- Green synthesis method of sitagliptin intermediate
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The invention relates to a green synthesis method of sitagliptin intermediate, and belongs to the technical field of drug intermediate synthesis. In order to solve the problems that an existing pollution is large and unstable, a green synthesis method of sitagliptin intermediate is provided, and the method comprises the following steps: in an ether solvent, reacting trifluoroacetic acid ethyl ester with ethylenediamine to generate 2 - trifluoroacetamide ethyl ethylamine. Under the presence of an acid binding agent, 2 - trifluoroacetamide ethyl ethylamine and halogenated ethyl acetate are condensed and reacted under the conditions of 45 °C - 65 °C DEG C to form an intermediate, and then, the temperature is raised to 90 - 110 °C for cyclization reaction to generate N - trifluoroacetyl piperidine. The N -trifluoroacetyl piperidine ketone is reacted with hydrazine hydrate to generate 1 -trifluoroacetylamino -2 -piperazinone. The product is reacted with hydrochloric acid to form a ring-forming reaction, and a product sitagliptin intermediate is obtained. The method provided by the invention has the advantages of high product yield and purity on the whole, and has the advantage of environmental friendliness.
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Paragraph 0032; 0044-0047; 0051-0052; 0056-0059
(2021/10/27)
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- Preparation method of sitagliptin intermediate
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The invention discloses a preparation method of a sitagliptin intermediate. The preparation method of the sitagliptin intermediate comprises the following step: in a solvent, carrying out a reaction as shown in the specification on a compound as shown in a formula 2 and a compound as shown in a formula 3 to obtain a compound as shown in a formula 4. The preparation method is high in yield, avoids the use of explosive reagents and phosphorus oxychloride, and is suitable for industrial production.
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Paragraph 0074-0076
(2021/06/22)
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- Preparation method of sitagliptin intermediate
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The invention relates to a preparation method of a sitagliptin intermediate, and belongs to the technical field of drug intermediate synthesis. In order to solve the problems of low product yield andpoor environmental protection property in the prior art, the invention provides a preparation method of a sitagliptin intermediate, and the method comprises the following steps: reacting 2-piperazinone with hydrazine hydrate in an alcohol solvent to generate piperazine hydrazone; in an acetonitrile or ether solvent, reacting the piperazine hydrazone with ethyl trifluoroacetate to obtain a corresponding intermediate N -[(2Z-) piperazine -2-subunit] trifluoroacethydrazide; and performing cyclization and salification reaction on the N -[(2Z-) piperazine -2-subunit] trifluoroacethydrazide in an alcohol solvent under the action of hydrochloric acid to obtain the corresponding sitagliptin intermediate 3-trifluoromethyl 5, 6, 7, 8-tetrahydro-1, 2, 4-triazole [4, 3-a] pyrazine hydrochloride. The reaction has the effects of high selectivity and high product yield.
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Paragraph 0024; 0030; 0034-0035; 0039-0040; 0044-0045; 0049
(2021/02/13)
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- Preparation method of sitagliptin intermediate
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The invention provides a method for preparing a sitagliptin intermediate, which comprises the following steps of: converting a compound 1 into a compound 2 at the reaction temperature of 55 to 80 DEGC by taking ethyl acetate as a reaction solvent under the protection of nitrogen and under an acidic condition to obtain turbid liquid containing the compound 2, wherein the ratio of the compound 1 toethyl acetate is controlled to be 1g:5-10ml. According to the present invention, with the method, the defects of the existing process are improved, the production efficiency is improved, the production cost is reduced, the good social benefits and the good economic benefits can be provided, and the economic value potential is large.
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Paragraph 0036
(2020/07/15)
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- Microwave-Assisted Synthesis and Antituberculosis Screening of Some 4-((3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-l)methyl)benzenamine Hybrids
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In the present investigation, a series of 4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzenamine analogs 6a–o were synthesized and characterized by IR, NMR (1H and 13C), and mass spectra. All newly synthesized compounds 6a–o were prepared under conventional and microwave irradiation methods. These compounds obtained in higher yields and in shorter reaction times in the microwave irradiation method when compared with the conventional method. Synthesized compounds 6a–o were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra using an established XTT reduction menadione assay. Among the screened compounds, 6i (IC50: 1.82?μg/mL), 6j (IC50: 1.02?μg/mL), and 6k (IC50: 1.59?μg/mL) showed excellent activity. Furthermore, compound 6i showed MIC90 value of 16.02?μg/mL. In summary, the results indicate the identification of some novel, selective, and specific inhibitors against M.?tuberculosis that can be explored further for the potential antitubercular drug.
