a positive sample, and nothing downstream will reveal the loss.
Spike the matrix, not the solvent, when establishing recovery. A spiked solvent blank measures the instrument. A spiked matrix measures the method.
Concentration ranges are wide
Adulterant quantities in one survey matched or exceeded those found in approved medicinal products [11]. Other reports describe trace-level findings. A method needs linear range across several orders of magnitude, and a calibration built only at the low end will saturate on the samples that matter most.
Thin layer chromatography still earns its place
The 2023 study used high performance thin layer chromatography as the screening tier (DOI), with retardation factors of 0.55 for sildenafil and 0.90 for tadalafil, then confirmed by high resolution mass spectrometry. For a laboratory without instrument time to spare, that is a defensible first pass. It costs little and it narrows the queue.
Designing a screen around this family
The literature above converges on a practical shape for method development. Four points do most of the work.
Start from the core, not from tadalafil
A method anchored on tadalafil treats every analog as a deviation. A method anchored on the unsubstituted core treats tadalafil as one substituted case among many, which is what the evidence describes. That framing changes which reference standards a laboratory buys first.
Use orthogonal detection, not one channel
Diode array alone cannot separate this family (DOI). Nor can low-mass fragmentation. Pair a chromatographic separation with high resolution accurate mass, and treat retention as evidence rather than as identification. Two channels that fail in different ways beat one channel that fails cleanly.
Screen broadly, then confirm narrowly
The immunoassay work points at a two-stage shape [14]. A group-reactive assay clears the majority of negative samples at low cost. Confirmation then runs only on the positives, where high resolution mass spectrometry and NMR earn their time. Building the expensive method first inverts that economy.
Expect the list to be incomplete
A targeted method finds what its library contains. Every compound in the table above entered the literature because a non-target approach flagged a peak nobody could name. A screen with no non-target component cannot discover, only confirm.
Build the acceptance criteria around that. Record unassigned peaks above a threshold rather than discarding them, and keep the raw high resolution data so a later library can be applied retrospectively. Several of the analogs above were sitting in old chromatograms before anyone had a name for them.
Frequently asked questions
What does the “nor” prefix mean?
Loss of a methyl group from the parent structure. Nortadalafil is tadalafil without the N-methyl on the piperazinedione ring, one CH2 lighter at 375.4 against 389.4.
Is this a generic version of an approved drug?
No. A generic contains the same active ingredient as the brand. This is a structurally different molecule with its own formula, its own CAS number and its own regulatory status, supplied as a research reference material.
Can ultraviolet detection identify it?
Not on its own. Two independent groups reported that analogs in this family have ultraviolet spectra almost identical to tadalafil, because substitution sits far from the chromophore [7][8].
Can mass spectrometry determine the configuration?
No. No. In the clearest published test, high resolution mass spectrometry could not separate a compound from two trans isomers. The answer took a chiral column, chiroptical measurement and NOESY [9].
How many analogs of this scaffold are known?
At least eight distinct substituents at the same nitrogen appear in the peer-reviewed isolation literature, spanning 2015 to 2022. The list continues to grow.
Does the sample matrix change the method?
Considerably. Published isolations came from honey, candy, coffee products, capsules and tonic liquor [1][7] and [10][12]. Validate recovery in the matrix itself rather than in solvent, since a cleanup that loses analyte produces a confident false negative.
Which stereoisomer does the catalogue supply?
The (6R,12aR) form, matching the configuration reported when the compound is isolated from real samples [1]. The defined stereo block in its InChIKey reflects that.
Why do reference standards for these exist at all?
Because regulators and analytical laboratories screen consumer products for undeclared pharmaceutical compounds, and confirming an identification requires an authentic sample of the suspected compound [12].
References
- Fukiwake T, Yamazaki M, Takahashi K, et al. The Configuration of Tadalafil and Tadalafil Analogues Found in Dietary Supplements. Shokuhin Eiseigaku Zasshi. 2021;62(2):65-72. PubMed DOI
- Xu Y, Kee CL, Ge X, et al. Isolation and characterization of a tadalafil analogue, N-cyclopentyl nortadalafil in health supplement. J Pharm Biomed Anal. 2015;118:235-241. PubMed DOI
- Huang YC, Lee HC, Lin YL, et al. Separation and identification of a novel tadalafil analogue adulterant in a dietary supplement. Food Addit Contam Part A. 2016;33(2):179-85. PubMed DOI
- Park HN, Lee JH, Park SK, et al. Identification of a new tadalafil analogue in commercial dietary supplements: isopropylnortadalafil. Food Addit Contam Part A. 2017;34(2):162-169. PubMed DOI
- Lee JH, Park HN, Ganganna B, et al. Isolation and structural elucidation of a new tadalafil analogue in health supplements: bisprenortadalafil. Food Addit Contam Part A. 2016;33(6):945-52. PubMed DOI
- Lee HC, Lin YL, Huang YC, et al. Identification of a new tadalafil analogue, N-3-hydroxypropylnortadalafil, in a supplement product. J Pharm Biomed Anal. 2018;158:257-261. PubMed DOI
- Dong PZ, Liu XP, Zhang L, et al. Isolation and characterisation of N-benzyl tadalafil as a novel adulterant in a coffee-based dietary supplement. Food Addit Contam Part A. 2020;37(12):2033-2039. PubMed DOI
- Liu J, Sun J, Wei H, et al. Isolation and characterization of a novel tadalafil analogue adulterant, N-cyclohexyl nortadalafil, in a dietary supplement. J Pharm Biomed Anal. 2023;227:115144. PubMed DOI
- Kee CL, Chin LC, Cheah NP, et al. Elucidation of the absolute configuration of a tadalafil analogue found as adulterant in a health supplement by mass spectrometry, chiroptical methods and NMR spectroscopy. J Pharm Biomed Anal. 2019;173:47-55. PubMed DOI
- Ding B, Wang Z, Xie J, et al. Phosphodiesterase-5 inhibitors in Chinese tonic liquors by liquid chromatography coupled with quadrupole time of flight mass spectrometry. Food Addit Contam Part B. 2018;11(3):214-222. PubMed DOI
- Gheorghiu ORC, Ciobanu AM, Guțu CM, et al. Determination of Phosphodiesterase Type-5 Inhibitors (PDE-5) in Dietary Supplements. Molecules. 2023;28(10):4116. PubMed DOI
- Zou P, Hou P, Low MY, Koh HL. Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product. Food Addit Contam. 2006;23(5):446-51. PubMed DOI
- Ulloa J, Sambrotta L, Redko F, et al. Detection of a tadalafil analogue as an adulterant in a dietary supplement for erectile dysfunction. J Sex Med. 2015;12(1):152-7. PubMed DOI
- Yang JY, Xie MC, Tan XC, et al. Improved molecular softness of tadalafil hapten enhancing antibody performance in immunoassay. J Food Sci. 2022;87(3):1342-1354. PubMed DOI
- Xia X, Song Z, He W, et al. Simultaneous determination of four PDE5 inhibitors and metabolites in rat plasma by UPLC-MS/MS. J Pharm Biomed Anal. 2025;262:116883. PubMed DOI
