- Highly efficient asymmetric synthesis of sitagliptin
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A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/tBu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.
- Hansen, Karl B.,Hsiao, Yi,Xu, Feng,Rivera, Nelo,Clausen, Andrew,Kubryk, Michele,Krska, Shane,Rosner, Thorsten,Simmons, Bryon,Balsells, Jaume,Ikemoto, Nori,Sun, Yongkui,Spindler, Felix,Malan, Christophe,Grabowski, Edward J. J.,Armstrong III, Joseph D.
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Read Online
- Identification of ammonium chloride as an effective promoter of the asymmetric hydrogenation of a β-enamine amide
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An investigation into the cause of substrate specific hydrogenation performance variability was conducted. A significant and unexpected correlation was observed between apparent pH of a solution of the substrate and rate of conversion and enantioselectivity. This observation led to the examination of low and variable levels of native ammonium chloride in different lots of substrate. The presence of ammonium chloride was found to have a positive effect on reaction rate and enantioselectivity when controlled within a relatively narrow range. Optimal performance was achieved with a mole ratio of 1:1 ammonium chloride to catalyst.
- Clausen, Andrew M.,Dziadul, Brianne,Cappuccio, Kristine L.,Kaba, Mahmoud,Starbuck, Cindy,Hsiao, Yi,Dowling, Thomas M.
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Read Online
- Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro
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Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents that are widely used in clinical practice to improve glycemic control in patients with type 2 diabetes. DPP-4 is also known as lymphocyte cell surface protein, CD26, and plays an important role in T-cell immunity. Recent studies suggest that DPP-4 inhibitors improve beta-cell function and attenuate autoimmunity in type 1 diabetic mouse models. To investigate the direct effect of DPP4 in immune response, human peripheral blood mononuclear cells (PBMC) from healthy volunteers were obtained by Ficoll gradient and cultivated in the absence (control) or presence of phytohemagglutinin (PHA), or stimulated with PHA and treated with sitagliptin. The immune modulation mechanisms analyzed were: cell proliferation, by MTT assay; cytokine quantification by ELISA or cytometric bead array (CBA), Th1/Th2/Th17 phenotyping by flow cytometric analysis and CD26 gene expression by real time PCR. The results showed that sitagliptin treatment inhibited the proliferation of PBMC-PHA stimulated cells in a dose dependent manner and decreased CD26 expression by these cells, suggesting that sitagliptin may interfere in CD26 expression, dimerization and cell signaling. Sitagliptin treatment not only inhibited IL-10 (p?A statistically significant increase (p?a significantly (p?+?IL-17+, T CD4+?IFNgamma+ and T CD4+?IL-4+ cells were significantly reduced (p??0.05) by sitagliptin. Our data demonstrated an immunosuppressive effect of sitagliptin on Th1, Th17 and Th2 lymphocytes differentiation that leads to the generation of regulatory TGF-beta1 secreting cells with low CD26 gene expression that may influence the state of pancreatic beta-cells and controlling DM1 patients.
- Pinheiro, Marcelo Maia,Stoppa, Caroline Lais,Valduga, Claudete Justina,Okuyama, Cristina Eunice,Gorj?o, Renata,Pereira, Regina Mara Silva,Diniz, Susana Nogueira
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Read Online
- Preparation method of chiral 4 - aryl - β β-amino acid derivative
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Provided is a method for preparing a chiral 4-aryl-β-amino acid derivative. The preparation method comprises hydrogenating an enamine compound having a structure as shown in Formula III in an organic solvent in the presence of a catalyst containing a transition metal and BIBOPs. The preparation method of the present invention uses a small amount of a selected asymmetric catalyst, and has a simple operation, mild reaction conditions, a high yield, a high stereoselectivity, and better industrial application and economic values.