- Patil, Yogesh,Shingare, Ramesh,Choudhari, Amit,Sarkar, Dhiman,Madje, Balaji
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p. 434 - 442
(2019/01/04)
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- Urea and thiourea derivatives of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo[4,3-a]pyrazine: Synthesis, characterization, antimicrobial activity and docking studies
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An efficient and robust synthetic procedure was developed primarily for the synthesis of a precursor compound; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo[4,3-a]pyrazine (11), from 2-chloropyrazine (7) through the chemical transformations such as hydrazine substitution, trifluoroacetyl group induction, cyclization and pyrazine ring reduction. A new series of urea derivatives 13a-e and thiourea derivatives 13f-j of compound 11 have been synthesized and the structures of all the compounds were confirmed using spectroscopic analyses such as IR, 1H NMR, 13C NMR, LC-MS and HRMS. The newly synthesized compounds were screened for their in vitro antimicrobial activity against five bacteria and two fungi, in which compounds 13d, 13i and 13j displayed potential activity against bacterial strains and 13a, 13d, 13g and 13j against fungal strains with the MIC values in the range of 6.25–25.0 μg/mL. An overall comparison of the activity results revealed that thiourea derivatives contain better activity than that of urea compounds. Molecular docking studies on poly (ADP-ribose) polymerase 15 (ARTD7, BAL3) demonstrated that all the synthesized compounds possess significant binding energies (-8.1 to -9.8 kcal/mol) with no adverse effect in the active site of protein.
- Mannam, Madhava Rao,Devineni, Subba Rao,Pavuluri, Chandra Mouli,Chamarthi, Naga Raju,Kottapalli, Raja Sekhara P.
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p. 922 - 932
(2019/03/07)
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- Design, synthesis, biological evaluation and computational study of novel triazolo [4,3-a]pyrazin analogues
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The triazolo [4,3-a]pyrazin analogues are of interest due to their potential activity against various infectious and non-infectious disease. In search of suitable potent drug candidate, we report here the design, synthesis, characterization, biological activities and computation study of novel triazolo [4,3-a]pyrazin analogues. The synthesized molecules were characterized by various spectroscopic studies such as IR, Mass, 1H NMR, 13C NMR and elemental analysis. The newly synthesized compounds were evaluated for their in vitro biological activities such as anti-malarial, anti-tuberculosis, anti-bacterial and anti-fungal activities against plasmodium falciparum, H37Rv, various bacterial and fungal strains, respectively. The molecular docking study was carried out with enzyme aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum to analyze their binding orientation in the active site of the aspartic proteinase enzyme. The best docking complex was subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. We have also calculated ADMET properties of all the synthesized compounds to predict the pharmacokinetic properties for the selection of the active and bioavailability of compounds.
- Jethava, Divya J.,Acharya, Prachi T.,Vasava, Mahesh S.,Bhoi, Manoj N.,Bhavsar, Zeel A.,Rathwa, Sanjay K.,Rajani, Dhanji P.,Patel, Hitesh D.
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p. 168 - 192
(2019/03/04)
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- Synthesis technology of Sitagliptin intermediate
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The invention discloses a synthesis technology of a Sitagliptin intermediate. The technology comprises specific steps as follows: a), in isopropanol, a compound 2 is converted into a Sitagliptin intermediate 1 in a certain temperature range under the acidic condition; b), a suspension containing the Sitagliptin intermediate 1 is obtained in isopropanol; c), in isopropanol, the Sitagliptin intermediate 1 is separated from the suspension containing the Sitagliptin intermediate 1 obtained in step b). Only one solvent, namely, isopropanol, is utilized in the whole synthesis technology, so that thesolvent dosage of the reaction process and product separation is reduced, meanwhile, introduction of other solvents in the whole technological process is prevented, and production efficiency is improved and the solvent is recycled while production is enlarged.
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Paragraph 0031; 0032; 0034; 0036; 0038
(2018/06/26)
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- PROCESS FOR THE PREPARATION OF TRIAZOLE AND SALT THEREOF
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An improved process for the preparation of Triazole and salts thereof, a key intermediate for the synthesis of Sitagliptine is disclosed.
