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, 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]
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.
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]
References
^
abUS 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.
^
abYu, 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.
PMID20560545.
^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.
S2CID225294672.
^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.
PMID32510946.
S2CID219552473.