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- Two methods for the preparation of sitagliptin phosphate: Via chemical resolution and asymmetric hydrogenation
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Two effective processes have been developed for the preparation of sitagliptin phosphate. The approach of chemical resolution obtained R-sitagliptin in five steps from commercially available starting materials using the inexpensive NaBH4 to reduce the enamine and then using (-)-di-p-toluoyl-l-tartaric acid to resolve racemates in 11% yield overall. The route successfully avoids the use of expensive noble metal as catalysts compared with traditional synthesis methods, resulting in greatly reduced costs and simplified synthetic routes. Other alternative asymmetric hydrogenation of β-ketomide routes for the synthesis of sitagliptin were found, two of the intermediates were synthesized for the first time. This journal is
- Ye, Fei,Zhang, Zhifeng,Zhao, Wenxia,Ding, Jianhai,Wang, Yali,Dang, Xueyan
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p. 4805 - 4809
(2021/02/03)
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- Synthesis method of sitagliptin free alkali and sitagliptin phosphate monohydrate
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The invention relates to a synthesis method of sitagliptin free alkali and sitagliptin phosphate monohydrate. According to the method, dry HOBt is removed or changed into HOBt hydrate, a solvent DMF is removed in the process, and a simple solvent easy to recover is used in the production process, so that the production cost is reduced, and the reaction safety is improved. According to the invention, with the in-situ process from a compound represented by a formula 2 to a compound represented by a formula 6, the yield can be improved, the operation steps can be reduced, and the methanol or isopropanol IPA is replaced with other solvents so as to avoid the generation of impurities represented by a formula 7, a formula 8 and a formula 9, such that the product purity and the yield can be substantially improved, and the HPLC purity of the sitagliptin free alkali is more than 99%.
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- Synthesis method of sitagliptin free alkali
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The invention belongs to the field of organic chemistry, and particularly discloses a synthesis method of sitagliptin free alkali. The synthesis method comprises the following specific steps: (1) dissolving (3R)-N-tert-butyloxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl) butyric acid and organic alkali in an organic solvent, adding a phosphorus-containing condensing agent, then adding 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-alpha]pyrazine hydrochloride to prepare a compound represented by a formula (II); and (2) removing t-butyloxycarboryl from the compound shown in the formula II under the action of acid to obtain a compound I namely sitagliptin free alkali. The method is mild in process reaction condition, easy to control, short in reaction time, free of extraction, simple to operate and beneficial to industrial production, and the process cost is reduced; and the prepared compound shown in the formula I is high in yield, high in purity and free of heavy metal residues.
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Paragraph 0024; 0054-0061
(2021/07/17)
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- Process method for improving yield and purity of sitagliptin
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The invention provides a process method for improving yield and purity of sitagliptin, which comprises the following steps: mixing Boc sitagliptin as shown in a formula iii with solvent ester and acid, carrying out hydrolysis reaction at 0-50 DEG C, neutralizing with acid and alkali after the reaction is finished, and removing a water layer to obtain an organic layer containing sitagliptin as shown in a formula iv. The process method disclosed by the invention has the advantages that degradation of sitagliptin iv in reaction and post-treatment processes can be avoided, so that the yield and quality of sitagliptin iv are effectively improved.
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Paragraph 0024-0062
(2021/01/24)
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- IMPROVED PROCESS FOR PREPARATION OF SITAGLIPTIN
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Provided herein is a process for the preparation of specific enantiomeric Sitagliptin with good chiral purity and higher yield using improved biocatalyst and by engineering an enzyme to mediate the efficient conversion of ketoamide to obtain enantiomerically pure Sitagliptin in presence of an amino group donor.
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(2021/12/31)
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- PROCESSES FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present application relates to improved processes for the preparation of Sitagliptin and pharmaceutically acceptable salts thereof. The present application also relates to the improved crystallization process for the preparation of Sitagliptin Phosphate. The present application also relates to the improved crystallization process for the preparation of Sitagliptin Hydrochloride monohydrate.
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(2020/06/19)
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- HIGHLY EFFICIENT PROCESS FOR THE PREPARATION OF SITAGLIPTIN VIA RHODIUM CATALYZED ASYMMETRIC HYDROGENATION
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The present invention provides highly efficient process for the preparation of enantiomerically enriched Sitagliptin of Formula (Ia). More particularly, a direct rhodium catalyzed asymmetric hydrogenation in the presence of bis-phosphine chiral ligand has been developed to yield enantiopure Sitagliptin product with the highest enantiomeric excess of 85-99.9%.