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Paragraph 0088; 0089; 0090; 0091; 0092; 0093; 0094; 0095
(2018/08/30)
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- A west he row sandbank intermediate triazole and pyrazine derivatives of preparation method
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The invention relates to a preparation method of a sitagliptin intermediate triazolopyrazine derivative. The method comprises the following steps: by using 2-chlorethamin hydrochloride as an initial raw material, reacting the 2-chlorethamin hydrochloride with trifluoroacetate and aminoacetate hydrochloride to generate 1-trifluoroacetyl-2-piperazino ketone (III), and carrying out condensation ring formation on the compound (III), hydrazine hydrate and hydrochloric acid to obtain the sitagliptin intermediate 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolyl[4,3-a]pyrazine hydrochloride (II). The high-activity triluoroacetyl carbonyl functional group and hydrazine hydrate are dehydrated into hydrazone, and the hydrochloric acid is directly added without separation, thereby performing intramolecular dehydration to generate the triazole ring. The method can avoid using thioketone, has the advantages of cheap and accessible raw materials, high reaction selectivity, short process, simple technical operation, high safety and environment friendliness.
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Paragraph 0052
(2017/08/25)
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- PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES
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The present invention relates to novel and improved processes for the preparation of Sitagliptin compound of formula (1) and its intermediates.
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Page/Page column 55
(2010/11/05)
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- PROCESSES FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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There is provided salts and polymorphs of sitagliptin, processes for the preparation thereof, and pharmaceutical compositions comprising the same.
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Page/Page column 27
(2009/08/14)
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- DODECYLSULFATE SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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The dodecylsulfate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan-2-amine is a potent inhibitor of dipeptidyl peptidase-IV and is useful for the treatment of Type 2 diabetes. The invention also relates to a crystalline anhydrate of the dodecylsulfate salt as well as a process for its preparation, pharmaceutical compositions containing this novel form and methods of use for the treatment of Type 2 diabetes, hyperglycemia, insulin resistance, and obesity.
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Page/Page column 9-10
(2008/06/13)
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- COMBINATION OF A DIPEPTIDYL PEPTIDASE-4 INHIBITOR AND AN ANTI-HYPERTENSIVE AGENT FOR THE TREATMENT OF DIABETES AND HYPERTENSION
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The present invention relates to pharmaceutical compositions comprising a combination of a particular dipeptidyl peptidase-4 (DPP-4) inhibitor and an anti-hypertensive agent selected from the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor, kits containing such combinations and methods of using such compositions for the treatment of diabetes, diabetes-related disorders, hypertension, and hypertension-related disorders.
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Page/Page column 34
(2008/06/13)
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- PROCESS TO CHIRAL BETA AMINO ACID DERIVATIVES BY ASYMMETRIC HYDROGENATION
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The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives which are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral beta amino acrylic acid derivative substrate in the presence of an ammonium salt and a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.
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Page/Page column 12; 13
(2008/06/13)
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- AMINOCYCLOHEXANES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to novel substituted aminocyclohexanes which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DPP-IV inhibitors") 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 42
(2008/06/13)
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- AMORPHOUS FORM OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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The present invention relates to a novel amorphous form of the dihydrogenphosphate salt of (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-a mine as well as a process for its preparation, pharmaceutical compositions containing this novel form, and methods of use of the novel form and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure.
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Page/Page column 9-10
(2008/06/13)
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- COMBINATION OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR AND A DUAL PPAR AGONIST FOR THE TREATMENT OF DIABETES AND OBESITY
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The present invention relates to pharmaceutical compositions comprising a combination of a particular dipeptidyl peptidase-IV (DPP-IV) inhibitor and a particular PPAR-α/γ dual agonist, kits containing such combinations and methods of using such compositions for the treatment of diabetes, diabetes associated with obesity, diabetes-related disorders, obesity, and obesity-related disorders.
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Page/Page column 17-18
(2010/11/24)
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- COMBINATION OF DIPEPTIDYL PEPTIDASE-IV INHIBITOR AND A CANNABINOID CB1 RECEPTOR ANTAGONIST FOR THE TREATMENT OF DIABETES AND OBESITY
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The present invention relates to pharmaceutical compositions comprising a combination of a particular dipeptidyl peptidase-IV (DPP-IV) inhibitor and a particular cannabinoid CB?1#191 receptor antagonist/inverse agonist, kits containing such combinations and methods of using such compositions for the treatment of diabetes, diabetes associated with obesity, diabetes-related disorders, obesity, and obesity-related disorders.
