5-Methyl-2-((2-nitrophenyl)amino)-3-thiophenecarbonitrile

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Contents

5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile
ROY (Red Orange Yellow).svg
Names
Preferred IUPAC name
5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile
Other names
ROY
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.101.989 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C12H9N3O2S/c1-8-6-9(7-13)12(18-8)14-10-4-2-3-5-11(10)15(16)17/h2-6,14H,1H3 Yes check.svgY
    Key: NPXUFPFFHANGDL-UHFFFAOYSA-N Yes check.svgY
  • Cc1cc(c(s1)Nc2ccccc2[N+](=O)[O-])C#N
Properties [1]
C12H9N3O2S
Molar mass 259.28 g·mol−1
Melting point 99–102 °C (210–216 °F; 372–375 K)
Hazards
GHS labelling: [2]
GHS-pictogram-pollu.svg
Warning
H410
P273, P391, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, also known as ROY (red-orange-yellow), is an organic compound which is a chemical intermediate to the drug olanzapine. It has been the subject of intensive study because it can exist in multiple well-characterised crystalline polymorphic forms. [3] [4] [5] [6]

Synthesis

The preparation of ROY was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s, which covered the pharmaceutical active ingredient later marketed as olanzapine. In the first step, a Gewald reaction using propionaldehyde, sulfur and malononitrile formed the thiophene ring system, as 2-amino-5-methylthiophene-3-carbonitrile. The amino group was then reacted with 2-fluoro-nitrobenzene in tetrahydrofuran to provide 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile. [1]

ROY synthesis.svg

Polymorphism

ROY has been crystallised in at least thirteen polymorphic forms. [7] [8] Five of them, including red, orange and yellow examples are shown in Figure 1.

Figure 1: Some major polymorphs of ROY ROY polymorphs.jpg
Figure 1: Some major polymorphs of ROY

When this ability to form multiple crystalline versions of different colours was reviewed in 2010, it was described as "extraordinary", particularly because many alternatives can crystallise simultaneously from a single solvent. As the thermodynamic properties of the various versions have been established, ROY has become an important test of computational models. [4] By 2020, ROY held the record for having the largest number of well-characterised polymorphs, with its nearest competitors being aripiprazole and galunisertib. [9] [10] [11] The various crystal forms display alternative conformers, a type of stereoisomerism where rotation at single bonds leads to a distinct three-dimensional configuration in the solid. [12] The molecule is piezochromic, with yellow and pale orange crystalline forms which transform reversibly to red at high pressure. [8]

In 2022, it was suggested that all the ROY polymorphs which are stable at ambient pressure have already been found and characterised. This work also calculated that additional polymorphs might be discovered using high pressures of about 10 GPa. [11]

Related Research Articles

<span class="mw-page-title-main">Polythiophene</span>

Polythiophenes (PTs) are polymerized thiophenes, a sulfur heterocycle. The parent PT is an insoluble colored solid with the formula (C4H2S)n. The rings are linked through the 2- and 5-positions. Poly(alkylthiophene)s have alkyl substituents at the 3- or 4-position(s). They are also colored solids, but tend to be soluble in organic solvents.

In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The final product is a β-amino-carbonyl compound also known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after Carl Mannich.

<span class="mw-page-title-main">Nucleation</span> Initial step in the phase transition or molecular self-assembly of a substance

In thermodynamics, nucleation is the first step in the formation of either a new thermodynamic phase or structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically defined to be the process that determines how long an observer has to wait before the new phase or self-organized structure appears. For example, if a volume of water is cooled significantly below 0 °C, it will tend to freeze into ice, but volumes of water cooled only a few degrees below 0 °C often stay completely free of ice for long periods (supercooling). At these conditions, nucleation of ice is either slow or does not occur at all. However, at lower temperatures nucleation is fast, and ice crystals appear after little or no delay.

<span class="mw-page-title-main">Iodic acid</span> Chemical compound (HIO3)

Iodic acid is a white water-soluble solid with the chemical formula HIO3. Its robustness contrasts with the instability of chloric acid and bromic acid. Iodic acid features iodine in the oxidation state +5 and is one of the most stable oxo-acids of the halogens. When heated, samples dehydrate to give iodine pentoxide. On further heating, the iodine pentoxide further decomposes, giving a mix of iodine, oxygen and lower oxides of iodine.