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(2020/07/08)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES
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The present invention relates to a process for the preparation of novel intermediates useful for the preparation of Sitagliptin or its pharmaceutically acceptable salts. The present invention relates to an efficient process for the preparation of Sitagliptin intermediates. The present invention relates to an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.
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Page/Page column 24; 25
(2020/05/29)
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- Preparation method of sitagliptin free alkali monomer (by machine translation)
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The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method, of sitagliptin salt or other water-soluble salt. after the reaction, is dissolved in water, with sodium hydroxide solution or other inorganic alkalis pH, at a temperature of 20 - 45 °C DEG C for, drying to obtain, g of sitagliptin free base monomer, with high yield after dissolution . The method is high. low, cost and easy, to obtain a high yield of, sitagliptin free base monomer (. s,). (by machine translation)
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Paragraph 0050-0051
(2020/03/12)
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- Microballs Containing Ni(0)Pd(0) Nanoparticles for Highly Selective Micellar Catalysis in Water
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Both Ni(0) complexes and nanoparticles (NPs) are unstable in water, which poses a significant hindrance to their application in aqueous synthetic catalysis. To overcome these barriers, ligated Ni(0) nanoparticles (diameter 1 nm) containing a minimum amount of Pd(0) in the microballs formed of amphiphile PS-750-M are developed and applied in the highly selective carbamate cleavage. Selectivity and functional group tolerance are thoroughly investigated. Control experiments revealed the importance of an individual component of the nanocatalyst. Use of our proline-based amphiphile PS-750-M is critical for achieving microball architecture, the stability of nanoparticles, and desired catalytic activity. Once formed, microballs can be isolated and stored at ambient temperature. Catalyst is thoroughly characterized by X-ray photoelectron spectroscopy, scanning electron microscopy, high-resolution transmission electron microscopy, thermogravimetric analysis, infrared, and cyclic voltammetry. For selective catalysis, zero oxidation state of both Ni and Pd is crucial. On the basis of catalyst characterization and control experiments, the plausible reaction mechanism is proposed.
- Bihani, Manisha,Bora, Pranjal P.,Nachtegaal, Maarten,Jasinski, Jacek B.,Plummer, Scott,Gallou, Fabrice,Handa, Sachin
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p. 7520 - 7526
(2019/08/15)
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- Preparation method of sitagliptin
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The invention discloses a preparation method of sitagliptin. The preparation method comprises the following steps: (1) carrying out a substitution reaction on a compound as shown in a formula I and bromoacetyl chloride to obtain a compound as shown in a formula II; (2) carrying out a cyclization reaction on the compound as shown in the formula III under conditions (i, ii and iii) to obtain a compound as shown in a formula IV; (3) removing HBr coupling from the compound as shown in the formula II and the compound as shown in the formula IV under the action of an alkali to obtain a compound as shown in a formula V; (4) reacting the compound as shown in the formula V with hydroxylamine to form a compound VI with a ketoxime structure; (5) carrying out a Beckmann rearrangement reaction on the compound as shown in the formula VI under the action of an acid to obtain a compound VII; and (6) hydrolyzing the compound as shown in the formula VII and carrying out decarboxylating under a strong heat condition to obtain the compound X, i.e., sitagliptin. The method for preparing sitagliptin has simple steps, uses easily-available raw materials, and is greatly reduced in side reactions and greatly increased in yield.
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- Preparation method of medication sitagliptin for treating diabetes
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The invention provides a preparation method of sitagliptin with a shorter route. In the presence of a chiral ligand, reductive amination is performed by borohydride to obtain a chiral amine compound,then activation of a carboxyl group is performed by N-hydroxysuccinimide to reduce the occurrence of side reactions, and obtain a sitagliptin product with a high yield and high purity, the reaction raw materials are cheap and easy to obtain, the reaction process is easy to operate, the yield of each step is high, the purity of the product is high, the production cost is reduced, and industrial production is facilitated.
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- NEW EFFICIENT PROCESS FOR THE PREPARATION OF SITAGLIPTIN.
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Object of the present invention is an efficient process for the preparation of the active pharmaceutical ingredient Sitagliptine and the 2,4,5-trifluorophenylacetic acid (TFAA) and salt thereof, which is a key intermediate for the synthesis of Sitagliptine. (I)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to provide an improved process for the preparation of sitagliptin (I) and its pharmaceutical acceptable salts thereof, which is simple, economical, efficient, user and environment friendly, moreover commercially viable.
