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]
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]
PolymorphismEdit
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]
ReferencesEdit
^ 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.
^Krämer, Katrina (2020-07-29). "Red–orange–yellow reclaims polymorph record with help from molecular cousin". chemistryworld.com. Retrieved 2021-05-07.
^ 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. PMID 20560545.
^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.
^ abTyler, 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. PMC7357602. PMID 32685768.
^ abWarren, 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. PMC8494124. PMID 34703557.
^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. PMC7642794. PMID 33209310.
^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.
^ abBeran, 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. PMC8809489. PMID 35222912.
^Cruz-Cabeza, Aurora J.; Bernstein, Joel (2014). "Conformational Polymorphism". Chemical Reviews. 114 (4): 2170–2191. doi:10.1021/cr400249d. PMID 24350653.
October 21, 2023
methyl, nitrophenyl, amino, thiophenecarbonitrile, correct, title, this, article, methyl, nitrophenyl, amino, thiophenecarbonitrile, substitution, brackets, technical, restrictions, methyl, nitrophenyl, amino, thiophenecarbonitrile, also, known, orange, yellow. 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 5 Methyl 2 2 nitrophenyl amino 3 thiophenecarbonitrile NamesPreferred IUPAC name 5 Methyl 2 2 nitrophenyl amino 3 thiophenecarbonitrileOther names ROYIdentifiersCAS Number 138564 59 7 Y3D model JSmol Interactive imageChEMBL ChEMBL1990114 YChemSpider 350550 YECHA InfoCard 100 101 989PubChem CID 395460UNII J7X181M78Y YCompTox Dashboard EPA DTXSID40160713InChI 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 YKey NPXUFPFFHANGDL UHFFFAOYSA N YSMILES Cc1cc c s1 Nc2ccccc2 N O O C NProperties 1 Chemical formula C 12H 9N 3O 2SMolar mass 259 28 g mol 1Melting point 99 102 C 210 216 F 372 375 K HazardsGHS labelling 2 PictogramsSignal word WarningHazard statements H410Precautionary statements P273 P391 P501Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox referencesSynthesis EditThe preparation of ROY was first disclosed in a series of patents from Eli Lilly amp 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 nbsp Polymorphism EditROY 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 nbsp 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 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 Edit a b US patent 5817655 Chakrabarti J K Hotten T M amp Tupper D E Methods of treatment using a thieno benzodiazepine issued 1998 10 06 assigned to Eli Lilly and Co Ltd 5 Methyl 2 2 nitrophenyl amino 3 thiophenecarbonitrile pubchem ncbi nlm nih gov Retrieved 2021 05 08 Kramer Katrina 2020 07 29 Red orange yellow reclaims polymorph record with help from molecular cousin chemistryworld com Retrieved 2021 05 07 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 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 amp Design 20 11 7093 7097 doi 10 1021 acs cgd 0c01017 S2CID 225294672 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 5 methyl 2 2 nitroanilino thiophene 3 carbonitrile ccdc cam ac uk Retrieved 2021 05 08 a b 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 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 Levesque 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 a b 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 Cruz Cabeza Aurora J Bernstein Joel 2014 Conformational Polymorphism Chemical Reviews 114 4 2170 2191 doi 10 1021 cr400249d PMID 24350653 Retrieved from https en wikipedia org w index php title 5 Methyl 2 2 nitrophenyl amino 3 thiophenecarbonitrile amp oldid 1144942230, wikipedia, wiki, book, books, library,