<span class="mw-page-title-main">Rubrene</span> Chemical compound

Rubrene (5,6,11,12-tetraphenyltetracene) is the organic compound with the formula (C18H84. It is a red colored polycyclic aromatic hydrocarbon. Because of its distinctive optical and electrical properties, rubrene has been extensively studied. It has been used as a sensitiser in chemoluminescence and as a yellow light source in lightsticks.

<span class="mw-page-title-main">Piezochromism</span>

Piezochromism, from the Greek piezô "to squeeze, to press" and chromos "color", describes the tendency of certain materials to change color with the application of pressure. This effect is closely related to the electronic band gap change, which can be found in plastics, semiconductors and hydrocarbons. One simple molecule displaying this property is 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, also known as ROY owing to its red, orange and yellow crystalline forms. Individual yellow and pale orange versions transform reversibly to red at high pressure.

In crystallography, polymorphism is the phenomenon where a compound or element can crystallize into more than one crystal structure.

<span class="mw-page-title-main">2-Pyridone</span> Chemical compound

2-Pyridone is an organic compound with the formula C
5
H
4
NH(O)
. It is a colourless solid. It is well known to form hydrogen bonded dimers and it is also a classic case of a compound that exists as tautomers.

<span class="mw-page-title-main">Crystal engineering</span> Designing solid structures with tailored properties

Crystal engineering studies the design and synthesis of solid-state structures with desired properties through deliberate control of intermolecular interactions. It is an interdisciplinary academic field, bridging solid-state and supramolecular chemistry.

<span class="mw-page-title-main">Anthranilic acid</span> Chemical compound

Anthranilic acid is an aromatic acid with the formula C6H4(NH2)(CO2H) and has a sweetish taste. The molecule consists of a benzene ring, ortho-substituted with a carboxylic acid and an amine. As a result of containing both acidic and basic functional groups, the compound is amphoteric. Anthranilic acid is a white solid when pure, although commercial samples may appear yellow. The anion [C6H4(NH2)(CO2)], obtained by the deprotonation of anthranilic acid, is called anthranilate. Anthranilic acid was once thought to be a vitamin and was referred to as vitamin L1 in that context, but it is now known to be non-essential in human nutrition.

<span class="mw-page-title-main">Tolfenamic acid</span> Non-steroidal anti-inflammatory drug

Tolfenamic acid is a member of the anthranilic acid derivatives class of NSAID drugs. Like other members of the class, it is a COX inhibitor and prevents formation of prostaglandins.

<span class="mw-page-title-main">Phenylglyoxal</span> Chemical compound

Phenylglyoxal is the organic compound with the formula C6H5C(O)C(O)H. It contains both an aldehyde and a ketone functional group. It is yellow liquid when anhydrous but readily forms a colorless crystalline hydrate. It has been used as a reagent to modify the amino acid, arginine. It has also been used to attach chemical payload (probes) to the amino acid citrulline and to peptides/proteins.

<span class="mw-page-title-main">Flufenamic acid</span> Chemical compound

Flufenamic acid (FFA) is a member of the anthranilic acid derivatives class of nonsteroidal anti-inflammatory drugs (NSAIDs). Like other members of the class, it is a cyclooxygenase (COX) inhibitor, preventing the formation of prostaglandins. FFA is known to bind to and reduce the activity of prostaglandin F synthase and activate TRPC6.

<span class="mw-page-title-main">PCMT1</span> Protein-coding gene in the species Homo sapiens

Protein-L-isoaspartate(D-aspartate) O-methyltransferase is an enzyme that in humans is encoded by the PCMT1 gene.

<i>Crystal Growth & Design</i> Academic journal

Crystal Growth & Design is a monthly peer-reviewed scientific journal published by the American Chemical Society. It was established in January 2001 as a bimonthly journal and changed to a monthly frequency in 2006. The editor-in-chief is Jonathan W. Steed from Durham University.

In materials science, cocrystals are "solids that are crystalline, single-phase materials composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts." A broader definition is that cocrystals "consist of two or more components that form a unique crystalline structure having unique properties." Several subclassifications of cocrystals exist.

<span class="mw-page-title-main">Amorphous calcium carbonate</span>

Amorphous calcium carbonate (ACC) is the amorphous and least stable polymorph of calcium carbonate. ACC is extremely unstable under normal conditions and is found naturally in taxa as wide-ranging as sea urchins, corals, mollusks, and foraminifera. It is usually found as a monohydrate, holding the chemical formula CaCO3·H2O; however, it can also exist in a dehydrated state, CaCO3. ACC has been known to science for over 100 years when a non-diffraction pattern of calcium carbonate was discovered by Sturcke Herman, exhibiting its poorly-ordered nature.

