cas 842133-18-0, Canagliflozin | Articles data

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Stereoselective Preparation of C-Aryl Glycosides via Visible-Light-Induced Nickel-Catalyzed Reductive Cross-Coupling of Glycosyl Chlorides and Aryl Bromides
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
p. 3025 - 3029
(2021/05/27)

Preparation method of SGLT-2 inhibitor and intermediate
The invention discloses a preparation method of an SGLT-2 inhibitor and an intermediate. The method comprises the following steps: (1) reacting a compound A with chlorosilane under the action of an acid-binding agent to generate a compound B; (2) mixing the compound B and a compound C to obtain a compound D; and (3) reacting the compound D with a reducing agent and a catalyst to obtain the SGLT-2 inhibitor compound.
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Paragraph 0112-0118

(2021/05/19)

METHOD FOR PRODUCING C-ARYL GLYCOSIDE DERIVATIVE
PROBLEM TO BE SOLVED: To provide a method that can produce a C-aryl glycoside derivative stably and inexpensively. SOLUTION: A method for producing a C-aryl glycoside derivative includes the step of mixing, for example, in an organic solvent, the following benzyl-protected C-aryl glycoside derivative (IaA), at least one silyl compound selected from trimethylsilyl chloride and trimethylsilyl bromide, and an alkali metal iodide, thereby producing the following C-aryl glycoside derivative (IIaA). SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0091-0097

(2021/06/25)

Preparation method of canagliflozin
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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(2020/02/14)

Syntheses of SGLT2 inhibitors by Ni- And Pd-catalyzed fukuyama coupling reactions
Nickel- and palladium-catalyzed Fukuyama coupling reactions of a D-gluconolactone-derived thioester with arylzinc reagents at ambient temperature provided the corresponding multifunctional aryl ketones in high yield. Ligand screening for the nickel-catalyzed Fukuyama coupling reactions indicated that 1,2- bis(dicyclohexylphosphino)ethane (dCype) served as a superior supporting ligand to improve the product yield. In addition, Pd/C was a practical alternative that enabled ligand-free Fukuyama coupling reactions and was efficiently applied to the key C-C bond-forming step to prepare canagliflozin and dapagliflozin, which are diabetic SGLT2 inhibitors of current interest.
Kato, Daiki,Mashima, Kazushi,Nagae, Haruki,Seki, Masahiko,Talode, Jalindar,Tsurugi, Hayato
p. 12382 - 12392
(2020/11/09)

Preparation method of canagliflozin
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; 0097; 0098; 0099; 0105; 0112; 0113; 0114

(2019/04/26)

Halopivalylglucopyranose and preparation method for SGLT2 inhibitor
The invention belongs to the technical field of drug synthesis. The invention relates to a novel method for preparing a compound (including Canagliflozin, Dapagliflozin, Empagliflozin and Ipragliflozin) with inhibitory activity on sodium-dependent glucose transporters (SGLT) existing in the intestines or the kidneys. The invention discloses a 1,2,3,4,6-penta-O-halopivalylglucopyranose, the generalstructural formula of which is formula I. The invention further discloses a 2,3,4,6-tetra-O-halopivalyl-Alpha-D-haloglucopyranose (haloglucose for short), the general structural formula of which is formula III. The invention further discloses a preparation method for an SGLT2 inhibitor. The SGLT2 inhibitor which is prepared by adopting the method disclosed by the invention has the technical advantages of high purity, high yield, easiness in operation, suitability for industrial production and the like.
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Paragraph 0170; 0171; 0186; 0187; 0188

(2019/01/14)

CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
The present invention relates to a process for the preparation of Canagliflozin (I), which is substantially free of hydroperoxide impurity (II).
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Page/Page column 9-10

(2019/07/19)

Preparation method of canagliflozin
The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.
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(2019/02/27)

Preparation method of canagliflozin
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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(2019/01/20)

Carbon-aryl glycoside SGLT-2 inhibitor precursor and synthesis method thereof
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 0022

(2019/03/28)

Preparing method of canagliflozin
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; 0046; 0052; 0058

(2018/07/15)

PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF CANAGLIFLOZIN
The present invention relates to an improved process for the preparation of amorphous form of Canagliflozin with high purity and high yield. Particularly the present invention is related to the direct isolation of amorphous form of Canagliflozin from reaction mixture and also related to purification of amorphous form of Canagliflozin through piperidine-4-carboxylic acid complex of Canagliflozin.
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Page/Page column 15

(2018/02/28)

