Highly efficient asymmetric synthesis of sitagliptin.

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Synthesis of Sitagliptin, the Active ..

(2010) Synthesis of Sitagliptin, the Active Ingredient in ..

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Asymmetric synthesis of (-)-(R)-sitagliptin - CORE

In conclusion, our synthesis of ent-sitagliptin highlights the potential utility of enantioselective allylic amination as an economically efficient and environmentally benign alternative for the production of pharmaceutical drugs. We anticipate that this method will be useful for the synthesis of other nitrogen-containing pharmaceutical agents from inexpensive and abundant unactivated olefins.

Highly efficient asymmetric synthesis of sitagliptin
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As a model system for our first step in the synthesis of ent-sitagliptin (7→6, ), we examined phenyl butene 2b, which lacked the three fluoride substituents in the aromatic ring of olefin 7 (). We anticipated that these carefully optimized palladium-catalyzed conditions for the generation of allylic amines 11 a with aliphatic substitution at the homoallylic position would be suitable for the conversion of phenyl butene 2b to allylic amine 11b with aromatic substitution at the homoallylic position. To our dismay, in the presence of 10 mol% Pd(TFA)2 and 12 mol% ligand 10a, allylic amine 11b was generated in only 4% enantiomeric excess (ee).

Biocatalytic Asymmetric Synthesis of Chiral Amines …

The resultant biocatalystsshowed broad applicability toward the synthesis of chiral amines thatpreviously were accessible only via resolution.
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Uttam K. Tambar moved from India to the United States when he was four years old. He received his A.B. degree from Harvard University in 2000 and his Ph.D. from the California Institute of Technology in 2006 with Professor Brian Stoltz. After he completed his NIH Postdoctoral Fellowship at Columbia University with Professor James Leighton in 2009, he began his independent research career at UT Southwestern Medical Center in Dallas. He is currently an Assistant Professor in the Biochemistry Department and a W. W. Caruth, Jr. Scholar in Biomedical Research. The Tambar lab is interested in asymmetric catalysis, natural product synthesis, and medicinal chemistry.

The new reaction conditions were utilized for the enantioselective allylic amination of trifluorophenyl butene 7 for the synthesis of ent-sitagliptin (). To our delight, trifluorophenyl butene 7 was smoothly converted to allylic amine derivative 6 through a hetero-ene reaction followed by a palladium-catalyzed enantioselective [2,3]-rearrangement. The resulting allylic amination product 6 was treated with methanolic K2CO3, which unveiled allylic sulfonamide 12 in 78% yield (for the three steps) and 93% ee. Hydroboration and extensive oxidation of olefin 12 generated α-amino acid 5. Coupling with amine 13 and subsequent deprotection of the sulfonamide furnished ent-sitagliptin (1).

Efficient stereocontrolled synthesis of sitagliptin phosphate

Highly Efficient Asymmetric Synthesis of Sitagliptin.
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Starting from an enzyme that had thecatalytic machinery to perform the desired chemistry but lacked anyactivity toward the prositagliptin ketone, we applied a substratewalking, modeling, and mutation approach to create a transaminase withmarginal activity for the synthesis of the chiral amine; this variantwas then further engineered via directed evolution for practicalapplication in a manufacturing setting.

Isolation of degradation products (DP’s) and synthesis of N-acetylated impurity: Based on the degradation profile obtained from forced degradation study, degradation products were generated by subjecting approximately 200mg sitagliptin API to suitable stress condition. The degradation was monitored using HPLC for reasonable conversion in to desired impurities. DP-I was generated by subjecting API to oxidative stress condition using 10% H2O2 at 60ºC for four days. DP-II and III were produced by subjecting API to 0.1N NaOH at 60ºC for two days. NaOH degradation sample was neutralized by dil. HCl.

Highly efficient asymmetric synthesis of Sitagliptin
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  • A further process for the synthesis of sitagliptin free ..

    of chiral molecules as the technique eliminates the problems associated with asymmetric synthesis.

  • Merck used a first-generation synthesis of sitagliptin to ..

    A new synthesis of sitagliptin ..

  • Biocatalytic Asymmetric Synthesis of ..

    Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture

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the final step of its sitagliptin synthesis.

N2 - The presence of nitrogen atoms in most chiral pharmaceutical drugs has motivated the development of numerous strategies for the synthesis of enantiomerically enriched amines. Current methods are based on multistep transformations of functionalized allylic electrophiles to form chiral allylic amines. The enantioselective allylic amination of nonactivated olefins would represent a more direct and more attractive strategy. We report the enantio selective synthesis of ent-sitagliptin through an allylic amination of a nonactivated terminal olefin.

Biocatalytic Asymmetric Synthesis of Chiral Amines from ..

AB - The presence of nitrogen atoms in most chiral pharmaceutical drugs has motivated the development of numerous strategies for the synthesis of enantiomerically enriched amines. Current methods are based on multistep transformations of functionalized allylic electrophiles to form chiral allylic amines. The enantioselective allylic amination of nonactivated olefins would represent a more direct and more attractive strategy. We report the enantio selective synthesis of ent-sitagliptin through an allylic amination of a nonactivated terminal olefin.

of sitagliptin was prepared by asymmetric reduction of ..

Present work focuses on the study of degradation behavior, isolation and characterization of major degradation products of sitagliptin in bulk and tablet by subjecting to various stress conditions. Further, developed a validated stability indicating mass compatible HPLC method for the determination of sitagliptin in bulk and tablet in presence of its degradation products (DP’s) and N-acetylated impurity. Out of the five degradation products reported in this study degradation product namely, DP-II and N-acetylated impurity were known as impurities of sitagliptin and DP-III was reported as an intermediate for the synthesis of sitagliptin 12, 13, 14. Remaining three degradation products observed during this degradation study (DP-I, DP-IV and DP-V) were found to be novel degradation products of sitagliptin.

Expedient synthesis of sitagliptin

Here, we report an efficientbiocatalytic process to replace a recently implemented rhodium-catalyzedasymmetric enamine hydrogenation for the large-scale manufacture of theantidiabetic compound sitagliptin.

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