Efficient Route to Canagliflozin via Anhydroketopyranose

Sasikala, Ch. V. A.; Ratnamala, A.; Basu, Debjit; Singarapu, Kiran Kumar; Mohammad, Aaseef; Bandichhor, Rakeshwar

doi:10.1021/acs.orglett.2c00980

Cited by 4 publications

(10 citation statements)

References 24 publications

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“…According to literature reports, − a possible reaction mechanism for methylation is depicted in Figure . Intermediate 10 in the dissolved state exists as a mixture of its isomers, i.e., the six-membered pyranose form ( 10 ), five-membered furanose form ( 10a ), and open-chain form ( 10b ).…”

Section: Resultsmentioning

confidence: 99%

“…Although most of the raw material 4 was converted, only a small amount of the expected product 5 was observed, and the reaction mainly produced a new product 20 (Table , entry 1). After the structure of compound 20 was confirmed, its production mechanism was analyzed according to related literature. − First, the reaction of raw material 4 is catalyzed by BF 3 ·Et 2 O to form oxyonium intermediate 10′ , which is transformed via two reaction pathways (path a and path b). In pathway A, 10′ is attacked by Et 3 SiH from the α-surface to obtain the expected product 5 .…”

Section: Resultsmentioning

confidence: 99%

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Optimization and Scale-Up of a Continuous Flow Synthesis of Dapagliflozin

Wang

Xuan

Huang

et al. 2023

Org. Process Res. Dev.

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Dapagliflozin is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The traditional synthesis method of dapagliflozin needs ultralow temperature (−78 °C) and is greatly affected by the environment. Here we report a continuous flow synthesis process for dapagliflozin. The mild and efficient synthesis of Br/Li exchange reaction and C-arylation was achieved with the aid of efficient mixing and heat transfer in the microreactor, and the reaction temperature could be increased from −78 °C to −20 °C. The closed environment can reduce the environmental interference of moisture in the ambient air in the methoxy reduction reaction, thereby minimizing the formation of impurities, meeting the quality requirements. The continuous flow synthesis method for dapagliflozin reported in this paper not only greatly shortened the reaction time (from 26 h to 43 min) but also significantly improved the safety of the process and increased the yield. The final product quality is improved, the purity of the product is 99.83%, and the existing scale output is as high as 4.13 kg/day.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Optimization and Scale-Up of a Continuous Flow Synthesis of Dapagliflozin

Wang

Xuan

Huang

et al. 2023

Org. Process Res. Dev.

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“…Combination of inexpensive reductants with various metal salts was tested using conversion of 5a to 1a as a typical example (Table ). For a control experiment, a known procedure using Et 3 SiH/BF 3 ·OEt 2 was tested to provide the desired product 1a in 41% yield (Table , entry 1) . Expecting cost reduction, either use of trichlorosilane (TCS) or polymethylhydrosilane (PMHS) in the presence of BF 3 ·OEt 2 was tried (Table , entries 2 and 3).…”

Section: Results and Discussionmentioning

confidence: 99%

“…. 7 To a suspension of 5-iodo-2-methylbenzoic acid 2a (5.00 g, 19.1 mmol) in CH 2 Cl 2 (35 mL) was added DMF (0.0700 g, 0.950 mmol) followed by SOCl 2 (4.77 g, 40.1 mmol) at 20−30 °C. The mixture was stirred at 50 °C for 1 h under an argon atmosphere.…”

Section: -(4-fluorophenyl)-thiophen)-2-yl-(5-iodo-2-methylphenyl)meth...mentioning

confidence: 99%

“…. 7 To a solution of (5-(4-fluorophenyl)-thiophen)-2-yl-(5iodo-2-methylphenyl)methanone (5a) (100 mg, 0.240 mmol) in DME (1 mL) was added NaBH 4 (14.0 mg, 0.370 mmol) and the mixture was stirred at 70 °C for 2 h. Then, the mixture was cooled down to 25 °C, and TiCl 4 (67.0 mg, 0.350 mmol) in CH 2 Cl 2 (0.2 mL) was added over 1 min, and the mixture was stirred at 50 °C for 5 h. The mixture was cooled down to 25 °C, water (5 mL) was added and the mixture was stirred for 30 min. The mixture was extracted with CHCl 3 (10 mL), and the organic phase was washed with water (2 × 5 mL) and evaporated.…”

Section: -(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1a)mentioning

confidence: 99%

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New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors

et al. 2023

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Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel–Crafts acylation with TiCl4, followed by reduction with TiCl4/NaBH4. The new protocol proceeded more cleanly than the previous methods employing AlCl3 and BF3·OEt2/Et3SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl3/Al/BF3·OEt2.

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Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction

Seki,

Tapkir,

Nadiveedhi

et al. 2023

J. Org. Chem.

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Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and i PrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

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Efficient Route to Canagliflozin via Anhydroketopyranose

Abstract: The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity.

Cited by 4 publications

References 24 publications

Optimization and Scale-Up of a Continuous Flow Synthesis of Dapagliflozin

Optimization and Scale-Up of a Continuous Flow Synthesis of Dapagliflozin

New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors

Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction

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