1280210-80-1

Upstream product

• 657428-42-7 4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester 
• 124-63-0 methanesulfonyl chloride 
• 98-11-3 benzenesulfonic acid 
• 6573-19-9 1,4,5,6-tetrahydropyrrolo[3, 4-c]pyrazole 
• 905274-02-4 tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate 
• 1280210-79-8 2,6-dihydropyrrole [3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester 
• 1226781-82-3 tert-butyl 2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate 

Downstream Products

• 1226781-44-7 Omarigliptin 
• 1226781-87-8 tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate 
• 1280210-87-8 tert-butyl {(2R,3S)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-6-oxopiperidin-3-yl}carbamate 
• 1280210-98-1 tert-butyl [(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-{2-[1-(methylsulfonyl)-1H-pyrazol-4-yl]ethyl}piperidin-3-yl]carbamate 
• 1280210-97-0 tert-butyl {(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(pyridin-2-ylmethyl)piperidin-3-yl}carbamate 
• 1280210-96-9 tert-butyl {(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(pyrazin-2-ylacetyl)piperidin-3-yl}carbamate 
• 1280210-95-8 tert-butyl {(2R,3S,5R)-1-acetyl-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate 
• 1280210-89-0 tert-butyl {(2R,3S,5S)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate 
• 1280210-88-9 tert-butyl {(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate 
• 1280211-17-7 tert-butyl {(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difiuorophenyl)-5-[2-(2-fluoro-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}carboxylate 
• 1280211-16-6 tert-butyl {(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difiuorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}carboxylate 
• 1280211-15-5 tert-butyl {(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difiuorophenyl)-5-[2-(2-hydroxy-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}carboxylate 
• 1280211-14-4 tert-butyl {(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difiuorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-1-yl}carboxylate 

Relevant academic research and scientific papers

Omarigliptin and preparation method of intermediate of Omarigliptin

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).

Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes

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.

Crystalline forms of a dipeptidyl peptidase-IV inhibitors

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.

Omarigliptin (MK-3102): A novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes

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.

NOVEL CRYSTALLINE FORMS OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR

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.

SUBSTITUTED AMINOTETRAHYDROTHIOPYRANS AND DERIVATIVES THEREOF AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel substituted aminotetrahydrothiopyrans and derivatives thereof 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.

SUBSTITUTED AMINOPIPERIDINES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel substituted aminopiperidines 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-?V 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.

SUBSTITUTED SEVEN-MEMBERED HETEROCYCLIC COMPOUNDS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel amino-substituted seven-membered heterocyclic compounds 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.