- A one-pot synthesis of omarigliptin and its analogues through stabilized beta-amino ketone intermediate
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We have discovered a unique stabilization condition for beta-amino ketone 7. With compound 7 as an unprecedented intermediate, omarigliptin 1 could be prepared in a highly efficient one-pot procedure with good yield. Also with this intermediate 7, some analogues of omarigliptin 1 were readily prepared for the first time.
- Li, You,Liu, Tongchao,Li, Chungang,Xiong, Bing,Zhao, Dongmei,Cheng, Maosheng,Chen, Guohua,Shen, Jingkang,Chen, Yue-Lei
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Read Online
- Synthesis process of omarigliptin
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The invention discloses a method for preparing omarigliptin and a method for preparing an intermediate. In the method for preparing the key intermediate compound 4 of the omarigliptin, a weak acid with the pKa value of 3.5-5 is added, so that the generation of byproducts is effectively inhibited, the yield of the intermediate compound 4 is very high, and finally, the yield of the omarigliptin is greatly improved.
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Paragraph 0045-0046; 0048-0049; 0051-0052; 0054-0055; 0057
(2020/10/30)
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- Preparation method for chiral tetrahydropyran derivative
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The invention discloses a preparation method for a chiral tetrahydropyran derivative. The compound 5 can be obtained from a compound 1 and a compound 3 or from a compound 2 and the compound 3 in a one-pot reaction. According to the invention, the method is simple, the reaction is rapid, and the intermediate product does not need to separate.
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Paragraph 0010; 0037; 0039; 0041
(2018/03/26)
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- Chiral tetrahydropyrane derivatives as well as preparation and application thereof
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The invention discloses compounds. The compounds are represented by a formula 22 in the description, wherein R is one selected from the group consisting of 5 to 6-membered aryl substituted with one ormore of halogen, C1-C3 alkyl, and C2-C3 alkenyl, 5 to 6-membered heteroaryl containing 1-2 sulfur atoms, C1-C3 alkyl substituted by C1-C3 alkylthio, and 5 to 6-membered cycloalkyl containing 1-2 sulfur atoms. The invention also discloses a preparation method and application of the compounds. The method provided by the invention can realize synthesis of a plurality of the novel tetrahydropyrane chiral derivatives without involving raw materials such as noble metal catalysts, and the costs are reduced.
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- PROCESS FOR THE PREPARATION OF OMARIGLIPTIN
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The present invention provides a process for preparing omarigliptin.
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- Synthesizing method of omarigliptin
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The invention provides a synthesizing method of an omarigliptin compound shown in a formula (1). The synthesizing method comprises the following steps: by using a compound shown in a formula (2) as an initial raw material, performing a series of following reaction, so as to finally obtain the compound shown in the formula (1), namely omarigliptin, wherein reaction formulae are shown in the description. Compared with the prior art with multiple synthesizing steps and complicated synthesizing technology for synthesizing the omarigliptin, the synthesizing method has the advantages that the method is simple, the implementing is easy, the cost is lower, the yield rate is higher, the product quality is higher, and the synthesizing method is suitable for large-scale industrialized production.
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Paragraph 0014; 0015
(2017/10/22)
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- Omarigliptin and preparation method of intermediate of Omarigliptin
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The invention discloses Omarigliptin and a preparation method of an intermediate of the Omarigliptin, and provides a preparation method of an Omarigliptin intermediate I. The preparation method comprises the following step: enabling a compound II and a compound III to undergo a condensation reaction in a polar aprotic organic solvent in the presence of lewis acid and sodium borohydride acetate to obtain the Omarigliptin intermediate I. The preparation method disclosed by the invention has the advantages of simple and safe operation, no need of special purification equipment, short reaction time, fewer by products, high yield and simple post treatment operation; column chromatography separating operation in a post treatment process is avoided; a prepared product is high in purity, the optical purity is greater than or equal to 99,9 percent, the purity of a related substance is greater than or equal to 98.5 percent, and the purities of all impurities are smaller than or equal to 0.5 percent separately; the preparation method is low in production cost and is suitable for industrial production. In addition, according to the Omarigliptin prepared from the Omarigliptin intermediate I obtained by adopting the preparation method disclosed by the invention, the purity is greater than or equal to 99.5 percent, the purities of all the impurities are smaller than or equal to 0.1 percent separately, and the standards of crude drugs are reached. (The formula is shown in the description).
