- Stereoselective Preparation of C-Aryl Glycosides via Visible-Light-Induced Nickel-Catalyzed Reductive Cross-Coupling of Glycosyl Chlorides and Aryl Bromides
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A nickel-catalyzed cross-coupling reaction of glycosyl chlorides with aryl bromides has been developed. The reaction proceeds smoothly under visible-light irradiation and features the use of bench-stable glycosyl chlorides, allowing the highly stereoselective synthesis of C-aryl glycosides. (Figure presented.).
- Mou, Ze-Dong,Wang, Jia-Xi,Zhang, Xia,Niu, Dawen
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p. 3025 - 3029
(2021/05/27)
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- Preparation method of canagliflozin
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The invention discloses a preparation method of canagliflozin. According to the method, the reaction of each step in a route is improved, so that the conversion rate of raw materials is increased, andintroduction of potential toxic compounds is avoided. In addition, reaction conditions are mild; operation is simple; purity of an obtained product is high; quality of drugs is improved; and the preparation method is suitable for industrial production.
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- Preparation method of canagliflozin
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The invention relates to a preparation method of canagliflozin, and the preparation method is characterized in that the preparation method comprises the following steps: 1) reacting 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl) methyl ] thiophene with an alkaline reagent and 2,3,4, 6-tetra-O-(trimethylsilyl)- D- glucolactone under a low-temperature condition, and carrying out methylation and deprotection reaction with a methanol solution of methanesulfonic acid to generate an intermediate 1; 2) under a low-temperature condition, reacting the intermediate 1 with triethyl silane and boron trifluoride diethyl etherate, and carrying out post-treatment to obtain an intermediate 2; 3) under a low-temperature condition, reacting the intermediate 2 with an organic base, DMAP and acetic anhydride,and purifying to obtain an intermediate 3; and 4) reacting the intermediate 3 with an alkaline water solution, and purifying after the reaction to obtain the canagliflozin. The method is mild in conditions, safe to operate, simple in post-treatment and high in product purity, no alpha-isomer is detected; the product is safer.
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Paragraph 0090; 0100; 0101; 0102; 0105; 0115; 0116; 0117
(2019/04/26)
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- Preparation method of canagliflozin
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The invention belongs to the technical field of chemical synthesis of medicines, and concretely relates to a preparation method of canagliflozin. The preparation method comprises the following steps:carrying out an acetylation and bromination reaction on d-glucose used as a starting raw material in order to prepare bromotetraacetylglucose; carrying out a Grignard exchange reaction on 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene and a Grignard reagent at a low temperature, and reacting the obtained reaction product with the bromotetraacetylglucose to form an acetyl protected intermediate; and reacting the intermediate with an alkaline solution, and purifying the obtained reaction product to obtain the canagliflozin. The preparation method has the advantages of mild conditions, safety in operation and simple post-treatment; and the product has a high purity, a detection result shows that the product contains no alpha-isomer, and the product is safe.
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Page/Page column 8-11
(2019/01/20)
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- Carbon-aryl glycoside SGLT-2 inhibitor precursor and synthesis method thereof
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The invention relates to a plurality of carbon-aryl glycoside SGLT-2 inhibitor precursors and a synthesis method thereof. The method takes glycosyl bromide and aryl iodide (bromide) as substrates, thesubstrates react for 1-2 days through ice water bath and the room temperature mixing condition under the effects of a catalyst, a ligand, a reducing agent and an additive, and a precursor compound ofcarbon-aryl glycoside SGLT-2 inhibitor drug is obtained. The synthesis method has the advantages that the precursor compound is convenient to hydrolyze, the conversion rate is high, the catalyst metal is cheap, the product is easily and massively prepared and not prone to deteriorating, the reaction is moderate, one-pot reaction and one-step reaction are achieved, the steps are simple, the methodis safe to operate, the yield is high, and the stereoscopic selectivity is good.
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Paragraph 0021
(2019/03/28)
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- Nickel-catalyzed reductive coupling of glucosyl halides with aryl/vinyl halides enabling β-selective preparation of C-aryl/vinyl glucosides
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This work describes stereoselective preparation of β-C-aryl/vinyl glucosides via mild Ni-catalyzed reductive arylation and vinylation of C1-glucosyl halides with aryl and vinyl halides. A broad range of aryl halides and vinyl halides were employed to yield C-aryl/vinyl glucosides in 42%–93% yields. Good to excellent β-selectivities were obtained for C-glucosides by using tridentate ligand.