Synthesis and Optimization of Canagliflozin by Employing Quality by Design (QbD) Principles
Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel-Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.
Metil, Dattatray S.,Sonawane, Swapnil P.,Pachore, Sharad S.,Mohammad, Aaseef,Dahanukar, Vilas H.,McCormack, Peter J.,Reddy, Ch. Venkatramana,Bandichhor, Rakeshwar
p. 27 - 39
(2018/01/28)

CO-CRYSTALS OF SGLT2 INHIBITORS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF
The present invention provides solid forms of SGLT2 inhibitors, to processes for their preparation and their use in the purification of SGLT2 inhibitors and also provided pharmaceutical compositions comprising them and their use in therapy.
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Page/Page column 37; 38

(2017/04/11)

Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals
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
p. 10693 - 10701
(2017/08/15)

SUBSTANTIALLY PURE CANAGLIFLOZIN
The present application provides substantially pure canagliflozin and a process for the preparation of substantially pure canagliflozin. The present application further provides substantially pure compound 18a' and a process for the preparation substantially pure compound 18a'.
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Page/Page column 12-14

(2017/07/06)

NOVEL PROCESS FOR THE PREPARATION OF CANAGLIFLOZIN
The present invention provides a novel process for the preparation of Canagliflozin (I) and its hydrates thereof by employing novel intermediates. The present invention is also provides commercially and industrial applicable process.
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(2017/04/04)

Method for continuously preparing canagliflozin by using microreactor one-pot method
The invention discloses a method for continuously preparing canagliflozin by using a microreactor one-pot method. The method is used for continuously preparing the canagliflozin by using the microreactor one-pot method, and microreactors are divided into a unit A, a unit B, a unit C and a unit D. The method comprises the steps of mixing a solution of M1 with n-butyl lithium in the unit A for carrying out a reaction; after the reaction is finished, enabling the reaction product to enter the unit B together with a solution of M3, and carrying out a reaction at the temperature of -15 to -5 DEG C to obtain an intermediate A; enabling reaction liquid containing the intermediate A to enter the unit C together with a methanol solution of methane sulfonic acid, and carrying out a reaction to obtain an intermediate B; enabling reaction liquid containing the intermediate B to directly react with boron trifluoride and triethyl silicane in the unit D to obtain the canagliflozin. The method greatly simplifies the operation steps, shortens the reaction time, greatly reduces the use of various solvents, lowers the production cost, improves the production safety, can realize continuous and automatic production, and is high in product purity and yield, thus being suitable for industrial production.
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Paragraph 0025; 0052; 0055

(2017/07/19)

PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL AGENT
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 11; 12

(2017/05/17)

Canagliflozin drug impurity as well as preparation method and application thereof
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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(2017/10/31)

1 - (β - D - pyran glucosyl) - 4 - methyl - 3 - [5 - (4 - fluorophenyl) - 2 - thienyl methyl] benzene synthesis process
The invention discloses a preparation method of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene. The method has the advantages of short route, no requirement on low temperature, solid starting raw materials and intermediate, convenience in purification, good stereoselectivity and the like.
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Paragraph 0017; 0031; 0041

(2017/11/16)

Pipeline synthesis process for liflozin drugs
The invention relates to a pipeline synthesis process for liflozin drugs. The synthesis process is based on a pipeline reactor, and the pipeline reactor comprises a first pipeline section used for preheating and a second pipeline section used for reacting. The synthesis process comprises the following steps: respectively dissolving raw materials in an organic solvent, respectively pumping the materials into the pipeline reactor, and enabling the materials to enter the first pipeline section to be preheated; preheating for multiple time, enabling the materials to respectively enter the second pipeline section, pumping an aqueous solution of inorganic base through a joint of the second pipeline section, remaining for multiple time and discharging, performing after-treatment, thereby obtaining the raw liflozin drugs. Compared with the prior art, the pipeline synthesis process disclosed by the invention has the beneficial effects that the equipment miniaturization and continuous production of production of the raw liflozin drugs can be realized by utilizing the pipeline reaction process, the mass transfer and heat transfer of the materials are stable, and the pipeline reaction has high synthesis efficiency compared with a batch reaction.
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Paragraph 0022; 0023

(2018/01/13)

PROCESS FOR THE PURIFICATION OF CANAGLIFLOZIN
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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Page/Page column 9

(2016/03/12)

TABLETS CONTAINING A 1-(?-D-GLUCOPYRANOSYL)-3-(PHENYLTHIENYLMETHYL)BENZENE COMPOUND
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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(2016/09/12)

