- Synthesis method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane
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The present invention relates to a method for preparing 5-bromo-2-chloro-4'-ethoxydiphenylmethane, first of all o-chlorobenzoic acid chlorination made of o-chlorobenzoyl chloride, and then fuucylation to make 2-chloro-4'-iodobenzophenone, further brominated to make 5-bromo-2-chloro-4'-iododibenzophenone, and then reduced to make 5-bromo-2-chloro-4'-iododiphenylmethane, and finally by substitution reaction to make 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The method of the present invention is streamlined, the resulting product purity is high, the raw materials used, excipients are common compounds, the use of low toxicity solvents and can be recycled, will not produce phosphorus-containing wastewater, high safety and environmental friendliness, low cost, low requirements for equipment, suitable for industrial production.
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- PREPARATION OF HIGHLY PURE AMORPHOUS DAPAGLIFLOZIN
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A novel and improved process for the preparation of amorphous dapagliflozin is disclosed. The present invention further provides pharmaceutical compositions containing amorphous dapagliflozin, optionally in a combination with one or more other active substances and methods for making the same.
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Page/Page column 24
(2021/12/13)
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- Synthesis method of dapagliflozin intermediate 5-bromo-2-chloro-4 '-ethoxydiphenylmethane
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The invention discloses a synthesis method of a dapagliflozin intermediate 5-bromo-2-chloro-4 '-ethoxydiphenylmethane. The method comprises the following steps: using 5-bromo-2-chlorobenzoic acid as araw material to be acylated by thionyl chloride, and then carrying out acylation reaction with 1-nitro-4-(phenoxymethyl) benzene, reducing, acetylating, hydrogenating and ethylating to obtain the dapagliflozin intermediate 5-bromo-2-chloro-4'-ethoxydiphenylmethane. The method can effectively avoid the acylation reaction ortho-position by-product so that the preparation of dapagliflozin is convenient for quality control, the reaction is mild, the yield is high and the method has an industrial application prospect.
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- Preparation method of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane
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The invention relates to a preparation method of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane. The preparation method is characterized by comprising the following steps: step S1, preparation of 5-bromo-2-chlorobenzoyl chloride, step S2, preparation of 5-bromo-2-chloro-4'-ethoxybenzophenone, and step S3, preparation of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane. The invention further discloses the 5-bromine-2-chloro-4 '-ethoxydiphenylmethane prepared according to the preparation method of the 5-bromine-2-chloro-4'-ethoxydiphenylmethane. The invention further discloses the 5-bromine-2-chloro-4 '-ethoxydiphenylmethane prepared according to the preparation method of the 5-bromine-2-chloro-4'-ethoxydiphenylmethane. According to the preparation method of the 5-bromo-2-chloro-4 '-ethoxydiphenylmethane, traditional preparation process conditions are optimized and innovated, the method effectively improves the product purity, the reaction conversion rate and the production efficiency, has no special requirements on reaction conditions and equipment, is suitable for industrial production, causes less pollution to the environment and effectively realizes good combination of economic benefits, social benefits and ecological benefits.
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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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- 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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- Design, synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents
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The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.
- Li, Zheng,Xu, Xue,Deng, Liming,Liao, Ruoxian,Liang, Ruiying,Zhang, Bo,Zhang, Luyong
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p. 3947 - 3952
(2018/06/27)
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- 6-halogenated glucose C-glycoside as well as preparation method and application thereof
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The invention discloses a 6-halogenated glucose C-glycoside as well as a preparation method and application thereof. A structure of 6-halogenated glucose C-glycoside is shown in formula I; an intermediate can be synthesized efficiently with cheap and easily available raw materials; meanwhile, when the raw material is used for synthesizing Jardiance, dapagliflozin and the like, a reaction yield ishigh, and an obtained product has high purity and relatively high industrial application prospect.
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- Studies towards the synthesis of ertugliflozin from L-Arabinose
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A new method for the diastereoselective synthesis of enantiomerically pure ertugliflozin was developed. The crucial step involves an aldol condensation between 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone and (4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolane-4-carbaldehyde, which was prepared from known 2-C-trityloxymethyl-2,3-O-isopropylidene-L-erythrose (easily accessible in three steps from L-arabinose) by standard reduction/oxidation and protection/deprotection manipulations. Dihydroxylation of the aldol condensation product and further global deprotection led to the formation of the target molecule.
- Triantakonstanti, Virginia V.,Mountanea, Olga G.,Papoulidou, Kyriaki-Eleni C.,Andreou, Thanos,Koftis, Theocharis V.,Gallos, John K.