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- AN ENZYMATIC PROCESS FOR THE PREPARATION OF (R)-SITAGLIPTIN
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The present invention relates to an enzymatic process for the preparation of (R)- Sitagliptin. The process involves reductive amination of Pro-Sitagliptin to (R)- Sitagliptin using novel transaminase enzymes. The invention also relates to the Nucleotide sequences encoding novel transaminase enzymes and process to prepare transaminase enzymes.
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Paragraph 23
(2019/11/12)
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- BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and preparation method thereof
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The invention provides a sitagliptin phosphate important intermediate BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and a preparation method and preparation thereof. TheBOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and the preparation method thereof have important significance for the following industrial production of bulk drugs.
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- Preparation Method Camphorsulfonic acid Salt of Sitagliptin
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The present invention provides a method for manufacturing a camsylate salt of sitagliptin and the camsylate salt manufactured by a manufacturing method thereof. The manufacturing method of the present invention has a simple manufacturing process, thereby being able to synthesize a sitagliptin camsylate salt economically in terms of time and/or cost. Therefore, it is possible to be usefully applied for mass production.COPYRIGHT KIPO 2019
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- Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas
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Carboxylic acids and their corresponding carboxylate anions are generally utilized as Br?nsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Br?nsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.
- Hayama, Noboru,Kuramoto, Ryuta,F?ldes, Tamás,Nishibayashi, Kazuya,Kobayashi, Yusuke,Pápai, Imre,Takemoto, Yoshiji
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supporting information
p. 12216 - 12225
(2018/09/25)
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- Method for synthesizing sitagliptin and intermediate thereof through biological catalysis
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The invention provides a method for synthesizing sitagliptin and an intermediate thereof through biological catalysis, and particularly provides compounds as shown in formula I and a formula II, or pharmaceutically acceptable salt thereof, polypeptide capable of synthesizing a compound as shown in the formula I to produce a compound as shown in the formula II, nucleic acid coding the polypeptide,and a vector and a cell containing the nucleic acid. In addition, the invention further provides a method for producing the compound as shown in the formula II and sitagliptin through the polypeptideand the compound as shown in the formula I, and a preparation method for preparing the polypeptide.
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Paragraph 0145; 0180; 0182; 0183; 0184
(2018/10/11)
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- Sitagliptin synthesis method
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The invention discloses a sitagliptin synthesis method, which comprises: carrying out a reaction on a compound represented by a formula IV, (R)-(+)-tert-butyl sulfinamide and hydrogen under the catalysis of a catalyst to obtain a compound represented by a formula V; and carrying out a hydrolysis reaction on the compound represented by the formula V to obtain a compound represented by a formula VI,ie., sitagliptin. According to the present invention, the method has advantages of easily available raw materials, simple steps, high yield and mild reaction conditions, and is suitable for industrial production. The formulas IV, V and VI are defined in the specification.
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- Practical asymmetric synthesis of Sitagliptin phosphate monohydrate
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Optically pure sitagliptin phosphate monohydrate is efficiently and practically synthesized through a chiral hemiacetal as the key intermediate in 54% overall yield starting from (E)-4-(2,4,5-trifluorophenyl)but-2-enal and N-boc-protected hydroxylamine. The chiral hemiacetal fragment is constructed by a tandem aza-Michael/hemiacetal reaction catalyzed by an organocatalyst and the influence of acidity of Br?nsted acid on tandem aza-Michael/hemiacetal reaction is researched in detail.
- Gao, Haoling,Yu, Jiangang,Ge, Chengsheng,Jiang, Qun
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- Synthesis method of sitagliptin
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The invention discloses a synthesis method of sitagliptin. The synthesis method comprises the following steps: 1) 3-oxopropionic acid is adopted as a starting raw material to react with an acylating chlorination reagent to obtain corresponding acyl chloride, then the obtained acyl chloride reacts with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol(4,3-a)pyridazine hydrochloride to obtain anamide compound III; 2) the compound III and R-(+)-tertbutylsulfenamide are condensed to obtain an acetal compound IV; 3) the compound IV and 2,4,5-trifluorophenylmethyl magnesium bromide are added toobtain a compound V; 4) the compound V is treated by acid deprotection to obtain a compound I, i.e., sitagliptin. The synthesis method disclosed by the invention has the beneficial effects that the steps are fewer, the operation is simple, and the use of an expensive chiral catalyst is avoided, so that the cost is reduced; the obtained product is high in purity, so that the synthesis method is suitable for industrial production.
