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

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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.

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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

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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.
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  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.
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  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.
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