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Page/Page column 41-42
(2008/06/13)
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- First generation process for the preparation of the DPP-IV inhibitor sitagliptin
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A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.
- Hansen, Karl B.,Balsells, Jaume,Dreher, Spencer,Hsiao, Yi,Kubryk, Michele,Palucki, Michael,Rivera, Nelo,Steinhuebel, Dietrich,Armstrong III, Joseph D.,Askin, David,Grabowski, Edward J. J.
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p. 634 - 639
(2012/12/25)
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- Synthesis of [1,2,4]triazolo[4,3-α]piperazines via highly reactive chloromethyloxadiazoles
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(Chemical Equation Presented) A concise, modular approach for the synthesis of [1,2,4]triazolo[4,3-α]piperazines via condensation of highly reactive chloromethyloxadiazoles with ethylenediamines is described. NMR studies of this reaction provide evidence that suggests a novel activation mechanism for electron-deficient chloromethyloxadiazoles.
- Balsells, Jaume,DiMichele, Lisa,Liu, Jinchu,Kubryk, Michele,Hansen, Karl,Armstrong III, Joseph D.
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p. 1039 - 1042
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED BETA AMINO ACID DERIVATIVES
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The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives wherein the amino group is unprotected. The product chiral beta amino acid derivatives are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of an amine-unprotected prochiral beta-amino acrylic acid or derivative thereof in the presence of a rhodium metal precursor complexed with a chiral mono- or bisphosphine ligand.
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Page/Page column 21-22
(2008/06/13)
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- PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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The dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine is a potent inhibitor of dipeptidyl peptidase-IV and is useful for the prevention and/or treatment of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes. The invention also relates to a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation, pharmaceutical compositions containing this novel form and methods of use for the treatment of diabetes, obesity, and high blood pressure.
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- NOVEL CRYSTALLINE SALTS OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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Novel crystalline salts of (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-α 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 salts, processes to prepare these salts and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes.
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Page/Page column 9-11
(2010/02/13)
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- NOVEL CRYSTALLINE FORM OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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The present invention relates to a novel crystalline anhydrate polymorph of the dihydrogenphosphate salt of (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-a mine as well as a process for their preparation, pharmaceutical compositions containing this novel form, and methods of use of the novel form and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure.
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Page/Page column 7; 9
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
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The present invention relates to crystalline anhydrate polymorphs of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine as well as a process for their preparation, pharmaceutical compositions containing these novel forms, and methods of use of the novel forms and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure. The invention also concerns novel crystalline solvates of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine as well as a crystalline desolvated polymorph and their use for the preparation of the anhydrate polymorphs of the present invention.
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Page/Page column 11
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF CHIRAL BETA AMINO ACID DERIVATIVES BY ASYMMETRIC HYDROGENATION
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The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives which are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral beta amino acrylic acid derivative substrate in the presence of a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.
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- PROCESS TO TETRAHYDROTRIAZOLOPYRAZINES AND INTERMEDIATES
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A novel process is provided for the preparation of substituted-5,6,7,8-tetrahydro[1,2,4]-triazolo[4,3-alpha]pyrazines which are useful in the synthesis of dipeptidyl peptidase-IV inhibitors for the treatment of Type 2 diabetes. Also provided are useful intermediates obtained from the process.
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- PROCESS TO BETA-KETOAMIDE INTERMEDIATES TO DIPEPTIDYL PEPTIDASE INHIBITORS
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A novel process is provided for the preparation of beta-ketoamide intermediates which are useful in the synthesis of dipeptidyl peptidase-IV inhibitors for the treatment of type 2 diabetes. Also provided are useful intermediates obtained from the process.
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF BETA-AMINO ACID AMIDE DIPEPTIDYL PEPTIDASE-IV INHIBITORS
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A novel process is provided for the preparation of chiral beta-amino acid amide inhibitors of the dipeptidyl peptidase-IV and the useful intermediates obtained therein. The products resulting from the instant process are inhibitors of dipeptidyl peptidase-IV and thereby useful for the treatment of Type 2 diabetes.
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