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p. 5700 - 5708
(2018/08/20)
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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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- 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 0037; 0038; 0050; 0051
(2018/04/01)
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- Dicyclic derivative of glucoside as well as preparation method and application of dicyclic derivative
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The invention relates to a dicyclic derivative of glucoside as well as a preparation method and the application of the dicyclic derivative. Specifically, the invention relates to a compound as shown in Formula I, a stereisomer or pharmaceutically acceptable salt or ester of the compound, a pharmaceutical composition of the compound, and application of the compound in preparation of drugs for treating diabetes or relevant diseases.
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- PROCESSES FOR THE PREPARATION OF EMPAGLIFLOZIN
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The present invention relates to processes for the preparation of empagliflozin. In particular, the present invention relates to the preparation of empagliflozin and intermediates thereof. The present invention also relates to co-crystal of empagliflozin and amino acid and amorphous form of empagliflozin.
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- A reach geleg only preparation method
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The invention relates to a preparation method for Dapagliflozin. The preparation method comprises the following steps that a compound 2 and phenetole are mixed to obtain a mixture, and then the mixture is dropped into a suspended aluminum trichloride solution, so that the content of generated ortho isomer impurities is smaller than 1 percent; a compound 4 in the preparation method is firstly reacted with butyl lithium to generate a compound 5 in the following formula; then the compound 5 is reacted with a compound 1, so that generation of sulphonate type genetic toxic impurities is avoided; therefore the utilization rate of raw materials is increased to a certain extent, the problem of complicated post-treatment is avoided, and the purity and the yield of products are improved. According to the preparation method, a compound 6 is reduced by using hydroboron and sulfuric acid, so that the reduction reaction and deprotection can be simultaneously carried out, and the pollution is greatly alleviated. The raw materials and the reagents which are adopted in the preparation method are relatively cheap and low in cost; meanwhile, the reaction conditions of the whole preparation process are mild, and the operation is simple and safe; industrial production can be conveniently realized.
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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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- Preparation method of dapagliflozin intermediate
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The invention provides a preparation method of a dapagliflozin intermediate. The preparation method comprises the following steps: (1) by taking 4-methylphenol and bromoethane as raw materials, a polar solvent as a reaction solvent and an inorganic base as a catalyst, carrying out reaction for preparing 4-ethyoxyl methylbenzene; (2) by taking N-chlorosuccinimide and 4-ethyoxyl methylbenzene obtained in the step (1) as raw materials, a non-polar solvent as a reaction solvent and dibenzoyl peroxide as an initiator, carrying out reaction, thus obtaining 4-ethyoxyl benzyl chloride; (3) dissolving 4-ethyoxyl benzyl chloride obtained in the step (2) and 4-bromaniline into ethyl acetate, adding a catalyst lewis acid, and carrying out reaction, thus obtaining 5-bromo-2-amino-4-ethyoxyl diphenylmethane; and (4) carrying out diazotization reaction on 5-bromo-2-amino-4-ethyoxyl diphenylmethane obtained in the step (3), and then reacting with cuprous chloride, thus synthesizing 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane. The preparation method provided by the invention has the advantages of low cost, low environmental stress and short synthetic route.
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- Preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane
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The invention provides a preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane. The preparation method comprises the following steps: (1) using 4-hydroxybenzaldehyde and bromoethane as raw materials, a polar solvent as a reaction solvent and inorganic base as a catalyst to react so as to prepare 4-ethoxy-benzaldehyde; (2) using hydroxylamine hydrochloride and 4-hydroxybenzaldehyde as raw materials and a hydroxyl-containing solvent as a reaction solvent to react so as to obtain oxime, and then reacting under the effect of a dehydrating agent so as to generate 4-ethoxyl benzonitrile; (3) using 4-bromaniline and 4-ethoxyl benzonitrile as raw materials, using lewis acid as a catalyst, and performing a Hoesch reaction to generate 5-bromine-2-amino-4'-ethyoxyl benzophenone; (4) performing a diazo-reaction on 5-bromine-2-amino-4'-ethyoxyl benzophenone, and then reacting with cuprous chloride to synthesize 5-bromine-2-chlorine-4'-ethyoxyl benzophenone; and (5) performing a reduction reaction on 5-bromine-2-chlorine-4'-ethyoxyl benzophenone to obtain 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane. The method is low in cost, low in environment stress and short in synthetic route.