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- A west he row sandbank and its salt synthesis method (by machine translation)
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The invention discloses a west he row sandbank and its salt synthesis method, in order to 2, 4, 5 - trifluorobenzene acetic acid as the starting material, through esterification, reduction, oxidation and Witting reaction, to obtain 4 - (2, 4, 5 - trifluorophenyl) - 2 - butene ethyl ester, or passes through the reduction, oxidation and Witting reaction after, to obtain 4 - (2, 4, 5 - trifluorophenyl) - 2 - butene ethyl ester. Then in BuLi or six methyl two silicon and nitrogen under the action of the alkane-sodium, with chiral amine on the hydroamination reaction, framed asymmetric amination product, through ester, condensation, hydrogenated three-step reaction to obtain sitagliptin. The west he of the spit of fland synthesis method of raw materials are cheap and easy to obtain, steps are less, the operation is easy, can be effectively reduced. The method can be the high purity of the sitagliptin, the salt of the phosphoric acid obtained after HPLC purity and sitagliptin ee values are in 99% or more, can be applied to the medical field. (by machine translation)
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- A highly stereoselective and efficient synthesis of enantiomerically pure sitagliptin
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A highly stereoselective and efficient synthesis of sitagliptin 1 consisting of a chiral β-amino acid unit has been achieved through 6 steps from commercially available 2,4,5-trifluorobenzaldehyde 4. The chiral antidiabetic drug was obtained with almost perfect enantiomeric purity (>99.9% ee) in 40.9% overall yield. The key feature of the synthesis is the addition of a malonate enolate to a chiral sulfinylimine in more than 99:1 dr. Our synthetic procedure proved to be highly efficient, economical, and sustainable.
- Kang, Sung Kwon,Cho, Gyeong Hi,Leem, Hyung Joon,Soh, Bong Kwan,Sim, Jaehoon,Suh, Young-Ger
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- A west he row sandbank chiral intermediate and asymmetric synthesis method
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The invention relates to a sitagliptin chiral intermediate and an asymmetric synthesis method thereof. The asymmetric synthesis method comprises the steps: with 2,4,5-trifluorophenyl acetic acid as a starting material, carrying out a reduction reaction to obtain 2-(2,4,5-trifluorophenyl)ethanol, then carrying out a reaction with an oxidant, carrying out condensation of the product without separation and (R)-(+)-tert-butyl sulfinamide to obtain corresponding acetal, carrying out a reaction of the obtained product with dialkyl malonate to obtain a key chiral intermediate, hydrolyzing to obtain a corresponding organic amine, carrying out a reaction of the amine with caustic alkali and then acidifying to obtain a corresponding carboxylic acid, then carrying out condensation with 3-(trifluoromethyl)-5,6,7,8- tetrahydro-[1,2,4] triazolo[4,3-a]pyrazine hydrochloride to obtain sitagliptin tert-butyl oxanamide, and finally deprotecting with hydrochloric acid to obtain sitagliptin. The yields of all the steps are all higher, the used reagents are all conventional cheap reagents, no expensive chiral catalysts are used, the reaction conditions are quite mild, and the asymmetric synthesis method is suitable for industrialization.
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- Application of trona to synthesis of sitagliptin
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The invention provides a method for synthesis of sitagliptin shown in a formula (1). A compound shown in a formula (2) is used as a starting material, and finally a compound shown in the formula (1), i.e., the sitagliptin, is obtained through a series of reactions, wherein the reaction process is shown in the specification. In comparison with the prior art in which more steps are needed for the synthesis of the sitagliptin and the synthesis process is complex, the synthesis method disclosed by the invention is simple and feasible, the cost is relatively lower, the yield is relatively high, the product quality is relatively good, and the method is suitable for large-scale industrial production.
