- Palladium-Catalyzed Reaction of Aryl Iodides and Glycal Enones: Application in the Preparation of Dapagliflozin Analogues
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An efficient approach for the preparation of C-1 aryl enones from aryl iodides and glycal enones by palladium-catalyzed cross-coupling reactions under ligand-free conditions was developed. A wide range of aryl iodides bearing electron-donating and withdrawing groups underwent oxidative C-1 arylation with galactal, glucal and rhamnal enones in the presence of Pd(OAc)2 and AgNO3 under mild conditions. The protecting groups, including benzyl, acetyl, pivaloyl, and benzoyl groups, were found to be compatible under standard reaction conditions. The developed methodology was applied for the preparation of dapagliflozin analogues (SGLT-2 inhibitors). Regioselective nitration of C-1 aryl enones provides C-2 nitro aryl enones in good yields.
- Kandasamy, Jeyakumar,Kumar Kanaujiya, Vimlesh,Kumar Singh, Adesh,Tiwari, Varsha,Venkatesh, Rapelly
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- Facile Approach to C-Glucosides by Using a Protecting-Group-Free Hiyama Cross-Coupling Reaction: High-Yielding Dapagliflozin Synthesis
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Access to unprotected (hetero)aryl pseudo-C-glucosides via a mild Pd-catalysed Hiyama cross-coupling reaction of protecting-group-free 1-diisopropylsilyl-d-glucal with various (hetero)aryl halides has been developed. In addition, selected unprotected pseudo-C-glucosides were stereoselectively converted into the corresponding α- and β-C-glucosides, as well as 2-deoxy-β-C-glucosides. This methodology was applied to the efficient and high-yielding synthesis of dapagliflozin, a medicament used to treat type 2 diabetes mellitus. Finally, the versatility of our methodology was proved by the synthesis of other analogues of dapagliflozin.
- Vaňková, Karolína,Rahm, Michal,Choutka, Jan,Pohl, Radek,Parkan, Kamil
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p. 10583 - 10588
(2021/06/25)
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- Process development of sotagliflozin, a dual inhibitor of sodium- Glucose cotransporter-1/2 for the treatment of diabetes
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The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium- glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagliflozin features five contiguous chiral centers on the carbohydrate core flanked by a thioether group and a biaryl moiety. Three chiral centers are obtained from the starting material L-xylose, while the other two were established (or modified) via three highly stereoselective transformations: Luche reduction (dr: 97/3), dynamic kinetic resolution of anomeric hemiacetal (dr: 95/5), and Lewis acid-promoted thiolation (dr: 1000/ 1). Global deprotection of the resulting penultimate intermediate with catalytic sodium methoxide followed by recrystallization furnishes sotagliflozin. The longest linear sequence consists of 10 steps from L-xylose with an overall yield of 40%. This process has been performed on multi-hundred kilogram batches to satisfy the drug substance development demands.
- Zhao, Matthew M.,Zhang, Haiming,Iimura, Shinya,Bednarz, Mark S.,Song, Qiu-Ling,Lim, Ngiap-Kie,Yan, Jie,Wu, Wenxue,Dai, Kuangchu,Gu, Xiaodong,Wang, Youchu
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p. 2689 - 2701
(2020/11/03)
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- Synthetic method of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene
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The invention belongs to the field of pharmaceutical synthesis and discloses a synthetic method of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene. The synthetic method comprises the following steps: (S1) dissolving 4-bromobenzene ether into a solvent, adding magnesium, and reacting under the catalysis of iodine, so as to obtain a Grignard reagent; and (S2) dissolving 2-(bromomethyl)-4-iodochlorobenzeneinto the solvent, adding the Grignard reagent prepared in the step S1, and reacting under the catalysis of cuprous iodide, so as to obtain 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene. The method is short in synthetic route, the final product purity reaches up to 99.5%, and the yield reaches up to 95.9%, so that the method is beneficial to the industrialization production.
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Paragraph 0028-0045; 0046-0051
(2019/02/04)
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- Design, synthesis and anticancer activities of halogenated Phenstatin analogs as microtubule destabilizing agent
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A series of halogenated Phenstatin analogs were designed as microtubule destabilizing agent by docking study. It was synthesized within three steps starting from 2-chloro-5-iodobenzoic acid and substituted benzene. All the products were characterized by 1H NMR and 13C NMR spectral analysis, and the stereochemical structure was also confirmed by a single crystal X-ray diffraction crystallographic analysis. The microtubule destabilizing activities were evaluated in vitro with human liver cancer Huh-7 cell line and human lung cancer A549 cell line. Some of the HPAs were achieved IC50 about 5.0 μM against human liver cancer Huh-7 cells. [Figure not available: see fulltext.].