A net card Geleg method for the preparation of
The invention discloses a preparation method of canagliflozin. The method comprises the following steps: (1) by using DMF (N,N-dimethylformamide) as a solvent, carrying out protective reaction on the main raw material SM1 by using benzoyl chloride to obtain an intermediate I; (2) by using acetonitrile as a solvent, removing methoxy group from the intermediate I under the action of trimethyl phosphite to obtain an intermediate II; and (3) by using tetrahydrofuran and anhydrous ethanol or methanol as solvents, removing benzoyl protection from the intermediate II under the action of sodium methoxide to obtain the canagliflozin. The purity of the product is at least 99.9%, and the yield is at least 81.6%. The method has the advantages of mild reaction conditions, high yield and high product quality, is economical and environment-friendly, and can easily implement industrial production.
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Paragraph 0050

(2017/01/31)

A NOVEL PROCESS FOR PREPARING (2S,3R,4R,5S,6R)-2-{3-[5-[4-FLUORO-PHENYL)- THIOPHEN-2-YLMETHYL]-4-METHYL-PHENYL}-6-HYDROXYMETHYL-TETRAHYDRO-PYRAN-3,4,5- TRIOL AND ITS STABLE AMORPHOUS HEMIHYDRATE FORM
The present invention discloses the process for preparation of (2S,3R,4R,5S,6R)-2-{3-[5- [4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro- pyran-3,4,5-triol and its stable amorphous hemihydrate form.
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Page/Page column 18

(2016/09/26)

Process for synthesizing card Geleg only (by machine translation)
The invention discloses a process for synthesizing card Geleg only, in order to 2?Methyl benzoic acid as starting material, use of improvised catalyst, reaction to produce the iodine iodate a in the middle, or in 2?Methyl benzoic acid as starting material, the metal reagent and under the action of catalyst, by adding liquid bromine, synthetic intermediates b; optionally intermediate one or intermediate two acylation reaction with thionyl chloride, to Friedel-crafts reaction produce intermediate three; in order to ALPHA?D?Glucose as raw material, with the reaction protection of all hydroxyl after pivalyl chloride, and then with zinc bromide, trimethyl silane reaction produce intermediate four; three intermediate the intermediate body, connecting delivery into intermediate five; finally under acidic conditions to remove the acyl special fifth heavenly stem, produce the target compound. card Geleg only of the present invention new process for the synthesis of high yield, mild condition, safety and reliability, is suitable for industrial production, raw material is cheap and easy to obtain, it is beneficial to control the production cost. (by machine translation)
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(2016/12/01)

PROCESS FOR THE PREPARATION OF SGLT INHIBITOR COMPOUNDS
The present invention DISCLOSES a novel process for preparing sodium glucose transporters 2 (SGLT2) inhibitor compounds of Formula IX. Wherein, R is halogen, alkyl or alkoxy group; and Ar is aryl group, substituted or unsustituted monocyclic polycyclic or heterocyclic ring selected from the residues A, B, C or D as given below.
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(2016/09/22)

A high-purity card Geleg net compound and its preparation method
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 0065; 0066

(2016/12/01)

Preparation method for canagliflozin
The invention relates to a novel synthesis method for 1-(Beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (canagliflozin). 2-(4-fluorophenyl)-5-[(5-halogeno-2-methylphenyl)methyl]thiophene and 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucono-1,5-lactone are dissolved in organic solvent and carry out condensation reaction under the catalysis of a metallic lithium derivative, and thereby intermediate (II) is produced; the intermediate (II) undergoes catalytic hydrogenation reaction, so that intermediate (III) is further produced, and finally, compound (I), namely the canagliflozin is obtained by acidification hydrolysis. Because the preparation method disclosed by the invention replaces a virulent BF3/triethyl silicane reduction system with the environment-friendly catalytic hydrogenation technique, the preparation method is technically safer, environment-friendly, low in cost and more suitable for industrial production.
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Paragraph 0053

(2016/11/24)

Preparation methods for canagliflozin and intermediate thereof and intermediate
The invention belongs to the field of medicine, and particularly relates to preparation methods for canagliflozin and an intermediate thereof and the intermediate. The preparation method for canagliflozin comprises the following steps: a compound having the structure represented by the formula (I) is subjected to a debenzylation reaction to obtain canagliflozin. The preparation methods provided by the invention have simple reaction route, the intermediate has no need for purification, and the products have high purity and high yield. Experimental results indicate that when the method provided by the invention is used for preparing canagliflozin, the product yield is greater than 88%, and the purity is greater than 99.5%.
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(2016/10/27)

