- AN EFFICIENT PROCESS FOR THE PREPARATION OF ERTUGLIFLOZIN L-PYROGLUTAMIC ACID AND INTERMEDIATES THEREOF
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The present invention relates to an efficient process for the preparation of Ertugliflozin L-pyroglutamic acid of formula (I) and intermediate thereof, in environment friendly conditions. The present invention further relates to a process for the preparation of substantially pure intermediate of formula (IV).
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Page/Page column 4; 13-14; 18
(2021/07/10)
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- Method for preparing intermediates of gliflozin hypoglycemic drugs
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The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.
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- Synthetic method of dapagliflozin
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Disclosed is a synthesis method of dapagliflozin. The method includes providing a microreactor having at least 4 reaction units in series, delivering a 5-bromo-2-chloro-4'-ethoxydiphenylmethane solution and an alkyllithium solution into a first reaction unit and controlling the reaction temperature in the first reaction unit to be -5 to -40 DEG C; after the reaction is completed, making a reactionsolution flow into a second reaction unit, and delivering trimethylsilyl protected gluconolactone or a solution thereof to the second reaction unit; after the reaction is completed, making a reactionsolution flow into a third reaction unit and delivering a mixed solution of methanol and methane sulfonic acid to the third reaction unit; making a reaction solution flow into a fourth reaction unitafter the reaction is completed and delivering a mixed solution of boron trifluoride diethyl etherate and Triethylsilane into the fourth reaction unit.
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Paragraph 0083-0085; 0087-0089; 0091-0093; 0095-0097
(2019/03/24)
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- Preparation method of sugar-reducing medicine dapagliflozin
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The invention discloses a preparation method for hypoglycemic drugdapagliflozin. The method comprises the steps that 4-hydroxybenzaldehyde is adopted as a starting raw material, alkylation, carbonyl reduction, chlorination and alkylation reaction with asepsin, diazotization and chlorination are performed to obtain a dapagliflozinmidbody 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane, then, the midbody and 2,3,4,6-tetra-O-trimethyl silicone-D-glucolactone are subjected to condensation, etherification and methoxyl removal to obtain the hypoglycemic drugdapagliflozin. The raw materials adopted by the technological path are low in price and easy to obtain, the technology can achieve industrialization easily, and the final product is high in purity; the technological path is novel, the syntheticroute is short, no risky or complex technology exists in the reactions, equipment is simple, operation is easy and convenient, and the method is suitable for industrial production.
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Paragraph 0050; 0069-0071
(2019/10/01)
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- Refining method of SGLT-2 inhibitor intermediate
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The invention discloses a refining method of an SGLT-2 inhibitor intermediate; the SGLT-2 inhibitor intermediate is represented by the formula (I), wherein the definition of substituent groups in theformula (I) is detailed in the specification. The refining method includes the following steps: the SGLT-2 inhibitor intermediate is dissolved in a polar organic solvent and cooled to ultra-low temperature, the non-polar organic solvent is added, and the solid SGLT-2 inhibitor intermediate is obtained. The refining method is different from a conventional recrystallization technology, and can refine materials that are not easy to solidify at room temperature. A new choice is provided for refining the materials with low melting point and high viscosity. The refining method is suitable for industrialized scale-up production.
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Paragraph 0049-0054
(2019/11/20)
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- Dapagliflozin preparation method
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The invention relates to a Dapagliflozin preparation method, which comprises the following steps: using 2-chlorobenzaldehyde as a starting material, carrying out bromination, reducing, chlorinating tosynthesize 5-bromo-2-chlorobenzyl chloride, carrying out Friedel-Crafts alkylation reaction between 5-bromo-2-chlorobenzyl chloride and phenetole to synthesize 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane, conducting condensation between 5-bromo-2-chloro-4'-ethyoxyldiphenylmethane and 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone, carrying out trimethylsilyl deprotection, conducting etherification, and reducing for demethylation to obtain a hypoglycemic drug Dapagliflozin. The invention has the following advantages: according to the Dapagliflozin preparation method, 2-chlorobenzaldehyde, whichis used as a starting material, is cheaper and easily available in comparison with 5-bromo-2-chlorobenzoic acid, and the technology is easy for industrialization; during the synthetic process, no rawmaterials which cause severe toxicity will be used and furthermore there is no dangerous process; the synthetic route is short and novel and the operation is simple; and through the synthetic route,purity of the final product can be raised, and the purity can reach 99% and above.
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Paragraph 0039; 0040; 0052; 0053
(2018/04/01)
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- Synthetic method for dapagliflozin
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The invention relates to a synthetic method for dapagliflozin. The synthetic method is characterized in that 4-methylphenol is taken as a starting raw material, alkylation and bromination are performed, an alkylation reaction is performed with antisepsin, diazotization and chlorination are performed, and condensation, etherification and desmethoxy are performed with 2,3,4,6-tetrakis-O-trimethylsilyl-D-gluconolactone to obtain a hypoglycemic drug (dapagliflozin). The synthetic method has the following advantages: 4-methylphenol is taken as the starting raw material, and 4-methylphenol is low inprice and easily accessible than 5-bromo-2-chlorobenzoic acid; by adoption of the process, industrialization can be easily realized; in the synthesis process, raw materials which are highly toxic arenot used, so that dangerous processes are avoided; the synthesis path is short and novel, so that the operation is simple and convenient; and by adoption of the synthesis path, the purity of a finalproduct can be improved, and the purity can be 99% or above.