Fiona C. Meldrum is a British scientist who is a Professor of Inorganic Chemistry at the University of Leeds where she works on bio-inspired materials and crystallisation processes. She won the 2017 Royal Society of Chemistry Interdisciplinary Prize.

<span class="mw-page-title-main">Lia Addadi</span> Israeli biochemist

Lia Addadi is a professor of structural biology at the Weizmann Institute of Science. She works on crystallisation in biology, including biomineralization, interactions with cells and crystallisation in cell membranes. She was elected a member of the National Academy of Sciences (NAS) in 2017 for “distinguished and continuing achievements in original research”, and the American Philosophical Society (2020).

<span class="mw-page-title-main">James Wuest</span> Canadian chemist

James D. Wuest is a Canadian chemist, materials scientist and academic. He is a professor of Chemistry at the Université de Montréal, where he teaches and leads a research group.

References

  1. 1 2 USpatent 5817655,Chakrabarti, J.K.; Hotten, T.M.& Tupper, D.E.,"Methods of treatment using a thieno-benzodiazepine",issued 1998-10-06, assigned to Eli Lilly and Co. Ltd.
  2. "5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile". pubchem.ncbi.nlm.nih.gov. Retrieved 2021-05-08.
  3. Krämer, Katrina (2020-07-29). "Red–orange–yellow reclaims polymorph record with help from molecular cousin". chemistryworld.com. Retrieved 2021-05-07.
  4. 1 2 Yu, Lian (2010). "Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and Yellow Crystals". Accounts of Chemical Research. 43 (9): 1257–1266. doi:10.1021/ar100040r. PMID   20560545.
  5. Li, Xizhen; Ou, Xiao; Rong, Haowei; Huang, Siyong; Nyman, Jonas; Yu, Lian; Lu, Ming (2020). "The Twelfth Solved Structure of ROY: Single Crystals of Y04 Grown from Melt Microdroplets". Crystal Growth & Design. 20 (11): 7093–7097. doi:10.1021/acs.cgd.0c01017. S2CID   225294672.
  6. 1 2 Tyler, Andrew R.; Ragbirsingh, Ronnie; McMonagle, Charles J.; Waddell, Paul G.; Heaps, Sarah E.; Steed, Jonathan W.; Thaw, Paul; Hall, Michael J.; Probert, Michael R. (2020). "Encapsulated Nanodroplet Crystallization of Organic-Soluble Small Molecules". Chem. 6 (7): 1755–1765. doi:10.1016/j.chempr.2020.04.009. PMC   7357602 . PMID   32685768.
  7. "5-methyl-2-(2-nitroanilino)thiophene-3-carbonitrile". ccdc.cam.ac.uk. Retrieved 2021-05-08.
  8. 1 2 Warren, Lisette R; McGowan, Evana; Renton, Margaret; Morrison, Carole A; Funnell, Nicholas P (2021). "Direct evidence for distinct colour origins in ROY polymorphs". Chemical Science. 12 (38): 12711–12718. doi:10.1039/d1sc04051k. PMC   8494124 . PMID   34703557.
  9. Reutzel-Edens, Susan M.; Bhardwaj, Rajni M. (2020). "Crystal forms in pharmaceutical applications: Olanzapine, a gift to crystal chemistry that keeps on giving". IUCrJ. 7 (6): 955–964. doi:10.1107/S2052252520012683. PMC   7642794 . PMID   33209310.
  10. Lévesque, Alexandre; Maris, Thierry; Wuest, James D. (2020). "ROY Reclaims Its Crown: New Ways to Increase Polymorphic Diversity". Journal of the American Chemical Society. 142 (27): 11873–11883. doi:10.1021/jacs.0c04434. PMID   32510946. S2CID   219552473.
  11. 1 2 Beran, Gregory J. O.; Sugden, Isaac J.; Greenwell, Chandler; et al. (2022). "How many more polymorphs of ROY remain undiscovered". Chemical Science. 13 (5): 1288–1297. doi: 10.1039/d1sc06074k . PMC   8809489 . PMID   35222912.
  12. Cruz-Cabeza, Aurora J.; Bernstein, Joel (2014). "Conformational Polymorphism". Chemical Reviews. 114 (4): 2170–2191. doi:10.1021/cr400249d. PMID   24350653.