- Liu, Jiandong,Lei, Chuanhu,Gong, Hegui
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p. 1492 - 1496
(2019/07/05)
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- C- aryl glycoside compound and synthesis method thereof
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The invention relates to a C-aryl glycoside compound and a synthesis method thereof. A structural formula of the compound is shown in the description, wherein R is H, acetyl, methyl formate group, NHBoc or 4-methoxy; basic reaction takes glycosyl bromide and aryl iodine (bromine) as a substrate, and reaction is gently performed for 6-12 hours under icy-water bath or normal temperature under actions of a catalyst, a ligand, a reducer and an additive, so that the C-aryl glycoside compound is obtained. The catalyst metal is relatively cheap, raw materials are simple and easily available, the reaction is moderate, one-step reaction is performed, steps are simple, operations are safe, and the yield is relatively high, so that stereoselectivity is relatively good.
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Paragraph 0073; 0074; 0075; 0076; 0077; 0078; 0079-0081
(2018/10/19)
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- Stereoselective Preparation of α- C-Vinyl/Aryl Glycosides via Nickel-Catalyzed Reductive Coupling of Glycosyl Halides with Vinyl and Aryl Halides
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Facile preparation of the α-C-vinyl and -aryl glycosides has been developed via mild Ni-catalyzed reductive vinylation and arylation of C1-glycosyl halides with vinyl/aryl halides. Good to high α-selectivities were achieved for C-glucosides, galactosides, maltoside, and mannosides, which were dictated by the employment of pyridine type ligands. As such, the present work represents unprecedented control for a high level of α-selectivity for C-vinyl-glucosides using cross-coupling approaches and offers hitherto optimal α-selective preparation of C-aryl glucosides via catalyst-controlled coupling strategies.
- Liu, Jiandong,Gong, Hegui
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supporting information
p. 7991 - 7995
(2019/01/04)
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- Preparing method of canagliflozin
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The invention relates to a preparing method of canagliflozin. The preparing method comprises the steps of after adding 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene into organic solvent A tobe subjected to dissolved clarification, preparing lithium salt at low temperature through an alkaline reagent, then conducting a reaction with gluconolactone protected by silylation, continuing to add methanesulfonic acid to be subjected to an etherification reaction, after the reaction is completed, adding an alkaline solution to adjust the pH value to 7-8, after liquid separation, using organic solvent B to extract the water layer, fusing organic layers and washing and concentrating to obtain an oil substance, an intermediate shown in the formula I; reducing the intermediate through a reductant at minus 50-minus 40 DEG C to obtain a coarse product of canagliflozin; further crystalizing the coarse product of canagliflozin through acetylation to obtain an intermediate of acetyl canagliflozin; finally hydrolyzing and crystalizing the intermediate of acetyl canagliflozin under alkaline conditions to obtain canagliflozin. Canagliflozin prepared according to the method is high in yield and purity.
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Paragraph 0042; 0047
(2018/07/15)
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- Canagliflozin drug impurity as well as preparation method and application thereof
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The invention discloses a canagliflozin drug impurity as well as a preparation method and application thereof. The invention provides a compound as well as a preparation method and application thereof. The method comprises the following steps: (1) enabling the compound as shown in formula 2 to be in contact with an alkaline lithium hydroxide aqueous solution to obtain a coarse product containing a compound as shown in formula 3, wherein the coarse product contains a compound as shown in formula 1; (2) crystallizing and filtering the coarse product to obtain mother liquor; (3) concentrating the mother liquor to obtain residues; and (4) crystallizing and filtering the residues in an L-proline-containing organic solvent, thus obtaining the compound as shown in formula 1. The method provided by the invention can realize directed preparation of the compound as shown in formula 1, and a reliable impurity contrast is provided for quality research on industrially produced canagliflozin-series diabetes treatment drug products and quantitative control over impurities.
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Paragraph 0055; 0056; 0057; 0058; 0059; 0060
(2017/10/31)
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- Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals
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We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.