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Paragraph 0014
(2017/11/16)
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- A west he row sandbank and intermediate preparation method
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The invention relates to the field of medicament synthesis and especially relates to a preparation method of sitagliptin and an intermediate thereof. The preparation method of a compound show as formula III is as below: in the presence of a first organic solvent, a compound shown as formula I and a compound shown as formula II conduct reductive amination reaction under the action of a reducing agent and organic acid, so as to obtain the compound shown in formula III. The preparation method provided by the invention does not use precious metal as the catalyst, reduces the cost, simplifies the synthesis process, increases the yield, and improves the chemical purity and optical purity of sitagliptin. R represents methyl or carbamyl, and Ar represents phenyl, monosubstituted phenyl or polysubstituted phenyl.
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- Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities
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The invention discloses sitagliptin phosphate impurities, a method for preparing the same and application of the sitagliptin phosphate impurities. The sitagliptin phosphate impurities are sitagliptin phosphate impurities A, sitagliptin phosphate impurities B and sitagliptin phosphate impurities C. The relevant sitagliptin phosphate impurities, the method and the application have the advantage of important monitoring significance on industrial production of sitagliptin phosphate crude medicines.
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- Novel preparation method for anti-type-II-diabetes drug sitagliptin
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The invention discloses a novel preparation method for an anti-type-II-diabetes drug sitagliptin. According to the invention, trifluorobenzene with a cheaper price is used as a fluorization reagent and a starting raw material and a basic skeleton of sitagliptin is successfully synthesized through effective acylation of trifluorobenzene and L-aspartic acid; a synthesis route in the invention, from starting raw material and final product, is completely different from schemes disclosed in the prior art; the route is optimized, and easily-available natural L-aspartic acid is used as a chiral source for successful synthesis of an optically pure sitagliptin product; the problems of asymmetric catalysis and complex splitting in the prior art are overcome; the method also effectively overcomes the problem of low yield of the basic skeleton of sitagliptin synthesized via Friedel-Crafts acylation of trifluorobenzene and improves yield; the method is lower in cost, more convenient to operate and more suitable for industrial production; and compared with the prior art, the method is simpler in the synthesis route and better in operability.
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Paragraph 0028; 0029; 0030
(2017/09/13)
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- SITAGLIPTIN INTERMEDIATE, METHOD OF SYNTHESIZING THE SITAGLIPTIN INTERMEDIATE, AND METHOD OF SYNTHESIZING SITAGLIPTIN USING THE SITAGLIPTIN INTERMEDIATE
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Disclosed is an intermediate compound of sitagliptin which has a molecular structure represented by chemical formula 1. The use of the intermediate compound of sitagliptin enables production of sitagliptin compounds which are used as dipeptidyl peptidase-4 (DPP-4) inhibitors in a cost effective and eco-friendly manner, without using expensive coupling agents.COPYRIGHT KIPO 2017
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Paragraph 0151; 0152
(2017/11/22)
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- A process for preparing phosphoric acid sitagliptin-free method of inhibiting I
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The present invention relates to a method for preparing an anhydrous crystal form I of sitagliptin phosphate. The method comprises: crystallizing by stirring a suspension of sitagliptin phosphate solid at a crystallization temperature, then separating the crystallized crystals, washing, and drying so as to obtain an anhydrous crystal form I of the sitagliptin phosphate, wherein the solvent for the suspension of the sitagliptin phosphate solid is selected from acetone or acetonitrile, or the solvent for the suspension of the sitagliptin phosphate solid is selected from a mixture of a C1-4 alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water. A single crystal form of sitagliptin phosphate in an anhydrous crystal form I can be prepared by the method of the present invention. The method facilitates the control of product quality and the establishment of a quality standard, and has advantages such as a simple and convenient crystallization process, mild reaction conditions, and a high product yield without a high temperature reaction for a long time.
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Paragraph 0069; 0070
(2018/11/03)
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- Synthesizing method of Sitagliptin
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The invention provides a synthesizing method of the compound, namely Sitagliptin, described in the formula (1). The compound described in the formula (2) as a starting material is subjected to the following series of reactions, and finally the compound, namely Sitagliptin, described in the formula (1) is prepared. Compared with the prior art in which a lot of Sitagliptin synthesizing steps exist and the synthesizing technology is complex, the synthesizing method is simple and easy to implement, low in cost, high in yield, good in product quality and suitable for large-scale industrial production.