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- Glucopyranosyl derivative preparation and medical application (by machine translation)
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The invention relates to a as sodium-dependent glucose transporter (SGLT) inhibitors of the glucopyranosyl derivative and its application in medicine, in particular of formula (I) indicated by the 6 - oxa bicyclo [3.2.1] octane derivative or its pharmaceutically acceptable salt or all of its stereoisomers as a medicine for treating diabetes and diabetes related diseases. (by machine translation)
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Paragraph 0082; 0090; 0091; 0092; 0093
(2017/08/29)
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- PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN AND ITS SOLVATE THEREOF
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The present invention provides for crystalline Dapagliflozin butane –1,2– diol solvate (VIII), crystalline Dapagliflozin (S) butane –1,2– diol solvate (VIIIa) and Dapagliflozin (R) butane –1,2– diol solvate (VIIIb). The present invention also provides industrial methods for production of crystalline Dapagliflozin butane –1,2– diol solvate (VIII), crystalline 5 Dapagliflozin (S) butane –1,2– diol solvate (VIIIa) and Dapagliflozin (R) butane –1,2– diol solvate (VIIIb). The present invention further provides an industrial method production of amorphous Dapagliflozin.
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Page/Page column 17-18
(2018/04/11)
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- PROCESSES FOR THE PREPARATION OF ERTUGLIFLOZIN
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The present invention relates to processes for the preparation of ertugliflozni. The present invention also provides compounds of Formula (III), Formula (IV), and Formula (VII), processes for their preparation, and their use for the preparation of ertugliflozin. The processes of the present invention involve protecting the ertugliflozin intermediate compound with a suitable protecting group which provides ertugliflozin having high purity and yield.
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- PROCESS FOR THE PREPARATION OF (1S)-1,5-ANHYDRO-1-C-{4-CHLORO-3-4[(4-ETHOXYPHENYL)METHYL]PHENYL]-GLUCITOL AND ITS SOLVATE THEREOF
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The present invention relates to a process for the preparation of (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol which is represented by the following structural formula-1 and its glycerol solvate.
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Paragraph 0081
(2017/02/24)
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- Dapagliflozin impurity compound
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The invention discloses an II type sodium ion dependent-glucose co-transporter (SGTL2) inhibitor and an impurity compound of II type diabetes treatment medicine dapagliflozin, and particularly relates to a prepration method of organically synthesized glucose open-loop impurities: 1-[4-chlorine-3-(4-methoxyl benzyl)-phenyl] hexane-1,2,3,4,5,6-n-hexanehexol (a compound 1).
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Paragraph 0026-0041
(2017/07/19)
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- Preparation method of SGLT-2 inhibitor compound
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The invention relates to a preparation method of SGLT-2 inhibitor compound. The preparation method comprises the following steps: performing hydroxyl protection, coupling reaction, hydroxyl de-protection, ketalation and the like to the compound A so as to obtain an intermediate I; and then preparing the SGLT-2 inhibitor compound by the obtained intermediate I.
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Paragraph 0022; 0023
(2016/10/09)
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- GLUCOPYRANOSYL DERIVATIVES AND THEIR USES IN MEDICINE
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Disclosed are glucopyranosyl derivatives used as sodium dependent glucose cotransporters (SGLTs) inhibitors, intermediates or preparation processes thereof, and pharmaceutical uses thereof, especially glucopyranosyl derivatives represented by Formula (I), or pharmaceutically acceptable salts or all stereoisomers thereof, pharmaceutical compositions containing these derivatives and their uses for treatment of diabetes and diabetes-related diseases.
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Paragraph 00135
(2015/04/15)
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- GLUCOPYRANOSYL DERIVATIVES AND THEIR USES IN MEDICINE
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Provided herein are glucopyranosyl derivatives used as sodium dependent glucose cotransporters (SGLTs) inhibitors and pharmaceutical uses thereof, particularly 6,8-dioxabicyclo [3.2.1] octane derivatives represented by Formula (I), or pharmaceutically acceptable salts or all stereisomers thereof, pharmaceutical composition containing the derivatives and their uses for treatment of diabetic and diabetes-related diseases.
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Paragraph 00115
(2015/04/15)
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- Development of an early-phase bulk enabling route to sodium-dependent glucose cotransporter 2 inhibitor ertugliflozin
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The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation-selective monodesilylation, primary alcohol oxidation, aldol-crossed-Cannizzaro reaction, and solid-phase acid-catalyzed bicyclic ketal formation. The final API was isolated as the Lpyroglutamic acid cocrystal.
- Bernhardson, David,Brandt, Thomas A.,Hulford, Catherine A.,Lehner, Richard S.,Preston, Brian R.,Price, Kristin,Sagal, John F.,Pierre, Michael J. St.,Thompson, Peter H.,Thuma, Benjamin
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supporting information
p. 57 - 65
(2014/05/20)
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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 0258; 0259
(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 0286-0291
(2013/11/05)
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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 0330-0332
(2013/10/22)
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- PROCESSES FOR THE PREPARATION OF SGLT2 INHIBITORS
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Provided are processes for the preparation of complexes that are useful in purifying compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The processes can reduce the number of steps needed to obtain the target compounds and the complexes formed in the processes are typically provided in a crystalline form.
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Page/Page column 35; 37-38
(2010/04/03)
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- CRYSTAL STRUCTURES OF SGLT2 INHIBITORS AND PROCESSES FOR PREPARING SAME
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The present invention relates to physical crystal structures of a compound of the formula I: wherein R1, R2, R2a, R3 and R4 are as defined herein, especially pharmaceutical compositions containing structures of compound I or II, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.
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Page/Page column 25-26
(2008/06/13)
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- Methods of producing C-aryl glucoside SGLT2 inhibitors
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Method for the production of C-aryl glucoside SGLT2 inhibitors useful for the treatment of diabetes and related diseases. and intermediates thereof. The C-aryl glucosides may be complexed with amino acid complex forming reagents.
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