- Preparation method of sitagliptin phosphate intermediate
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The invention discloses a preparation method of a sitagliptin phosphate intermediate. In the existing synthesis method of the sitagliptin phosphate intermediate, a corresponding post-treatment method is not reported or the reported post-treatment method is tedious in operation, low in solvent recovery rate, capable of generating a large amount of three wastes, and not beneficial to environmental protection. The method comprises the following steps: directly evaporating to remove a solvent after the synthesis reaction of the sitagliptin phosphate intermediate is completed, adding a crystallization solvent, cooling, stirring for crystallization, washing and drying to obtain the corresponding sitagliptin phosphate intermediate. According to the invention, the yield and the purity of the sitagliptin phosphate intermediate are improved; the method is simple in process, high in solvent recovery rate and suitable for large-scale industrial production, and wastewater is not generated in the production process.
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Paragraph 0030-0031; 0038-0043
(2021/11/21)
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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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- Sitagliptin impurity as well as removal method and application thereof
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The invention provides a sitagliptin impurity as well as a removal method and an application of the sitagliptin impurity, and particularly discloses an impurity in the production of a sitagliptin intermediate 4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7-(8H)-yl]-1-(2, 4, 5-trifluorophenyl) butyl-2-ketone, and through the discovery of the impurity, the quality standard of sitagliptin or sitagliptin phosphate hydrate can be remarkably improved.
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Paragraph 0046-0050
(2021/07/17)
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- Method for preparing Sitagliptin intermediate
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The invention belongs to the field of organic synthesis and particularly relates to a method for preparing a Sitagliptin intermediate. The intermediate has a structure represented by a formula A shownin the description, wherein R1 and R2 are the same, or are differently hydrogen or C1-C5 alkyl, more preferably, R1 is tert-butyl, and R2 is hydrogen.
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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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- 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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- A west he row sandbank phosphate key intermediate for the preparation of
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The invention relates to a low cost method for preparing a sitagliptin phosphate salt key intermediate. The method comprises the steps of: with existence of suitable solvents and inorganic bases, preparing 3-oxalysine-[3-(trifluoromethyl)-5,6-dihydrogen[1,2,4]triazolo[4,3-a]pyrazinyl-7(8H)]propionitrile(IV) by reacting cyanoethanoate ester with 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride(III)amidation and removing alcohol; and compound IV then reacting with a Grignard reagent that is prepared by 2,4,5-trifluoro-1-halogenated methyl benzene and magnesium, so as to obtain 4-oxalysine-4-[3-(trifluoromethyl)-5,6-dihydrogen[1,2,4]triazolo[4,3-a]pyrazinyl-7(8H)]-1-(2,4,5-trifluorophenyl)-2-butanone(II). According to the method provided by the invention, the expensive Michaelis acid, trimethylacetyl chloride and diisopropylethylamine are not used; the raw material used is cheap and easy to obtain and has less waste water in the production process; the product is high in yield, has few impurities, and is low in cost.
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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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Paragraph 0059; 0060
(2017/08/25)
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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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Page/Page column 16-17
(2015/11/10)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Paragraph 0399
(2013/09/12)
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- DRUG DERIVATIVES
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The present invention relates to derivatives of known active pharmaceutical compounds. These derivatives are differentiated from the parent active compound by virtue of being redox derivatives of the active compound. This means that one or more of the functional groups in the active compound has been converted to another group in one or more reactions which may be considered to represent a change of oxidation state. We refer to these compounds generally as redox derivatives. The derivatives of the invention may be related to the original parent active pharmaceutical compound by only a single step transformation, or may be related via several synthetic steps including one or more changes of oxidation state. In certain cases, the functional group obtained after two or more transformations may be in the same oxidation state as the parent active compound (and we include these compounds in our definition of redox derivatives). In other cases, the oxidation state of the derivative of the invention may be regarded as being different from that of the parent compound. In many cases, the compounds of the invention have inherent therapeutic activity on their own account. In some cases, this activity relative to the same target or targets of the parent compound is as good as or better than the activity which the parent compound has against the target or targets.
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Page/Page column 109
(2012/05/31)
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- PROCESS FOR PREPARATION OF (2R)-4-OXO-4-[3- (TRIFLUOROMETHYL)-5,6-DIHYDRO [1,2,4]-TRIAZOLO[4,3-A]PYRAZIN- 7(8H)-YL]-L-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE and NEW IMPURITIES IN PREPARATION THEREOF
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The present invention relates to synthesis of β-amino acid derivatives of formula (I) and its salts of formula (Ia) by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4-oxo-4-[3-Ctrifluoromethyl)-5,6-dihydrol[1,2,4]triazolo[4,3-alpyrazin-7(8H)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine. In an embodiment the invention disclosed polymorphic forms of formula (I), phosphate salt of formula (I) and also a Dibenzoyl-L-tartaric acid salt of formula (I).
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Page/Page column 12
(2011/09/20)
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- PREPARATION OF SITAGLIPTIN AND SALTS THEREOF
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Processes for preparing sitagliptin and its pharmaceutically acceptable salts, and process intermediates.
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Page/Page column 17
(2011/04/14)
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- PROCESS FOR THE PREPARATION OF R-SITAGLIPTIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides processes for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof.
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Page/Page column 11
(2010/12/29)
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- IMPROVED PROCESS FOR PREPARATION OF (2R)-4-OXO-4-[3- (TRIFLUOROMETHYL)-5,6-DIHYDRO [1,2,4]-TRIAZOLO[4,3-A]PYRAZIN- 7(8H)-YL]-L-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE and NEW IMPURITIES IN PREPARATION THEREOF
-
The present invention relates to synthesis of β-amino acid derivatives of formula (I) and its salts of formula (Ia) by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4-oxo-4- [3-Ctrifluoromethyl)-5, 6-dihydrol [1,2,4]triazolo [4,3-alpyrazin-7(8H)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine. In an embodiment the invention disclosed polymorphic forms of formula (I), phosphate salt of formula (I) and also a Dibenzoyl-L-tartaric acid salt of formula (I).
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Page/Page column 27
(2010/04/25)
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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 53
(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 28
(2009/08/14)
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- A PROCESS FOR THE PREPARATION OF R-SIT AGLIPTIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides processes for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof.
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Page/Page column 23
(2009/08/14)
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- 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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supporting information; experimental part
p. 8798 - 8804
(2009/12/04)
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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 10-11
(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 34-35
(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 14-15
(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 11
(2008/06/13)
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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 43-44
(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 18
(2010/11/24)
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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 9; 10
(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 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 12-13
(2008/06/13)
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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 23
(2008/06/13)
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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 11-12
(2010/02/13)
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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 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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- Mechanistic evidence for an α-oxoketene pathway in the formation of β-ketoamides/esters via Meldrum's acid adducts
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A practical, one-pot process for the preparation of β-keto amides via a three-component reaction, including Meldrum's acid, an amine, and a carboxylic acid, has been developed. Key to development of an efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process. Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis which provided a means of profiling the concentration of both the anionic and free acid forms of the Medrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of β-keto amides from acyl Meldrum's acids occurs via α-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated α-oxoketene intermediates 3 or nucleophilic addition-elimination pathways.
- Xu, Feng,Armstrong III, Joseph D.,Zhou, George X.,Simmons, Bryon,Hughes, David,Ge, Zhihong,Grabowski, Edward J. J.
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p. 13002 - 13009
(2007/10/03)
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