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Paragraph 0014; 0015
(2017/10/28)
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- A PROCESS FOR PREPARING 7-[(3R)-3-AMINO-1-OXO-4-(2,4,5TRIFLUOROPHENYL)BUTYL]- 5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-1,2,4-TRIAZOLO[4,3-A]PYRAZINE PHOSPHATE MONOHYDRATE AND ITS NOVEL CRYSTALLINE FORM H
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The present invention discloses the process for preparation of 7-[(3R)-3-amino-1-oxo-4- (2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3- a]pyrazine phosphate monohydrate.
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Page/Page column 5; 7; 8
(2017/01/26)
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- A method for synthesizing row sandbank west he
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The invention discloses a synthetic method for sitagliptin. The method comprises the following steps that: 2,4,5-trifluorobenzaldehyde is used as a starting raw material and undergoes the Wittig reaction and hydrolysis with hydrochloric acid so as to obtain 2-(2,4,5-trifluorophenyl)acetaldehyde; 2-(2,4,5-trifluorophenyl)acetaldehyde and (R)-(+)-t-butyl sulfenamide are subjected to condensation so as to obtain corresponding acetal; acetal and ethyl bromoacetate undergo the Reformatsky reaction, and then an obtained product undergoes hydrolysis so as to obtain organic acid; the organic acid and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride are subjected to condensation so as to obtain acetal of t-butyl sulfenamide of sitagliptin; and finally methanol hydrochloride is used for deprotection so as to obtain sitagliptin. The invention has the following advantages: yield in each step is high, operation is simple, reagents used in the method are conventional reagents, usage of an expensive chiral catalyst is avoided, and good industrial prospect is obtained.
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- NOVEL BETA-SULFINAMINO MALONATE DERIVATIVES AND PROCESS FOR PREPARING THE SAME, AND PROCESS FOR PREPARING SITAGLIPTIN USING THE SAME
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The present invention relates to beta-sulfinamino malonate derivatives having a high diastereomeric ratio (DR) value manufactured through a stereoselective addition reaction of chiral sulfinyl imine and malonate derivatives, to optically pure Sitagliptin by using the same, and to a method for manufacturing pharmaceutically acceptable salt thereof. According to the present invention, the method is capable of manufacturing novel beta-sulfinamino malonate derivatives which are intermediate in the manufacture of Sitagliptin, with high optical purity and high yields without using a solvent under mild conditions, and ultimately manufacturing optically pure Sitagliptin in an efficient manner by using the same.COPYRIGHT KIPO 2016
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- A synthetic west he row sandbank of the new method
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The invention discloses a novel method for synthesizing sitagliptin. The method has the advantages of low cost, simplicity in operation, low environmental pollution, high yield and purity of product and the like, and is particularly applicable to industrial production.
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- METHOD FOR PREPARING INTERMEDIATE COMPOUND OF SITAGLIPTIN
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The present invention provides a method for preparing an intermediate compound of sitagliptin represented by formula I. The preparation method comprises: dissolving a compound represented by formula II into an organic solvent; and under the catalysis of fatty acid and effect of chlorosilane, performing a reduction reaction of carbon-carbon double bonds, so as to obtain the intermediate compound of sitagliptin represented by formula I, R being methyl or formoxyl. The preparation method of the present invention avoids precious metal as a catalyst, and accordingly, the cost is low, the post-treatment is simple, the product has a high yield, chemical purity and optical purity, and de % is greater than 99.6%, and the preparation method can be used in synthesis of sitagliptin and is suitable for industrial production.
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Paragraph 0040
(2016/09/12)
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- Improved method of sitagliptin
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The present invention relates to an improved method for manufacturing sitagliptin, comprising a step of preparing N-Boc protected sitagliptin using diphenyl phosphite suitable for mass production as a reagent and a deprotection step.
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- For preparing sitagliptin intermediate and its preparation method and application (by machine translation)
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The invention relates to the field of organic chemistry, in particular to a process for preparing a sitagliptin intermediate and its preparation method and application, the intermediate A has the following structure: Wherein R is hydrogen atom or (by machine translation)
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- Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin
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In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (?)-(R)-sitagliptin.