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- Omarigliptin salt, crystal form products of omarigliptin salt, preparing methods of omarigliptin salt and crystal form products and pharmaceutical composition
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The invention relates to novel omarigliptin salt and crystal form products of the omarigliptin salt, and belongs to the technical field of pharmaceutical chemicrystallization. Compared with existing omarigliptin crystal form products, the omarigliptin salt and the crystal form products of the omarigliptin salt have the advantages of being better in crystal form product stability and solubility, higher in dissolving rate and the like, the bioavailability of medicine can be improved, and the omarigliptin salt and the crystal form products of the omarigliptin salt are better suitable for an application of a solid preparation. The invention also relates to the omarigliptin salt, a preparing method of the crystal form products of the omarigliptin salt, a pharmaceutical composition of the omarigliptin salt and applications of the omarigliptin salt to medicine for treating type 2 diabetes mellitus.
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Paragraph 0123; 0124
(2017/08/30)
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- Synthetic method for omarigliptin
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The invention provides a synthetic method for a formula (I) compound omarigliptin. A formula (2) compound and a formula (3) compound are taken as initial raw materials and are subjected to a series of reactions shown in the specification, so that the formula (1) compound omarigliptin is finally prepared. Compared with the prior art defects that omarigliptin synthetic steps are more and synthetic technology is complex, the synthetic method is simple and practicable, relatively low in cost, relatively high in yield, relatively good in product quality, and is suitable for large-batch industrialized production.
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Paragraph 0041; 0086; 0087
(2017/01/12)
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- PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS
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A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of, reductive amination of:.
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- Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes
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Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions: (1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, (2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and, finally, (3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. The regioselective synthesis of a N-Boc-1-mesyl pyrazole fragment was achieved via base-promoted mesyl group isomerization to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multikilogram deliveries and improves the overall diastereoselectivity and efficiency of the route.
- Chung, John Y. L.,Scott, Jeremy P.,Anderson, Camille,Bishop, Brian,Bremeyer, Nadine,Cao, Yang,Chen, Qinghao,Dunn, Robert,Kassim, Amude,Lieberman, David,Moment, Aaron J.,Sheen, Faye,Zacuto, Michael
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p. 1760 - 1768
(2015/12/01)
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- Crystalline forms of a dipeptidyl peptidase-IV inhibitors
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Novel crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine are potent inhibitors of dipeptidyl peptidase-IV and are useful for the treatment of non-insulin dependent (Type 2) diabetes mellitus. The invention also relates to pharmaceutical compositions containing these novel forms, processes to prepare these forms and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes.
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- Omarigliptin (MK-3102): A novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes
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In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
- Biftu, Tesfaye,Sinha-Roy, Ranabir,Chen, Ping,Qian, Xiaoxia,Feng, Dennis,Kuethe, Jeffrey T.,Scapin, Giovanna,Gao, Ying Duo,Yan, Youwei,Krueger, Davida,Bak, Annette,Eiermann, George,He, Jiafang,Cox, Jason,Hicks, Jacqueline,Lyons, Kathy,He, Huaibing,Salituro, Gino,Tong, Sharon,Patel, Sangita,Doss, George,Petrov, Aleksandr,Wu, Joseph,Xu, Shiyao Sherrie,Sewall, Charles,Zhang, Xiaoping,Zhang, Bei,Thornberry, Nancy A.,Weber, Ann E.
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p. 3205 - 3212
(2014/05/20)
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- NOVEL CRYSTALLINE FORMS OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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Novel crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine are potent inhibitors of dipeptidyl peptidase-IV and are useful for the treatment of non-insulin dependent (Type 2) diabetes mellitus. The invention also relates to pharmaceutical compositions containing these novel forms, processes to prepare these forms and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes.
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Page/Page column 15; 16
(2013/03/26)
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- AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved
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Page/Page column 24
(2010/06/11)
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