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

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The correct title of this article is 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile. The substitution of any brackets is due to technical restrictions.

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 Edit this at Wikidata
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 checkY
    Key: NPXUFPFFHANGDL-UHFFFAOYSA-N checkY
  • 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]
GHS09: Environmental hazard
Signal word
 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).
Infobox references

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]

Synthesis of ROY in two steps

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[6]

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 competitor being aripiprazole.[8][9][10] 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.[11] The molecule is piezochromic, with yellow and pale orange crystalline forms which transform reversibly to red at high pressure.[8]

References[]

  1. ^ a b US patent 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. ^ a b 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.
  6. ^ a b 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. ^ a b c 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.
  11. ^ Cruz-Cabeza, Aurora J.; Bernstein, Joel (2014). "Conformational Polymorphism". Chemical Reviews. 114 (4): 2170–2191. doi:10.1021/cr400249d. PMID 24350653.
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