- Method for preparing saxagliptin
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The invention discloses a method for preparing saxagliptin, and belongs to the technical field of drug synthesis. The method comprises the following steps: (a) converting amide on a compound shown ina formula I into cyano and removing Boc groups to obtain a compound shown in a formula II; (b) condensing the compound shown in the formula II and a compound shown in a formula III to obtain a compound shown in a formula IV; and (c) removing Boc groups on the compound shown in the formula IV to obtain a compound shown in a formula V. According to the method, different raw materials and reaction reagents are selected, and a process route is changed, so that four procedures of salifying, condensing, cyanating and de-protecting are shortened into three procedures of cyanating, condensing and de-protecting; meanwhile, cyanating and condensation reaction are realized at the room temperature, the requirements on reaction conditions are reduced, and industrial production can be realized.
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Paragraph 0039; 0046; 0048; 0057; 0059; 0062; 0064
(2020/06/16)
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- Preparation method of saxagliptin
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The invention discloses a preparation method of saxagliptin. The preparation method comprises the following steps: reacting (S)-N-tert-butyloxycarbonyl-(3-hydroxyadamantan-1-yl)glycine with (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride under the catalysis of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate/N,N-diisopropylethylamine to obtain (1S)-2-(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3,1,0]hex-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxoethyl tert-butyl carbamate, and removing protecting groups under acidic adjustment so as to obtain (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]decan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-nitrile. The method has the advantages of safety, easiness in operation, usage cheap and easily available raw materials, mild and easily controllable reaction conditions, simple post-reaction treatment, high yield and the like.
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Paragraph 0011
(2020/06/02)
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- Preparation method of medication saxagliptin for treating diabetes
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The invention provides a preparation method of saxagliptin with a shorter synthetic route. (S)-3-amino-3-cyano-propionic ether protected by diethyl acetylenedicarboxylate and an amino group is used asa starting material in the presence of an organic phosphine ligand and a palladium catalyst, and is subjected to cyclization, decarboxylation and cyclopropanation to obtain an intermediate product (1S, 3S, 5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile p-toluenesulfonate, and then the intermediate product is reacted with carboxyl-activated (S)-N-t-butyloxycarboryl-(3-hydroxyadamantane-1-yl)glycineto increase the reaction rate and obtain a saxagliptin product with a high yield and high purity, the reaction route is greatly shortened, the yield in each step is high, the reaction time is short, the production cost is reduced, and industrial production is facilitated.
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- Novel intermediates for preparing saxagliptin, preparing methods thereof and preparing methods of saxagliptin using the same
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The present invention relates to a novel intermediate used in the production of saxagliptin, a production method thereof, and a method for producing saxagliptin using the same. According to the present invention, the use of the novel intermediate which is represented by chemical formula 1 enables the production of high purity saxagliptin or a pharmaceutically acceptable salt thereof in high yield through a simple and economical way.COPYRIGHT KIPO 2017
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Paragraph 0164; 0165
(2017/08/02)
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- Method for synthesizing Saxagliptin and intermediate
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A method for synthesizing Saxagliptin and its intermediate is disclosed. According to the method, propylphosphonic anhydride is used in a peptide coupling reaction and a dehydration reaction of formamide, thus reducing side reaction of racemization and decreasing toxicity of aftertreatment; and ethylene glycol diethyl ether is preferably used as a solvent in the dehydration reaction of formamide, thus increasing reaction temperature of propylphosphonic anhydride dehydration and shortening reaction time so as to reduce side reaction of racemization.
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- PROCESS FOR PREPARING DIPEPTIDYL PEPTIDASE IV INHIBITORS AND INTERMEDIATES THEREFOR
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A process for preparing an amine of the structure which comprises a. treating an aqueous solution of a keto acid of the structure with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified phenylalanine dehydrogenase and/or formate dehydrogenase enzyme (PDH/FDH); and b. adjusting pH of the reaction mixture with sodium hydroxide to form the desired amine which is substantially free of undesirable excess ammonium ions.