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- C- ARYL GLYCOSID DERIVATIVES, PHARMACEUTICAL COMPOSITION, PREPARATION PROCESS AND USES THEREOF
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This invention relates to a kind of C-aryl glycoside derivatives, its pharmaceutical compositions, preparation methods, and uses thereof. The preparation method comprises: method 1: in a solvent, deprotecting the acetyl protecting groups of compound 1-f in the presence of a base; method 2: 1) compound 2-g reacts with via Mitsunobu reaction; 2) deprotecting the acetyl protecting groups of compound 2-f obtained from step 1; method 3: 1) compound 2-g reacts with via nucleophilic substitution reaction; 2) deprotecting the acetyl protecting groups of compound 3-f obtained from step 1. The pharmaceutical composition comprises a kind of C-aryl glycoside derivatives; it's pharmaceutically acceptable salts and/or prodrugs thereof and excipient thereof. This invention further relates to a kind of C-aryl glycoside derivatives, it's pharmaceutically acceptable salts or pharmaceutical compositions thereof for the use in preparation of a SGLT inhibitor. The C-aryl glycoside derivatives of this invention provides a new direction for the study of SGLT inhibitors.
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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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- Novel method for synthesizing dapagliflozin intermediate compound
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The invention discloses a novel method for synthesizing a dapagliflozin intermediate compound. The method comprises the following steps: (1) by taking dichloromethane as a solvent and pyridine as a catalyst, reacting 5-bromo-2-chlorobenzoic acid and thionyl chloride to obtain 5-bromo-2-chlorobenzoyl chloride; (2) by taking dichloromethane as a solvent and solid acid as a catalyst, reacting phenetole and the 5-bromo-2-chlorobenzoyl chloride to obtain 5-bromo-2-chloro-4-ethoxydiphenylketone; and (3) by taking THF as a solvent, adding the 5-bromo-2-chloro-4-ethoxydiphenylketone concentrated solution obtained in the step (2); by taking acetic acid and aluminum trichloride as catalysts, adding sodium borohydride, and performing a reduction reaction; and after the reaction is completed, adding a saturated saline solution, and performing quenching at 25 DEG C or below to obtain 5-bromo-2-chloro-4-ethoxydiphenylmethane. The novel method disclosed by the invention has the advantages of cheap and available raw materials, simple and easy operation, no discharge of three wastes, high reaction yield and the like.
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- ISOLATED INTERMEDIATE OF DAPAGLIFLOZIN, PROCESS FOR THE PREPARATION OF ISOLATED INTERMEDIATE OF DAPAGLIFLOZIN, PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN
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Aspects of the present invention relates to an isolated intermediate of Dapagliflozin (Formula III) and its preparation, process for the preparation of Dapagliflozin, process for the preparation of crystalline propane-1,2,3-triol solvate of dapagliflozin, process for the preparation of L-proline complex of Dapagliflozin, solid premix of dapagliflozin with the polymer selected from the group consisting of eudragit, syloid, MCC Avicel PH 102 (1:1) and MCC Avicel PH 102 (1:2).
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Page/Page column 32; 33
(2017/03/28)
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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 077-0078
(2017/02/24)
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- PROCESS FOR PREPARATION OF DAPAGLIFLOZIN
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The present invention relates to a process for the preparation of amorphous dapagliflozin. The present invention relates to 2,3-butanediol solvate of dapagliflozin and process for its preparation.
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- C - aryl glucoside SGLT2 inhibitor
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The invention relates to the field of medicines related to diabetes mellitus and particularly relates to a 2-type sodium-glucose co-transporter (SGLT2) inhibitor with a multi-aryl glucoside structure and shown as the specification, a preparation method thereof, a medicine composition taking the compound as an active components and an application thereof in preparing medicines for resisting diabetes mellitus.
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- 5-bromo-2-chloro -4 the-oxethyl diphenylmothane [...] preparation method
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The invention relates to the chemical field and particularly relates to a novel synthesis method for preparing a key intermediate 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane of a drug dapagliflozin for treating diabetes mellitus II. The preparation method comprises the following steps: enabling a starting raw material ortho-toluidine to firstly perform bromization and then perform chlorination after diazotization on a benzene ring with N-bromo-succinimide; then, in the presence of a halogenating agent, performing halogenating reaction of beta-position; and finally, performing Friedel-Crafts alkylation synthesis with phenetole, thereby obtaining the key intermediate. The preparation method is simple and convenient, economical and relatively high in reaction yield in each step, and suitable for industrial production.
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- PROCESS FOR THE PREPARATION OF 4-BROMO-1-CHLORO-2-(4-ETHOXYBENZYL)BENZENE
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The present invention provides a process for the preparation of 4-bromo-1-chloro- 2-(4-ethoxybenzyl)benzene of Formula III, which can be used as an intermediate for the preparation of dapagliflozin, or solvates thereof.