PROCESS FOR THE PREPARATION OF CANAGLIFLOZIN
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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(2016/06/28)

Preparation method of SGLT-2 inhibitor compound
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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(2016/10/09)

PROCESS FOR PREPARATION OF CANAGLIFLOZIN
The present invention relates to a process for the preparation of canagliflozin and intermediates thereof.
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(2015/12/17)

STEREOSELECTIVE SYNTHESIS OF INTERMEDIATES IN THE PREPARATION OF ?-C-ARYLGLUCOSIDES
The invention belongs to the fields of pharmaceutical industry, and particularly to an improved stereoselective synthesis of intermediate compounds for the preparation of gliflozins, for example canagliflozin or structurally similar gliflozins. Gliflozins, such as canagliflozin, dapagliflozin, empagliflozin, or ipragliflozin, inhibit the sodium-dependent glucose cotransporter 2 (SGLT2) in the kidney and as such are useful in the treatment of type-2 diabetes.
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Page/Page column 25

(2015/12/08)

β-Selective C-Arylation of Diisobutylaluminum Hydride Modified 1,6-Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups
The β-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (10), pretreated with i-Bu2AlH, i-Bu3Al, Et3Al, Me3Al, or n-octyl3Al, with triphenylalane or aryl(chloro)alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (1a), from commercially available 10 in one C-C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required. (Chemical Presented).
Henschke, Julian P.,Lin, Chen-Wei,Wu, Ping-Yu,Tsao, Wen-Shing,Liao, Jyh-Hsiung,Chiang, Pei-Chen
p. 5189 - 5195
(2015/05/27)

β-Selective C-arylation of silyl protected 1,6-anhydroglucose with arylalanes: The synthesis of SGLT2 inhibitors
The stereoselective arylation of hydroxy protected 1,6-anhydro-β-d-glucose with arylalanes to provide β-C-arylglucosides is reported. Modification of triarylalanes, Ar3Al, with strong Br?nsted acids (HX) or AlCl3 produced more reactive arylating agents, Ar2AlX, while the incorporation of alkyl dummy ligands into the arylating agents was also viable. Me3Al and i-Bu2AlH were found useful in the in situ blocking of the C3-hydroxyl group of 2,4-di-O-TBDPS protected 1,6-anhydroglucose. The utility of the method was demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin.
Henschke, Julian P.,Wu, Ping-Yu,Lin, Chen-Wei,Chen, Shi-Feng,Chiang, Pei-Chen,Hsiao, Chi-Nung
p. 2295 - 2309
(2015/09/21)

Process for the Preparation of ?-C-Aryl Glucosides
The present invention provides processes for stereoselectively preparing C-arylglucosides that can be useful as synthetic building block or drugs, including SGLT2 inhibitors.
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Paragraph 0274; 0275

(2014/05/20)

PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT2
The present invention is directed to a novel process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof; comprising: reacting a compound of formula (V) wherein LG1 is a leaving group, with a mixture of a zinc salt and an organo-lithium reagent; in a first hydrocarbon solvent; at a temperature in the range of from about -78°C to about room temperature; to yield a mixture of the corresponding compound of formula (VI), wherein M1 is lithium, and the zinc salt; admixing to the mixture of the compound of formula (VI) and the zinc salt, a first ether solvent; to yield the corresponding compound of formula (VII), wherein M2 is a reactive zinc species.
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(2012/11/06)

PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT2
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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(2011/04/25)

THERAPEUTIC USES OF SGLT2 INHIBITORS
Provided are methods of using one or more SGLT2 inhibitors, independently or in combination, for treating edema or reducing fluid retention. The invention also provides methods of using one or more SGLT2 inhibitors for the preparation of a medicament for treating edema or fluid retention. Methods are also provided for treating diabetes with an amount of one or more SGLT2 inhibitors and one or more PPAR-gamma agonists.
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(2011/04/19)

Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus (1)
We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
Nomura, Sumihiro,Sakamaki, Shigeki,Hongu, Mitsuya,Kawanishi, Eiji,Koga, Yuichi,Sakamoto, Toshiaki,Yamamoto, Yasuo,Ueta, Kiichiro,Kimata, Hirotaka,Nakayama, Keiko,Tsuda-Tsukimoto, Minoru
experimental part
p. 6355 - 6360
(2010/11/03)

PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT
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 39

(2010/05/13)

PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT
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 81

(2009/04/25)