- Synthesis of Tofogliflozin as an SGLT2 Inhibitor via Construction of Dihydroisobenzofuran by Intramolecular [4 + 2] Cycloaddition
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The synthesis of tofogliflozin (1), a sodium glucose cotransporter 2 (SGLT2) inhibitor, was achieved through the key steps of intramolecular [4 + 2] cycloaddition of dienone-yne intermediate, aerobic aromatization, and anomeric equilibration, thus enablin
- Murakata, Masatoshi,Kawase, Akira,Kimura, Nobuaki,Ikeda, Takuma,Nagase, Masahiro,Koizumi, Masatoshi,Kuwata, Kazuaki,Maeda, Kenji,Shimizu, Hitoshi
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p. 548 - 557
(2019/03/07)
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- 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
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The regioselective bromine-lithium exchange reaction of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (2), which resulted in optimized selectivity of 220:1, is described. Applying this method to the synthesis of tofogliflozin (1) as a SGLT2 inhibi
- Murakata, Masatoshi,Ikeda, Takuma,Kimura, Nobuaki,Kawase, Akira,Nagase, Masahiro,Kimura, Masahiro,Maeda, Kenji,Honma, Akie,Shimizu, Hitoshi
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p. 655 - 660
(2017/01/16)
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- Preparation method of Tofogliflozin monohydrate
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The invention relates to a preparation method of Tofogliflozin monohydrate. In the route, p-Hydroxybenzoic acid used as a starting material is subjected to acylation, iodination, Friedel-Crafts and reduction reaction to obtain an iodinated diphenylmethane framework; by means of the characteristic that an iodinated substance is reactive, the splicing the diphenylmethane framework and a saccharide ring is realized under mild conditions through the effect of isopropyl magnesium chloride lithium chloride; and the eleven-step total yield is 22%. The route is high in yield, favorable in selectivity, low in production cost and mild in reaction conditions, does not use flammable, explosive or high-toxicity reagent, obtains products and intermediate compounds which are easy to purify, and is suitable for industrial production.
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Paragraph 0049; 0050; 0051
(2017/06/19)
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- A Scalable Synthesis of Tofogliflozin Hydrate
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A newly process for the synthesis of tofogliflozin hydrate, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, was described. Three improvements were achieved, including the development of a regioselective Friedel-Crafts reaction, a high-yield reduction, and a mild metal-halogen exchange. These improvements ultimately resulted in the isolation of tofogliflozin hydrate as a white solid in >99% purity (HPLC area) and 23% overall yield after 12 steps without column chromatography.
- Yang, Xiu-Dong,Pan, Zhao-Xi,Li, Da-Jun,Wang, Guan,Liu, Min,Wu, Rong-Gui,Wu, Yan-Hua,Gao, Yong-Chen
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p. 1821 - 1827
(2016/10/31)
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- Method for preparing derivatives of spiroketal
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Provided is a process for the preparation of a spiroketal derivative via a compound represented by general formula (II) [wherein each variable group and each variable number are as defined in the description].
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- Development of a Scalable Synthesis of Tofogliflozin
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An efficient and scalable synthesis of an antidiabetic drug, tofogliflozin (1), which was identified as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is described. A key factor in the synthesis of 1 was the selection of the purpose-designed protecting group, which plays a strategic role in protection, chemoselective activation, and crystalline purification. The developed and optimized method made it possible to prepare 1 on a multidecagram scale without any column chromatography.
- Ohtake, Yoshihito,Emura, Takashi,Nishimoto, Masahiro,Takano, Koji,Yamamoto, Keisuke,Tsuchiya, Satoshi,Yeu, Sang-Yong,Kito, Yasushi,Kimura, Nobuaki,Takeda, Sunao,Tsukazaki, Masao,Murakata, Masatoshi,Sato, Tsutomu
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p. 2148 - 2153
(2016/03/15)
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- Improved preparation of (1S,3′R,4′S,5′S,6′R)-5- chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro- 6′-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′, 4′,5′-triol
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A convenient approach for the preparation of (1S,3′R,4′S, 5′S,6′R)-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′, 5′,6′-tetrahydro-6′-(hydroxymethyl)-spiro[isobenzofuran-1(3H), 2′-[2H]pyran]-3′,4′,5′-triol is developed. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and the isomers of undesired ortho-products were avoided during the preparation.
- Liu, Yong-Hai,Fu, Ting-Ming,Ou, Chun-Yan,Fan, Wen-Ling,Peng, Guo-Ping
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p. 131 - 133
(2013/06/26)
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- Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes
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Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition o
- Ohtake, Yoshihito,Sato, Tsutomu,Kobayashi, Takamitsu,Nishimoto, Masahiro,Taka, Naoki,Takano, Koji,Yamamoto, Keisuke,Ohmori, Masayuki,Yamaguchi, Marina,Takami, Kyoko,Yeu, Sang-Yong,Ahn, Koo-Hyeon,Matsuoka, Hiroharu,Morikawa, Kazumi,Suzuki, Masayuki,Hagita, Hitoshi,Ozawa, Kazuharu,Yamaguchi, Koji,Kato, Motohiro,Ikeda, Sachiya
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p. 7828 - 7840
(2012/11/07)
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- CRYSTAL OF SPIROKETAL DERIVATIVE, AND PROCESS FOR PRODUCTION THEREOF
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The present invention provides a process for preparing a spiroketal derivative, via an intermediate represented by Formula (VI): wherein variable groups and numbers are as defined in the specification, which can be produced from dihalobenzene derivatives in one pot reaction.
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Page/Page column 21-22
(2011/04/25)
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- SPIROKETAL DERIVATIVE AND USE THEREOF AS DIABETIC MEDICINE
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The present invention provides a compound of Formula (I): wherein R1, R2, R3 and R4 are each independently selected from a hydrogen atom, an optionally substituted C1-C6 alkyl group, an opt
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Page/Page column 21
(2008/06/13)
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