- Adak, Laksmikanta,Kawamura, Shintaro,Toma, Gabriel,Takenaka, Toshio,Isozaki, Katsuhiro,Takaya, Hikaru,Orita, Akihiro,Li, Ho C.,Shing, Tony K. M.,Nakamura, Masaharu
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supporting information
p. 10693 - 10701
(2017/08/15)
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- Canagliflozin single crystal, method for preparing same and application of canagliflozin single crystal
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The invention relates to a canagliflozin single crystal, a method for preparing the same and application of the canagliflozin single crystal. X-ray powder of the canagliflozin single crystal has characteristic peaks when the X-ray powder is diffracted at diffraction angles 2 theta of 7.95 degrees, 10.92 degrees, 13.94 degrees, 15.46 degrees, 15.94 degrees, 18.82 degrees, 20.27 degrees, 22.72 degrees and 26.78 degrees, the obtained single crystal is not reported, crystal structures of the canagliflozin single crystal are orthorhombic systems as shown by means of measurement, space groups are P2(1)2(1)2(1), and the numbers Z of molecules in crystal packs are 4. The canagliflozin single crystal, the method and the application have the advantages that the canagliflozin single crystal is a colorless needle crystal at the normal temperature and is excellent in morphology, and the purity of the canagliflozin single crystal can reach 99%; canagliflozin can be effectively separated from other impurities by the aid of the method, and the method is good in repeatability.
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- PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL AGENT
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This invention provides a process for preparing canagliflozin, comprising: (a) reacting a tricyclic aromatic derivative and a substituted cyclic ester, quenching and deprotecting the resulting intermediate to provide a compound comprising a substituted tetrahydropyran-tricyciic aromatic derivative, and (b) reducing the tetrahydropyran-tricyclic aromatic derivative to provide canagliflozin. The invention also provides a process for preparing canagliflozin hemihydrate.
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Page/Page column 12
(2017/05/17)
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- card Geleg net bulk drug and preparation (by machine translation)
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The invention relates to a net card Geleg bulk drug and preparation, the preparation method of states card Geleg net raw material comprises a compound 1 With TMSCI, N - methyl morpholine reaction to produce compound CAN - C Compound CAN - A With a compound CAN - C, MeOH reaction to produce the compound E Compound E, acetic anhydride, N - methyl morpholine and DMAP mixing, reaction to produce the compound F Add triethyl silane, boron trifluoride ether, acetonitrile and water mixing, reaction to produce compound CAN - G Namely card Geleg net bulk drug. The preparation comprises the following weight percentage of each component: card Geleg net bulk drug, microcrystalline cellulose, anhydrous lactose, or microcrystalline cellulose aqueous solution, sodium carboxy methyl cellulose, magnesium stearate. The card gliclazide net of the raw material preparation method has high reaction yield, reagent is easy to get the advantages of the raw materials, greatly reduces the production cost of the card Geleg net raw material. (by machine translation)
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- TABLETS CONTAINING A 1-(?-D-GLUCOPYRANOSYL)-3-(PHENYLTHIENYLMETHYL)BENZENE COMPOUND
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The present invention is directed to a tablet containing a 1-(β-D-glucopyranosyl)-3-(phenylthienylmethyl)benzene compound in high drug loading, in particular, containing the compound ranging from 30 to 95% by weight of tablet and pharmaceutically acceptable additives.
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Paragraph 0103; 0104
(2016/09/12)
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- PROCESS FOR THE PREPARATION OF CANAGLIFLOZIN
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The present invention relates to a novel process for the preparation of canagliflozin of formula I, (I) and to novel intermediates which are produced during the course of carrying out the novel process.
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Page/Page column 5; 13
(2016/06/28)
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- PROCESS FOR THE PURIFICATION OF CANAGLIFLOZIN
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The present invention provides a process for the preparation of (1S)-2,3,4,6-tetra- O-acetyl-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D- glucitol of Formula III. The invention also provides a process for the purification of canagliflozin using (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-5 thienyl]methyl]-4-methylphenyl]-D-glucitol of Formula III.
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- A high-purity card Geleg net compound and its preparation method
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The invention belongs to the field of drug synthesis and relates to a high-purity canagliflozin compound represented by a formula I shown in a drawing and a preparation method thereof. According to the canagliflozin compound provided by the invention, the content of an alpha-configuration impurity represented by a formula II shown in a drawing is lower than 1% and is further lower than 0.5%. The preparation method comprises the steps of preparing a eutectic substance from canagliflozin and amino acid in a solvent, separating the eutectic substance, and then, decomposing the eutectic substance, thereby obtaining the canagliflozin compound.
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Paragraph 0072; 0073
(2016/12/01)
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- PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT
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The present invention is directed to a novel process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporter (SGLT) being present in the intestine or kidney.
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Page/Page column 37
(2010/05/13)
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- PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT
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The present invention is directed to a novel process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporter (SGLT) being present in the intestine or kidney.
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Page/Page column 80
(2009/04/25)
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