The regioselective bromine-lithium exchange reaction of alkoxymethyldibromobenzene: A new strategy for the synthesis of tofogliflozin as a SGLT2 inhibitor for the treatment of diabetes

Murakata, Masatoshi; Ikeda, Takuma; Kimura, Nobuaki; Kawase, Akira; Nagase, Masahiro; Kimura, Masahiro; Maeda, Kenji; Honma, Akie; Shimizu, Hitoshi

doi:10.1016/j.tet.2016.12.028

Cited by 10 publications

(10 citation statements)

References 25 publications

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“…n -BuLi was employed for the halogen–metal exchange and subsequent glycosylation to generate intermediate 54 . According to the authors, when the reaction was carried out in a mixture of toluene and methyl tert -butyl ether (MTBE) (7.3:0.7), a homogeneous solution was obtained, which allowed the formation of 54 . The authors also emphasized the importance of the slow addition of n -BuLi to preferentially obtain the ortho-lithiated intermediate.…”

Section: Synthesis Of Gliflozinsmentioning

confidence: 99%

“…The regioselectivity of the bromide–lithium exchange was explained by the coordination between the oxygen atom of the methoxy group and a lithium atom. Thus, intermediate 54 was preferentially formed as a result of the proximity to the ortho position; the regioselectivity of the reaction was 53:1 (ortho:para), and 98% conversion was observed . Then a second lithiation was carried out using n -BuLi followed by the addition of the lithiate to 4-ethylbenzaldehyde to afford 56, which undergoes deprotection and intramolecular cyclization in the presence of HCl in THF/H 2 O to produce spiroketal derivative 57.…”

Section: Synthesis Of Gliflozinsmentioning

confidence: 99%

“…To avoid chromatographic purification of the amorphous active pharmaceutical ingredient (API) as a final step, the authors reported the preparation of tetracarbonate 58 to allow the desired product to be purified by crystallization …”

Section: Synthesis Of Gliflozinsmentioning

confidence: 99%

“…According to the authors, when the reaction was carried out in a mixture of toluene and methyl tert-butyl ether (MTBE) (7.3:0.7), a homogeneous solution was obtained, which allowed the formation of 54. 99 The authors also emphasized the importance of the slow addition of n-BuLi to preferentially obtain the ortho-lithiated intermediate. The regioselectivity of the bromide−lithium exchange was explained by the coordination between the oxygen atom of the methoxy group and a lithium atom.…”

Section: Organic Process Research and Developmentmentioning

confidence: 99%

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Synthetic Strategies toward SGLT2 Inhibitors

Aguillón

Mascarello²,

Segretti³

et al. 2018

Org. Process Res. Dev.

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Gliflozins are an important class of prescription drugs used to treat type II diabetes. They reduce blood sugar levels by targeting the sodium-glucose transport protein 2 (SGLT2) and consequently inhibit glucose reabsorption in the kidney. There are currently several FDA-approved gliflozins as well as others in the pipeline to be launched in the next few years. This review describes the synthetic strategies used for manufacturing SGLT2 inhibitors on both bench and industrial scales. Moreover, the drawbacks to the strategies and the improvements made to obtain selected gliflozins and their glucose derivatives over the years are highlighted.

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Section: Synthesis Of Gliflozinsmentioning

confidence: 99%

Section: Synthesis Of Gliflozinsmentioning

confidence: 99%

Section: Synthesis Of Gliflozinsmentioning

confidence: 99%

Section: Organic Process Research and Developmentmentioning

confidence: 99%

See 2 more Smart Citations

Synthetic Strategies toward SGLT2 Inhibitors

Aguillón

Mascarello²,

Segretti³

et al. 2018

Org. Process Res. Dev.

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“…Tofogliflozin (TFG), which is an inhibitor of sodium glucose cotransporter 2 (SGLT2), was developed for the treatment of type 2 diabetes, 21) and its chemical structure is shown in Fig. 2.…”

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confidence: 99%

Tofogliflozin Salt Cocrystals with Sodium Acetate and Potassium Acetate

Takata

Tanida

Nakae

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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We investigated the salt cocrystals formed by tofogliflozin with sodium acetate and potassium acetate by determining the crystal structures of the salt cocrystals and characterizing the solid states. The salt cocrystal screening using the slurry method and the liquid-assisted grinding method resulted in the formation of tofogliflozin-sodium acetate 1 : 1 and tofogliflozin-potassium acetate 1 : 1 salt cocrystals. Single-crystal X-ray diffraction revealed that, although each salt cocrystal belongs to a different space group, both of the salt cocrystals have almost similar structural features, including the conformation of tofogliflozin molecules, the coordination to Na /K ions, and hydrogen bonds. The salt cocrystals exhibited extreme hygroscopicity with deliquescence, which is also a property of sodium acetate and potassium acetate. In addition, tofogliflozinpotassium acetate salt cocrystal had two polymorphs, which were enantiotropically related.

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