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Page/Page column 6
(2015/05/19)
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- Inhibitor of Sodium-Dependent Glucose Transport Protein and Preparation Method Therefor and Use Thereof
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Disclosed is a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, wherein R1 and R2 are each independently hydrogen, —OH, alkyl, —CF3, —OCHF2, —OCF3 or halogen; R3 is cycloalkyl, —OCH2CF3, —OCH2CHF2, —OCH2CH2F or —OCH2CH3; R4 is hydrogen, —OH, —O aryl, —OCH2 aryl, alkyl, cycloalkyl, —CF3, —OCHF2, —OCF3, —OCH2CF3, —OCH2CHF2, —OCH2CH2F or halogen; A is —CX1X2, wherein X1 and X2 are each independently H, F and Cl, and when both X1 and X2 are H, R3 is not —OCH2CH3. The compound has an activity of inhibitors of sodium-dependent glucose transport protein. Also disclosed is a method for preparing the compound, a pharmaceutical composition comprising the compound, use of the compound and pharmaceutical composition thereof in preparing medicaments of SGLT2 inhibitors and treating related diseases.
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- Synthesis and biological evaluation of novel C-aryl D-glucofuranosides as sodium-dependent glucose co-transporter 2 inhibitors
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Novel C-aryl-d-glucofuranosides were synthesized and evaluated for their capacity to inhibit human sodium-dependent glucose co-transporter 2 (hSGLT2) and hSGLT1. Compound 21q demonstrated the best in vitro inhibitory activity against SGLT2 in this series (EC50 = 0.62 μM).
- Lin, Tzung-Sheng,Liw, Ya-Wen,Song, Jen-Shin,Hsieh, Tsung-Chih,Yeh, Hsien-Wei,Hsu, Lih-Ching,Lin, Chun-Jung,Wu, Szu-Huei,Liang, Pi-Hui
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p. 6282 - 6291
(2013/10/22)
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- FAMILY OF ARYL, HETEROARYL, O-ARYL AND O-HETEROARYL CARBASUGARS
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The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLTl, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti- inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin.
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Page/Page column 53
(2012/12/13)
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- DEUTERATED BENZYLBENZENE DERIVATIVES AND METHODS OF USE
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Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by SGLT inhibition.
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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
(2010/04/03)
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- ETHOXYPHENYLMETHYL INHIBITORS OF SGLT2
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The present invention relates to new ethoxyphenylmethyl modulators of SGLT2, pharmaceutical compositions thereof, and methods of use thereof. (Formula I)
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Page/Page column 31
(2010/05/13)
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- (1 S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio- d -glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment
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Derivatives of a novel scaffold, C-phenyl 1-thio-d-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5- (4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (3p) exhibited potent SGLT2 inhibition activity (IC50 = 2.26 nM), with 1650-fold selectivity over SGLT1. Compound 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clinical candidate for treating type 2 diabetes. We observed that compound 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clinical trials of 3p (TS-071) are currently ongoing.
- Kakinuma, Hiroyuki,Oi, Takahiro,Hashimoto-Tsuchiya, Yuko,Arai, Masayuki,Kawakita, Yasunori,Fukasawa, Yoshiki,Iida, Izumi,Hagima, Naoko,Takeuchi, Hiroyuki,Chino, Yukihiro,Asami, Jun,Okumura-Kitajima, Lisa,Io, Fusayo,Yamamoto, Daisuke,Miyata, Noriyuki,Takahashi, Teisuke,Uchida, Saeko,Yamamoto, Koji
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scheme or table
p. 3247 - 3261
(2010/10/02)
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- BENZYLBENZENE DERIVATIVES AND METHODS OF USE
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Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by SGLT inhibition.
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- Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes
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The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
- Meng, Wei,Ellsworth, Bruce A.,Nirschl, Alexandra A.,McCann, Peggy J.,Patel, Manorama,Girotra, Ravindar N.,Wu, Gang,Sher, Philip M.,Morrison, Eamonn P.,Biller, Scott A.,Zahler, Robert,Deshpande, Prashant P.,Pullockaran, Annie,Hagan, Deborah L.,Morgan, Nathan,Taylor, Joseph R.,Obermeier, Mary T.,Humphreys, William G.,Khanna, Ashish,Discenza, Lorell,Robertson, James G.,Wang, Aiying,Han, Songping,Wetterau, John R.,Janovitz, Evan B.,Flint, Oliver P.,Whaley, Jean M.,Washburn, William N.
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p. 1145 - 1149
(2008/09/20)
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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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- C-aryl glucoside SGLT2 inhibitors and method
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An SGLT2 inhibiting compound is provided having the formula A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with another antidiabetic agent or other therapeutic agent.
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- C-aryl glucoside SGLT2 inhibitors and method
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An SGLT2 inhibiting compound is provided having the formula A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with another antidiabetic agent or other therapeutic agent.
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