- Hu, Shengquan,Sun, Wuji,Wang, Yeming,Yan, Hong
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p. 465 - 472
(2019/02/09)
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- A SGLT2 inhibitor intermediates preparation method (by machine translation)
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The invention discloses a SGLT2 inhibitor intermediates preparation method, comprises the following steps: (1) 5 - halo - 2 - chlorobenzoic acid and fluorobenzene to Friedel-crafts reaction, to obtain (5 - halo - 2 - chlorophenyl) (4 - fluorophenyl) a ketone; (2) under the action of the inorganic base, (5 - halo - 2 - chlorophenyl) (4 - fluorophenyl) methanone and ethanol undergo the substitution reaction, after the reaction is finished after treatment to obtain (5 - halo - 2 - chlorophenyl) (4 - ethoxy) a ketone; (3) (5 - halo - 2 - chlorophenyl) (4 - ethoxy) methanone in the reducing agent under the effect of the reduction reaction of carbonyl, get said SGLT2 inhibitor intermediates. The preparation method is through adopting the inorganic alkali and ethanol instead of the ethoxide reagent and DMSO (or DMF), not only can effectively reduce the cost, but also more environmentally friendly. (by machine translation)
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- COMPOSITIONS COMPRISING (2S,3R,4R,5S,6R)-2-(4- CHLORO-3-(4-ETHOXYBENZYL)PHENYL)-6-(METHYLTHIO)TETRAHYDRO-2H-PYRAN-3,4,5-TRIOL
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Pharmaceutical dosage forms useful for improving the cardiovascular and/or metabolic health of patients, particularly those suffering from type 2 diabetes, are disclosed, as well as methods of their manufacture.
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- SGLT-2 inhibitor intermediate synthesis method
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The invention discloses a SGLT-2 inhibitor intermediate synthesis method. The method utilizes a NaBH4-TMSCl complex reducing agent to reduce carbonyl into methylene. The synthesis method has the characteristics of less side reactions, good environmental friendliness, low price, use of easily available raw materials and large scale production feasibility.
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- PROCESS FOR THE PREPARATION OF BENZYLBENZENE SGLT2 INHIBITORS
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Provided are methods of making compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides synthetic intermediates useful for preparing such compounds.
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Page/Page column 0309-0310
(2013/10/22)
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- PROCESS FOR THE PREPARATION OF BENZYLBENZENE SGLT2 INHIBITORS
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Provided are methods of making compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides synthetic intermediates useful for preparing such compounds.
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Paragraph 0257
(2013/11/05)
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- PROCESS FOR PREPARATION OF BENZYLBENZENE SODIUM-DEPENDENT GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS
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Provided are methods of making compounds having an inhibitory effect on sodium-dependent glucose cotransporter (SGLT) and synthetic intermediates useful for preparing such compounds.
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Paragraph 0269
(2013/11/05)
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- COMPOSITIONS COMPRISING AND METHODS OF USING INHIBITORS OF SODIUM-GLUCOSE COTRANSPORTERS 1 AND 2
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Pharmaceutical dosage forms useful for improving the cardiovascular and/or metabolic health of patients, particularly those suffering from type 2 diabetes, are disclosed, as well as methods of their manufacture.
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- Solid forms of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol and methods of their use
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Solid forms of anhydrous (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol are disclosed, in addition to methods of their use in the treatment of various diseases and disorders.
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- SOLID FORMS OF (2S,3R,4R,5S,6R)-2-(4-CHLORO-3-(4-ETHOXYBENZYL)PHENYL)-6-(METHYLTHIO)TETRAHYDRO-2H-PYRAN-3,4,5-TRIOL AND METHODS OF THEIR USE
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Solid forms of anhydrous (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol are disclosed, in addition to methods of their use in the treatment of various diseases and disorders.
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Page/Page column 5-6
(2010/02/17)
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- METHODS AND COMPOUNDS USEFUL FOR THE PREPARATION OF SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS
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Methods of synthesizing sodium glucose co-transporter 2 inhibitors, as well as compounds useful therein, are disclosed. Particular inhibitors are compounds of formula I:
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Page/Page column 9
(2009/02/11)
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