- 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 0028-0029; 0032-0037
(2021/11/21)
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- 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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Paragraph 0026-0028
(2021/11/14)
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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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- 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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- (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride and preparation method and application thereof
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The invention provides (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride and a preparation method and application thereof and belongs to the technical field of medicinalchemistry. According to the technical problem of low synthesis efficiency of sitagliptin is solved. The technical scheme is that the structural formula of the (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride is in the description below. The (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride has the advantages that the (S)-2-amino-3-(2,4,5-trifluorophenyl)propionic acid menthyl ester hydrochloride is a novel compound, raw materials used for preparation are cheap and easy to obtain, the process is simple, and the yield is as high as 83.3%.
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Paragraph 0034-0035; 0044; 0050
(2019/01/14)
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- Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate
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The invention relates to a chiral synthesis method for chiral beta-amino acid. The chiral synthesis method comprises the following steps: reacting a compound shown in formula (II) with an acylation reagent to prepare anhydride intermediate reaction liquid under the action of alkali; adding Meldrum's acid into the anhydride intermediate reaction liquid, and performing reaction to generate a compound shown in formula (III); reacting the compound shown in formula (III) with a compound shown in formula (IV) to generate a compound shown in formula (V); reducing the compound shown in formula (V) to generate a compound shown in formula (VI); performing acidic hydrolysis on the compound shown in formula (VI) to generate a compound shown in formula (I), i.e., the chiral beta-amino acid. The chiral synthesis method has the advantages of convenience for synthesis, low cost and simple process, and compared with a disclosed preparation method, is more suitable for industrial production.
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Paragraph 0061; 0062; 0063; 0064
(2018/01/11)
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- Method for synthesizing sitagliptin intermediate
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The invention relates to a method for synthesizing a sitagliptin intermediate. The method is characterized in that asymmetric reduction ammonification of a compound of formula II and ammonia or ammonium salt in the presence of a chiral phosphorus coordinated transition metal catalyst in an appropriate organic solvent containing an acidic additive to obtain a compound of formula I. The R- or S- configuration of a stereocenter is represented by *, and the formula I with the R configuration can be used to prepare sitagliptin. A reaction equation is shown in the description; and R and R in the reaction equation are respectively independently selected from hydrogen, C1-C12 linear or branched alkyl groups, C3-C12 cycloalkyl groups, C2-C12 alkene groups, C2-C12 alkynyl groups and C7-C12 arylalkyl groups. The method has the advantages of high yield and ee% value, mild reaction conditions, simple operation, convenient purification, low production cost, environmental protection, and suitableness for industrial production.
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Paragraph 0042; 0043; 0044
(2016/10/24)
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- A west he row sandbank intermediate chiral separation method
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The invention relates to a preparation method of a sitagliptin intermediate compound (R)-3-amino-4-(2,4,5-trifluorobenzene)benzyl butyrate (compound (1)). According to the method, a racemate of the compound (1) form a salt with a resolving agent in a solvent; the salt is precipitated, and the mixture is filtered; the resolved salt is dissociated, such that the compound (1) is obtained. With the method provided by the invention, the compound (1) with high purity and high chirality can be obtained. The method has advantages of stable process and simple operation. The solvent can be recycled and applied. Therefore, the method is suitable for industrialized productions.
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Paragraph 0025; 0026
(2017/03/17)
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- plants the deuterium mark sitagliptin a process for the preparation of
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The present invention discloses a method for preparing deuterium-labeled sitagliptin. The deuterium-labeled sitagliptin-D4 is synthesized by an eight-step reaction with hydrazine hydrate as a starting material and ethylene-D4 as a deuterium-labeled initiator. The optimal preparation steps and reaction conditions are screened through a plurality of experiments in the invention and the entire process is reasonable in design and high in operability. The deuterium-labeled sitagliptin prepared by the invention has purity of over 98% and the yield up to 70% or more, and isotopic abundance is greater than 99%. The deuterium-labeled sitagliptin prepared by the invention can provide test samples for a research on the metabolic mechanism of sitagliptin and has important application value.
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Paragraph 0054-0056
(2017/04/06)
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- SITAGLIPTIN SYNTHESIS
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The present invention relates to novel processes for the preparation of enantiomerically enriched β-amino acid derivatives such as β-amino esters useful for the synthesis of enantiomerically enriched biologically active molecules such as sitagliptin. The key step involves the resolution of the racemate with mandelic acid.
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Page/Page column 9
(2012/05/07)
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- PROCESSES FOR THE PREPARATION OF R-SITAGLIPTIN AND INTERMEDIATES THEREOF
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The present invention relates to the synthesis of R-sitagliptin. The present invention also relates to a compound of formula (IV) or its salt, that are useful as key intermediate in the synthesis of R-sitagliptin or pharmaceutically acceptable salts thereof.
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Page/Page column 26-27
(2012/04/17)
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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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- 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
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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 25-26
(2010/04/25)
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- SITAGLIPTIN SYNTHESIS
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The present invention relates to novel processes for the preparation of enantiomerically enriched β -amino acid derivatives such as β -amino esters useful for the synthesis of enantiomerically enriched biologically active molecules such as sitagliptin. The key step involves the resolution of the racemate with mandelic acid.
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Page/Page column 25-26
(2010/12/17)
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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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- 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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- 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 27-28
(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 22-23
(2009/08/14)
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- Synthesis, biological evaluation and structural determination of β-aminoacyl-containing cyclic hydrazine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors
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Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of β-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)but an-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.
- Ahn, Jin Hee,Shin, Mi Sik,Jun, Mi Ae,Jung, Sun Ho,Kang, Seung Kyu,Kim, Kwang Rok,Rhee, Sang Dal,Kang, Nam Sook,Kim, Sun Young,Sohn, Sang-Kwon,Kim, Sung Gyu,Jin, Mi Sun,Lee, Jie Oh,Cheon, Hyae Gyeong,Kim, Sung Soo
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p. 2622 - 2628
(2008/02/11)
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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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- 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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- 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 a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand with in situ protection of the primary amine product. The invention also relates to a novel process for the preparation of chiral beta-amino acid amides as inhibitors of the dipeptidyl peptidase-IV of structural formula III 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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Page/Page column 21; 22
(2010/11/08)
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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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- 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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- 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 11-12
(2008/06/13)
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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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- 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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