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Efficient and Straightforward Syntheses of Two United States Pharmacopeia Sitagliptin Impurities: 3-Desamino-2,3-dehydrositagliptin and 3-Desamino-3,4-dehydrositagliptin.

ABSTRACT: Various organic impurities (starting materials, reagents, intermediates, degradation products, by-products, and side products) could be present in active pharmaceutical ingredients affecting their qualities, safeties, and efficacies. Herein, we present the efficient syntheses of two United States Pharmacopeia impurities of an antidiabetic drug sitagliptin, a potent and orally active dipeptidyl peptidase IV inhibitor: 3-desamino-2,3-dehydrositagliptin and 3-desamino-3,4-dehydrositagliptin. Our three-step synthetic approach is based on the efficient cobalt-catalyzed cross-coupling reaction of 1-bromo-2,4,5-trifluorobenzene and methyl 4-bromocrotonate in the first step, followed by hydrolysis of corresponding ester with 3 M HCl to (E)-(2,4,5-trifluorophenyl)but-2-enoic acid in high overall yield, whereas the reaction with 3 M NaOH resulted in the carbon-carbon double bond regio-isomerization and hydrolysis to give the (E)-(2,4,5-trifluorophenyl)but-3-enoic acid in 92% yield. Both acid derivatives were converted to title compounds via the amide bond formation with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine. Extensive screening of coupling/activation reagents, bases, and solvents reviled that the amide bond is formed the most efficiently using the (COCl)2/Et3N in THF or alternatively EDC/NMM/(DMAP or HOBt) in DMF obtaining the title compounds in 68-76% yields and providing the overall yields for the three-step process in the range of 57-64% on a gram scale. The presented study also demonstrates the importance of a proper selection of solvent, base, and coupling/activating reagent for amide bond formation using Michael acceptor-type allylbenzene derivatives as coupling partners to minimize the carbon-carbon double bond regio-isomerization.

SUBMITTER: Sova M

PROVIDER: S-EPMC7081400 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Efficient and Straightforward Syntheses of Two United States Pharmacopeia Sitagliptin Impurities: 3-Desamino-2,3-dehydrositagliptin and 3-Desamino-3,4-dehydrositagliptin.

Sova Matej M Frlan Rok R Gobec Stanislav S Časar Zdenko Z

ACS omega 20200303 10

Various organic impurities (starting materials, reagents, intermediates, degradation products, by-products, and side products) could be present in active pharmaceutical ingredients affecting their qualities, safeties, and efficacies. Herein, we present the efficient syntheses of two United States Pharmacopeia impurities of an antidiabetic drug sitagliptin, a potent and orally active dipeptidyl peptidase IV inhibitor: 3-desamino-2,3-dehydrositagliptin and 3-desamino-3,4-dehydrositagliptin. Our th ...[more]

PMID: 32201825

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Project description:IntroductionThe objective of this study was to compare the clinical effectiveness of liraglutide with sitagliptin and assess the associated economic outcomes in patients with type 2 diabetes mellitus (T2DM) treated in real-world practice in the United States (US).MethodsThis retrospective cohort study used a large US claims database to identify patients with T2DM who initiated liraglutide or sitagliptin between January 2010 and December 2012. Adults (≥18 years old) with persistent use of therapy for ≥3 months were included. Changes in glycated hemoglobin A1c (A1C) and the proportion of patients achieving A1C targets (≤6.5% and <7%) were examined at 6-month follow-up. Diabetes-related total, medical, and pharmacy costs over the follow-up period were assessed. Multivariable regression models were used to estimate the outcomes associated with liraglutide relative to sitagliptin, adjusting for differences in patient demographics and clinical characteristics.ResultsThe study included 1,465 patients with T2DM who initiated liraglutide (N = 376) or sitagliptin (N = 1,089) (mean age [standard deviation (SD)]: 54 [8.9] vs. 58 [10.8] years; 43.9% vs. 61.8% males; both P < 0.01). After controlling for confounding factors, liraglutide patients experienced 0.31% points greater reduction in A1C (0.95% vs. 0.63% points; P < 0.01) at 6-month follow-up than sitagliptin patients and were more likely to reach A1C targets of ≤6.5% (odds ratio [OR]: 2.00; P < 0.01) and <7% (OR: 1.55; P < 0.01). Liraglutide patients had $994 lower mean diabetes-related medical costs ($1,241 vs. $2,235; P < 0.01), but $544 higher diabetes-related pharmacy costs ($2,100 vs. $1,556; P < 0.01) during the follow-up. No difference was found in the total mean diabetes-related costs between the two cohorts.ConclusionLiraglutide showed greater improvement in glycemic outcomes than sitagliptin among adult patients with T2DM in real-world clinical practice. Although diabetes-related pharmacy costs for patients using liraglutide were higher compared with sitagliptin, these were offset by significantly lower diabetes-related medical costs, resulting in similar total diabetes-related costs between the two treatment groups.

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Efficient and Straightforward Syntheses of Two United States Pharmacopeia Sitagliptin Impurities: 3-Desamino-2,3-dehydrositagliptin and 3-Desamino-3,4-dehydrositagliptin.

Publications

Efficient and Straightforward Syntheses of Two United States Pharmacopeia Sitagliptin Impurities: 3-Desamino-2,3-dehydrositagliptin and 3-Desamino-3,4-dehydrositagliptin.

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