OpenSourceMalaria:GSK Amino-thienopyrimidine Series

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Contents

GSK Thienopyrimidine Series

The first structure in this series, | TCMDC 135294, has the following structure:

GSK Thienopyrimidine Series: TCMDC 135294
GSK Thienopyrimidine Series: TCMDC 135294

| ChEMBL 581088 link.

| ChemSpider link.

SMILES: Nc1ncnc2cc(sc12)c3cccc(c3)S(=O)(=O)N

InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)

Synthesis

The proposed synthesis for this compound is below:

Proposed synthesis for the above compound
Proposed synthesis for the above compound

Alternatives

The step that involves n-BuLi would best be avoided, and if a more direct route of arriving at the Suzuki coupling step could be discovered, that would take a potentially dangerous and difficult step out of the synthetic route.

One possibility, involving NIS and an ionic liquid such as 1-Butyl-3-methylimidazolium tetrafluoroborate (which our lab doesn't have, but which is available from Aldrich in catalytic quality from $247/5g), is found below:

[doi:10.1016/j.tetlet.2011.03.010 DOI]

[dx.doi.org/10.1139/V09-125 Here] is another alternative, where the direct iodonation of arenes can be carried out using oxone and NaI. Whether or not this would work in my compound, given selectivity issues, is something that I'll have to investigate.

This paper shows a method of direct halogenation of thiophenes. This uses [Bis(trifluoroacetoxy)iodo]benzene, which we don't have lying around, but which can be bought from Aldrich for $136/10g. The reactivity of thiophenes vs pyrimidines is something I'll have to look into. UPDATE: I've read Clayden et al. (2012, p 727) and I'm informed that pyridine is, generally speaking, terrible at electrophilic aromatic substitution reactions. My understanding is that pyrimidine has the same reactivity as does pyridine, so there shouldn't be any selectivity problems with any of these reactions (a result that was perhaps anticipated by the BuLi reaction proceeding at the alpha position on the thiophene ring in the first place).

--- July 9th.

The BuLi reactions have literature precedent. Heffron (2010) acheives a very similar reaction, albeit with protection of a pyrimidine position (which doesn't seem to be reacting in my case anyway). Snegaroff (2009) uses (TMP)3CdLi to acheive the metallation/iodination. This less harsh base can be used at rt. This author discovered the reagent, so they are probably interested in self promotion. In any case, there is precedent for the lithium metallation proceeding.

Thiophene Starting Material Synthesis

Additionally, the thiophene available from Sigma Aldrich for $159/10g can be made from the following synthesis.

Proposed synthesis for the above compound
Proposed synthesis for the above compound

Analogues

TCMDC 135294 is part of a series with one other member, | TCMDC 135255, shown below:

TCMDC 135255
TCMDC 135255

| ChEMBL639249 link.

| ChemSpider link.

SMILES: Nc1ncnc2cc(sc12)c3cccc(NC(=O)Nc4ccccc4)c3

InChI=1S/C19H15N5OS/c20-18-17-15(21-11-22-18)10-16(26-17)12-5-4-8-14(9-12)24-19(25)23-13-6-2-1-3-7-13/h1-11H,(H2,20,21,22)(H2,23,24,25)

A list of commercially available compounds with similar structures to the one I'm trying to synthesise were identified with much help from Iain Wallace. If you're reading this and are interested in donating samples of these compounds, feel free to contact me: Jim Cronshaw

Iain Wallace created a cytoscape file which details purchaseable compounds related to the two series that I am trying to make. The file can be found here, and Cytoscape can be downloaded for free here (one will need to activate the chemviz plugin, which can be activated from within Cytoscape). The results of this work, in the form of a list of purchaseable compounds, can be found here

A list of the above compounds in .csv format, with InChi, InChiKey, SMILES and eMolecules identifiers, can be found here.

These compounds, and relevant data, are shown below:

References

| Barker, J. M.; Huddleston, P. R.; Wood, M. L., A RAPID CONVERSION OF 3-OXOTHIOLANES INTO 3-AMINOTHIOPHENES. Synthetic Communications 2002, 32 (16), 2565-2568.

| Baykal, A. T.; Kakalis, L.; Jordan, F., Electronic and nuclear magnetic resonance spectroscopic features of the 1 ',4 '-iminopyrimidine tautomeric form of thiamin diphosphate, a novel intermediate on enzymes requiring this coenzyme. Biochemistry 2006, 45 (24), 7522-7528.

Brown, G. B.; Baker, B. R.; Bernstein, S.; Safir, S. R., BIOTIN. II. 3,4-trans-DIAMINOTHIOPHANE. The Journal of Organic Chemistry 1947, 12 (1), 155-159.

Castenado, G.; Dotson, J.; Goldsmith, R.; Gunzo, J.; Heffron, T.; Mathieu, S.; Oliveo, A.; Staben, S.; Sutherlin, D.P.; Tsui, V.; Wang, S.; Zhu, B.; Bayliss, T.; Chuckowree, I.; Folkes, A.; Wan, N.C. (Genentech, Inc., USA; Piramed Limited). Thienopyrimidine and furopyrimidine derivatives as phosphoinositide 3-kinase inhibitor and their preparation, pharmaceutical compositions and use in the treatment of cancer. World Intellectual Property Organisation 2008073785 A2, 2008; SciFinder Scholar AN 2008:735944 (accessed 2/2/2012).

| Diel, B. N.; Han, M. C.; Kole, P. L.; Boaz, D. B., Synthesis of (C-13(6)-Ring-(U))-(+/-)-benzo(a)pyrene metabolites from (C-13(6)-Ring-(U))benzene. Journal of Labelled Compounds & Radiopharmaceuticals 2007, 50 (5-6), 551-553.

| F, Duus., A study of the tautomerism of 2- and 4-ethoxycarbonylthiolan-3-ones implicating stereochemical effects of ring-substitution. Tetrahedron 1981, 37 (15), 2633-2640.

Son, J.B.; Jung, S. H.; Choi, W.I.; Jung, Y.H.; Choi, J.Y.; Song, J.Y.; Lee, K.H.; Lee, J.C.; Kim, E.Y.; Ahn, Y.G.; Kim, M.S.; Choi, HG.; Sim, T.B.; Ham, Y.J.; Park, D.; Kim, H.; Kim, D. (Hanmi Holdings Co., Ltd., S. Korea; Korea Institute of Science and Technology; Catholic University Industry Academic Cooperation Foundation). Preparation of thienopyrimidine derivatives for use as protein kinase inhibitors. World Intellectual Property Organisation 2011093684 A2, 2011; SciFinder Scholar AN 2011:971406 (accessed 3/2/2012).

Woodward, R. B.; Eastman, R. H., Tetrahydrothiophene ("Thiophane") Derivatives. J. Am. Chem. Soc. 1946, 68 (11), 2229-2235.

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