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- A hypoglycemic compound, preparation method thereof, pharmaceutical composition containing the same and its use
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The invention provides a blood sugar reducing compound, a preparation method of the blood sugar reducing compound, a medicine composition including the blood sugar reducing compound and an application of the medicine composition. The compound is a compound shown in a general formula (I) or a pharmaceutically acceptable salt, a solvate, a polymorphism body, an enantiomer or a racemic mixture thereof, the general formula is described in the specification, wherein R1, R2, R3 and R4 are independently H, optionally substituted alkyl, optionally substituted naphthenic base, optionally substituted alkoxy, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted naphthenic base formed by R1 and R2, or optionally substituted heterocyclic radical formed by R2 and R3, or optionally substituted heterocyclic radical formed by R3 and R4. The compound is actively transported by a PepT1 transporter to be absorbed by the gastrointestinal tract, and decomposed in the intestinal tract and the liver to slowly generate saxagliptin, thus the blood concentration of the saxagliptin is increased, and the retention time of the saxagliptin in blood is prolonged. The blood sugar reducing treatment effect is favorably increased and the side reaction is favorably reduced due to stable blood concentration.
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Paragraph 0513
(2016/10/07)
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- PROCESS FOR THE PREPARATION OF SAXAGLIPTIN AND ITS INTERMEDIATES
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The present invention provides intermediates of saxagliptin and processes for their preparation. The present invention also provides a process for the preparation of saxagliptin or salts or hydrates thereof by using the intermediates.
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- PROCESS FOR THE PREPARATION OF INTERMEDIATES OF SYNTHESIS OF SAXAGLIPTIN AND NOVEL COMPOUNDS
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The object of the present invention is the preparation of saxagliptin and novel intermediate compounds.
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Page/Page column 5-6
(2014/08/19)
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- A PROCESS FOR PREPARING PHARMACEUTICALLY ACCEPTABLE SALT OF SAXAGLIPTIN
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The present invention relates to a process for the preparation of intermediate of Saxagliptin, amide compound of Formula (II), and its conversion to pharmaceutically acceptable salt Saxagliptin.
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Page/Page column 19
(2014/07/23)
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- Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin
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All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.
- Dong, Jizhe,Gong, Yanchun,Liu, Jun,Chen, Xiangfeng,Wen, Xiaoan,Sun, Hongbin
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p. 1383 - 1393
(2014/03/21)
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- POLYMORPHS OF SAXAGLIPTIN HYDROCHLORIDE AND PROCESSES FOR PREPARING THEM
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The invention provides polymorphs of Saxagliptin hydrochloride, processes for preparing polymorphs of Saxagliptin hydrochloride, and pharmaceutical compositions of polymorphs of Saxagliptin hydrochloride.
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Page/Page column 6
(2012/04/11)
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- RACEMISATION OF (R)-N-BOC-3-HYDROXYADAMANT-1-YL GLYCINE
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The present invention refers to the preparation of racemic N-Boc-3-hydroxyadamant-1-yl glycine
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- SAXAGLIPTIN INTERMEDIATES, SAXAGLIPTIN POLYMORPHS, AND PROCESSES FOR PREPARATION THEREOF
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The invention provides Saxagliptin Schiff bases, polymorphs of Saxagliptin and (1S,3S,5S)-2-[(2S)-2-propan-2-ylideneamino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, processes for preparing Saxagliptin hydrates, and pharmaceutical compositions thereof.
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Page/Page column 10
(2011/11/13)
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- Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
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Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of β-quaternary amino acid linked L-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the β-position of α-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zuckerfa/fa rats. Extension of this approach to adamantylglycine- derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
- Augeri, David J.,Robl, Jeffrey A.,Betebenner, David A.,Magnin, David R.,Khanna, Ashish,Robertson, James G.,Wang, Aiying,Simpkins, Ligaya M.,Taunk, Prakash,Huang, Qi,Han, Song-Ping,Abboa-Offei, Benoni,Cap, Michael,Xin, Li,Tao, Li,Tozzo, Effie,Welzel, Gustav E.,Egan, Donald M.,Marcinkeviciene, Jovita,Chang, Shu Y.,Biller, Scott A.,Kirby, Mark S.,Parker, Rex A.,Hamann, Lawrence G.
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p. 5025 - 5037
(2007/10/03)
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