- Bae, Han Yong,Kim, Mun Jong,Sim, Jae Hun,Song, Choong Eui
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supporting information
p. 10825 - 10829
(2016/09/03)
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- NOVEL INTERMEDIATES FOR PREPARING DPP-IV INHIBITORS, PREPARING METHOD THEREOF AND PREPARING METHOD OF DPP-IV INHIBITORS USING THE SAME
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Disclosed are novel intermediates for use in preparing DPP-IV inhibitors, methods for preparing the same, and methods for preparing DPP-IV inhibitors using the same. Using the novel intermediates of the present invention, highly pure DPP-IV inhibitors can be produced in a simple and economical manner at a high yield.
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Paragraph 208-211
(2017/01/02)
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- Preparation method of 3R-amino substituted butyrylamide derivative
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The invention relates to a preparation method of a 3R-amino substituted butyrylamide derivative. The preparation method of the 3R-amino substituted butyrylamide derivative comprises the following steps: carrying out hydrogenation reduction on enamine II for preparing 3R,3S-amino substituted butyrylamide racemate III; carrying out resolution, and filtering, so as to obtain 3R-amino substituted butyrylamide R(-) mandelate with high ee% value, alkalifying to obtain the 3R-amino substituted butyrylamide derivative; and oxidizing the obtained mother liquor, so as to obtain enamine II in a recycling manner, and repeating oxidation-reduction cycle for multiple times until products at specified yield are obtained. The preparation method of the 3R-amino substituted butyrylamide derivative has the advantages that a cyclic method is utilized for converting 3S-amino substituted butyrylamide racemate or 3R,3S-amino substituted butyrylamide mixture in any ratio into the 3R-amino substituted butyrylamide derivative with high ee% value, so that the mother liquor is effectively utilized; meanwhile, an expensive catalyst or asymmetric reductive amination with high demand condition does not need to be adopted, thereby being beneficial to reduction of cost and clean production.
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Paragraph 0080; 0083
(2016/10/09)
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- CHIRAL AMINES, A PROCESS FOR PREPARATION AND USE THEREOF
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Described herein is the general synthesis of chiral amine from vinyl nitro compounds using Josiphos catalyst. The process is applied to develop a novel route to Sitagliptin (a DPP-IV inhibitor).
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- PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND NOVEL INTERMEDIATES
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The present invention provides an improved process for the preparation of β-amino acid derivatives. More particularly, the present invention relates to an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts of formula 1. The present invention also provides novel intermediates used in the preparation of Sitagliptin.
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- PROCESS FOR THE PREPARATION OF SITAGLIPTIN PHOSPHATE
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The present invention relates to a method for the preparation of sitagliptin phosphate and sitagliptin phosphate anhydrous of Formula (I′) and monohydrate of Formula (I),
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- AMORPHOUS FORM OF SITAGLIPTIN FREE BASE
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The present invention provides an amorphous form of sitagliptin free base of Formula (I). The invention further provides a process for preparation of an amorphous form of sitagliptin free base. The process comprises a) providing a solution or suspension of sitagliptin free base in one or more solvents; and b) obtaining the amorphous form of sitagliptin free base by the removal of the solvent.(I)
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Paragraph 0090
(2015/09/23)
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- PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATE
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The present invention provides a process for the preparation of sitagliptin. The present invention also provides a process for the preparation of tert-butyl [(2R)-4-oxo-4- [3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-yl]carbamate, an intermediate of sitagliptin.
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Page/Page column 10
(2015/12/08)
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- Practical, asymmetric route to sitagliptin and derivatives: Development and origin of diastereoselectivity
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The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S=O, consistent with MsOH being crucial for high selectivity. The second is a novel C-H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.
- Gutierrez, Osvaldo,Metil, Dattatray,Dwivedi, Namrata,Gudimalla, Nagaraju,Chandrashekar,Dahanukar, Vilas H.,Bhattacharya, Apurba,Bandichhor, Rakeshwar,Kozlowski, Marisa C.
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p. 1742 - 1745
(2015/04/14)
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