- A concise and practical stereoselective synthesis of ipragliflozin L-proline
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A concise and practical stereoselective synthesis of ipragliflozin L-proline was presented starting from 2-[(5-iodo-2-fluorophenyl)methyl]-1-benzothiophene and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide without catalyst via iodine–lithium–zinc exchange. The overall yield was 52% in three steps and the product purity was excellent. Two key diastereomers were prepared with efficient and direct access to the α-C-arylglucoside.
- Ma, Shuai,Liu, Zhenren,Pan, Jing,Zhang, Shunli,Zhou, Weicheng
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- Preparation method of diabetes-treating medicine, namely ipragliflozin or derivative thereof
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The invention provides a preparation method of a diabetes-treating medicine, namely ipragliflozin or a derivative thereof. According to the preparation method, alpha-O-alkenyl sulfone is used as an electrophilic reagent for the Suzuki-Miyaura coupling reaction; the reaction raw material alpha-O-alkenyl sulfone is simple to prepare and stable in structure, and can overcome the defects of instability, preparation difficulty and the like when organic halide and sulfonic acid are used as electrophilic reagents for the Suzuki-Miyaura coupling reaction. Meanwhile, the reaction are mild in reaction conditions, compatible with a wide range of heterocyclic rings and various functional groups, high in yield and capable of realizing large-scale process production. Since alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, high-yield generation of aryl glucoside and open-chain alkenyl ether can be realized, medicines for treating type 2 diabetes mellitus, namely ipragliflozin and 2-deoxyipragliflozin can also be prepared, and the application scope of the preparation method is wide.
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Paragraph 0368; 0372-0373
(2020/11/01)
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- Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as electrophilic reagent and application thereof
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The invention provides a Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as an electrophilic reagent. The reaction comprises the following steps: weighing alpha-O-alkenyl sulfone, an organic boron reagent, a ligand, an alkali and a catalyst, and carrying out reacting in a solvent. The invention also provides application of the coupling reaction. According to the invention, alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, and the reaction raw material alpha-O-alkenyl sulfone is simple to prepare and stable in structure, and can overcome the defects of instability, preparation difficulty and the like when organic halide and sulfonic acid are used as electrophilic reagents for the Suzuki-Miyaura coupling reaction. Meanwhile,the reaction are mild in reaction conditions, compatible with a wide range of heterocyclic rings and various functional groups, high in yield and capable of realizing large-scale process production.Since the alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, high-yield generation of aryl glucoside and open-chain alkenyl ether can be realized, medicines for treating type 2 diabetes mellitus, namely ipragliflozin and 2-deoxyipragliflozin can also be prepared, and the application scope of the reaction is wide.
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Paragraph 0405; 0409-0410
(2020/11/01)
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- Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
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We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
- Gong, Liang,Sun, Hong-Bao,Deng, Li-Fan,Zhang, Xia,Liu, Jie,Yang, Shengyong,Niu, Dawen
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- Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones to Prepare C-Aryl Glycals and Acyclic Vinyl Ethers
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We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
- Gong, Liang,Sun, Hong-Bao,Deng, Li-Fan,Zhang, Xia,Liu, Jie,Yang, Shengyong,Niu, Dawen
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p. 7680 - 7686
(2019/05/22)
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- Halopivalylglucopyranose and preparation method for SGLT2 inhibitor
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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 0090; 0092; 0109-0111; 0127; 0129; 0130; 0164-0166
(2019/01/14)
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- Method for synthesizing ipragliflozin
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The invention discloses a method for synthesizing ipragliflozin. The method comprises the following steps: (1) generating alkylation reaction by formula-4 compound and formula-5 compound to generate aformula-6 compound; (2) carrying out deprotection on the formula-6 compound to generate a formula-7 compound, i.e., ipragliflozin. Compared with the prior art, the preparation method disclosed by theinvention is characterized in that adopted starting raw materials are cheap and can be easily obtained, a synthesis route is short, operation is convenient, cost is lower and general yield is high. The method conforms to the concept of green chemistry and is suitable for industrial production. (The formulas are shown in the description.).
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- Pipeline synthesis process for liflozin drugs
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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 0024; 0025
(2018/01/13)
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- Synthetic method of Ipragliflozin
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The invention provides a synthetic method of Ipragliflozin. The synthetic method comprises the following steps: exchanging a prepared compound organic metallic reagent and 2-(5-bromo-2-benzyl) benzothiophene halogen to obtain an arene metal compound intermediate; enabling coupling reaction between the arene metal compound intermediate and glucolactone; conducting dehydroxylation protection to obtain 1-C-[3-(benzo[B]thien-2-ylmethyl)-4-fluorophenyl]-ALPHA-D-pyran glucitol; reducing 1-C-[3-(benzo[B]thien-2-ylmethyl)-4-fluorophenyl]-ALPHA-D-pyran glucitol to obtain crude Ipragliflozin; conducting acylation, recrystallization and deacylation reaction on crude Ipragliflozin to obtain pure Ipragliflozin. As the compound organic metallic reagent is adopted, the reaction temperature is improved, the cost is lowered, and the synthetic method is suitable for industrial production; as water solution dehydroxylation protection of acid is adopted, the crude product is a solid but not an oily substance; the disposal is convenient and the reaction time is shortened.
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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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- Discovery of Ipragliflozin (ASP1941): A novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus
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A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-Ay mice and STZ rats.
- Imamura, Masakazu,Nakanishi, Keita,Suzuki, Takayuki,Ikegai, Kazuhiro,Shiraki, Ryota,Ogiyama, Takashi,Murakami, Takeshi,Kurosaki, Eiji,Noda, Atsushi,Kobayashi, Yoshinori,Yokota, Masayuki,Koide, Tomokazu,Kosakai, Kazuhiro,Ohkura, Yasufumi,Takeuchi, Makoto,Tomiyama, Hiroshi,Ohta, Mitsuaki
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experimental part
p. 3263 - 3279
(2012/07/14)
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- THERAPEUTIC USES OF SGLT2 INHIBITORS
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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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- METHOD FOR PRODUCING C-GLYCOSIDE DERIVATIVE AND SYNTHETIC INTERMEDIATE THEREOF
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The present invention provides a method for producing a C-glycoside derivative, which can produce the C-glycoside derivative at a high yield and at a low cost, which conforms to environmental protection, and which is applicable industrially. The C-glycoside derivative is useful for treating and preventing diabetes such as insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes) and the like and various diabetes-related diseases including insulin-resistant diseases and obesity.
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Page/Page column 15
(2009/10/06)
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- COCRYSTAL OF C-GLYCOSIDE DERIVATIVE AND L-PROLINE
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A cocrystal of (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol and L-proline. It is a cocrystal of known compound A, which has a constant quality, is superior in storage stability, has no moisture absorptivity, and is suitable as a crystal of a drug substance used for preparing pharmaceuticals.
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Page/Page column 6-7
(2009/01/24)
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- C-GLYCOSIDE DERIVATIVES AND SALTS THEREOF
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The present invention provides C-glycoside derivatives and salts thereof, wherein B ring is bonded to A ring via -X- and A ring is directly bonded to the glucose residue, and it is usable as a Na+-glucose cotransporter inhibitor, especially for a therapeutic and/or preventive agent for diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes related diseases such as an insulin-resistant diseases and obesity.
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Page/Page column 61
(2008/06/13)
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