2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone

Description

It is usually used as the intermediate and raw material in the chemistry synthesis and pharmaceutical industry. Especially, this chemical has been widely used in the design and synthesis of sodium-glucose transporter inhibitors.¹ For example, this substance can be employed as raw material in the preparation of (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-ethoxylphenyl)methyl]phenyl]-D-glucitol, which is commonly known as Dapagliflozin that act as the sodium dependent glucose transporters for treating type 2 diabetes.² Moreover, it can also function as the intermediate for synthesizing empagliflozin, which is a novel and selective sodium glucose co-transporter-2 inhibitor.³ In addition, canagliflozin, another sodium glucose co-transporter-2 inhibitor, can be obtained by utilizing this substance as the intermediate.⁴

Reference

1. Guo, C.; Hu, M.; DeOrazio, R. J.; Usyatinsky, A.; Fitzpatrick, K.; Zhang, Z. J.; Maeng, J. H.; Kitchen, D. B.; Tom, S.; Luche, M.; Khmelnitsky, Y.; Mhyre, A. J.; Guzzo, P. R.; Liu, S., The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties. Bioorg. Med. Chem. 2014, 22, 3414-3422.
2. S Thirumalai Rajan; Eswaraiah, S., Process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxylphenyl)methyl]phenyl]-D-glucitol and its solvate thereof. US Patent 2015, WO 2015/132803 A2.
3. Hrapchak, M.; Latli, B.; Wang, X. J.; Lee, H.; Campbell, S.; Song, J. J.; Senanayake, C. H., Synthesis of empagliflozin, a novel and selective sodium-glucose co-transporter-2 inhibitor, labeled with carbon-14 and carbon-13. J. Label. Compd. Radiopharm. 2014, 57, 687-694.
4. Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M., Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. J. Med. Chem. 2010, 53, 6355-6360.

Chemical Properties

Pale yellow oil

Uses

2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone is an antidiabetic agent and an intermediate of Dapagliflozin (D185370). 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone acts as a reagent in the synthesis of trans-cyclohexane-bearing C-glucose as sodium glucose co-transporter 2 inhibitors.

Synthesis

At present, the publicly reported synthesis process of 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone is mainly prepared by the synthesis of D-gluconolactone and trimethylsilyl chloride in the presence of an acid-binding agent or the preparation of D-gluconolactone and hexamethyldisilazane in dichloromethane reflux. The former has problems such as high pH requirements, low atom economy, and severe pollution. In contrast, the latter has such problems as the large amount of hexamethyldisilazane used, the strong volatility of dichloroethane, and severe pollution. Therefore, Li et al. developed a method for preparing 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone, comprising the following operations: reacting D-gluconolactone with hexamethyldisilazane in an ionic liquid at standard pressure, and removing the ionic liquid by reduced pressure distillation after the reaction is completed to obtain 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone; the cation in the ionic liquid is an alkyl imidazolium ion, and the anion in the ionic liquid is hexafluorophosphate, tetrafluoroborate, tetrachloroaluminate or chloride ion.

References

[1] Patent: US2011/237789, 2011, A1. Location in patent: Page/Page column 11-12
[2] Patent: US2011/237526, 2011, A1. Location in patent: Page/Page column 7; 8
[3] Patent: US2013/267694, 2013, A1. Location in patent: Page/Page column 0297-0301
[4] Patent: WO2015/43473, 2015, A1. Location in patent: Paragraph 00113
[5] Patent: US2015/191502, 2015, A1. Location in patent: Paragraph 0084