- Preparation method of 1,3-dicarbonyl compound and intermediate of the 1,3-dicarbonyl compound
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The invention discloses a preparation method of a 1,3-dicarbonyl compound and an intermediate of the 1,3-dicarbonyl compound, and particularly discloses a preparation method of a compound as shown ina formula I. The preparation method comprises the following step: in a solvent, performing an elimination reaction as shown in the specification on a compound as shown in a formula II to obtain the compound as shown in the formula I, wherein R is a tert-butoxy group, a methoxy group, an ethoxy group or a methyl group. The preparation method disclosed by the invention is relatively low in cost andbeneficial to industrial production.
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- Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione
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The invention discloses a preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione, and belongs to the technical field of organic synthesis. The preparation method comprises the following step: under the action of a metal chelating agent and an alkali, carrying out a reaction of the following formula on a compound 2 and a compound 3 in an organic solvent to obtain a compound 1. The preparation method disclosed by the invention is high in yield, simple in post-treatment, simple, feasible, mild in reaction condition and suitable for industrial production.
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Paragraph 0087-0088; 0090
(2020/05/02)
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- A west geleg sandbank intermediate biological synthesis method (by machine translation)
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The invention discloses a west geleg sandbank intermediate biological synthesis method, namely in order to 4 - (2, 4, 5 - trifluoro methyl) uracil as the substrate under the action, by the one-pot preparation, Or, 4 - (2, 4, 5 - trifluoro methyl) uracil enzyme preparation obtained the situation that the (R)- 3 - carbamoyl amino - 4 - (2, 4, 5 - trifluorophenyl) butanoic acid, after separation, then the role of the enzyme or acid producing the (R)- 3 - amino - 4 - (2, 4, 5 - trifluorophenyl) butanoic acid, The west geleg sandbank intermediate the biological synthesis of simple process, without special request to device, to obtain a high EE value of the product, is suitable for industrial production. (by machine translation)
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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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Paragraph 0034-0037
(2019/06/07)
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- Glutamate as an Efficient Amine Donor for the Synthesis of Chiral β- and γ-Amino Acids Using Transaminase
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A recyclable glutamate amine donor system employing transaminase (TA), glutamate dehydrogenase (GluDH) and mutant formate dehydrogenase (FDHm) was developed, wherein amine donor Glu was regenerated using GluDH and thereby circumvented the inhibition of TA by α-ketoglutarate. Various enantiopure β-, γ-amino acids, and amines were successfully synthesized with high conversions and excellent enantiomeric excess using this system.
- Kim, Geon-Hee,Jeon, Hyunwoo,Khobragade, Taresh P.,Patil, Mahesh D.,Sung, Sihyong,Yoon, Sanghan,Won, Yumi,Sarak, Sharad,Yun, Hyungdon
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p. 1437 - 1440
(2019/02/06)
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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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- Preparation method of 3-aminopropanol or 3-aminopropionic acid derivative
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The invention provides a preparation method of an optically active 3-aminopropanol or 3-aminopropionic acid derivative, and belongs to the technical field of organic synthesis. A compound having a structure as shown in a formula II and a formula III is used as a raw material, and the optically active 3-aminopropanol or 3-aminopropionic acid derivative is obtained through four basic steps, namely dehydration condensation, hydrogenation reduction, reduction and hydrolysis. The raw materials adopted in the preparation method are easy to obtain and low in cost; as a chiral phosphine-transitional metal catalyst is used in the hydrogenation reduction reaction, the optically active 3-aminopropanol or 3-aminopropionic acid derivative is efficient, high in selectivity, low in cost and suitable forlarge-scale production. Compared with existing chemical resolution and chiral introduction, the asymmetric hydrogenation synthesis method provided by the invention only produces one chiral product, ishigh in yield, and has relatively high advantages in economy and raw material utilization rate.
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Paragraph 0180; 0191; 0192; 0195
(2018/10/11)
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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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- Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method
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The invention provides a compound shown by a formula I, a purpose of a stereoisomer, a geometrical isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmacologically acceptable salt or prodrug of the compound in Sitagliptin preparation, and a Sitagliptin preparation method. The formula I is shown in the description, wherein R1 is a substitutional group containing the hydroxyl group. The compound shown by the formula I or the stereoisomer, the geometrical isomer, the tautomer, the oxynitride, the hydrate, the solvate, the metabolite, the pharmacologically acceptable salt or the prodrug of the compound shown by the formula I has high water solubility, and is used for obtaining a chiral amino intermediate to further obtain the Sitagliptin. Compared with the prior art, the compound has the advantages that the amino group conversion rate is greatly improved; the yield of the Sitagliptin is also greatly improved.
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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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- Substrate screening of amino transaminase for the synthesis of a sitagliptin intermediate
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We reported herein a new enzymatic route to synthesize a sitagliptin intermediate using an aminotransferase. Substrate profile indicated that hydroxyethyl-3-oxo-4-(2,4,5-trifluorophenyl)butanoate, among 11 analogs, showed the best biocatalytic performance, partially due to its best solubility in the enzymatic system. The corresponding amino esters showing strong product inhibition on the reaction, were inclined to autohydrolyze, thus driving the reaction forward, which indicated the contribution of the rapid hydrolysis of hydroxyethyl ester to the biocatalytic performance. The reaction was performed at 100?mM with 82% conversion in 24?h. The amino ester product was further transformed to Boc-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid, the key intermediate of sitagliptin.
- Hou, Anwei,Deng, Zixin,Ma, Hongmin,Liu, Tiangang
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p. 4660 - 4664
(2016/07/15)
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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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Page/Page column 26; 27
(2016/01/01)
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- Chemical kinetic resolution of unprotected β-substituted β-amino acids using recyclable chiral ligands
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The first chemical method for resolution of N,C-unprotected β-amino acids was developed through enantioselective formation and disassembly of nickel(II) complexes under operationally convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled along with isolation of the target β-substituted-β-amino acids in good yields and excellent enantioselectivity. The method features a broad synthetic generality including β-aryl, β-heteroaryl, and β-alkyl-derived β-amino acids. The procedure is easily scaled up, and was used for the synthetically and economically advanced preparation of the anti-diabetic drug sitagliptin. The nick of time: A chemical method for resolution of unprotected β-amino acids rac-1 was developed through enantioselective formation and disassembly of nickel(II) complexes to deliver the target β-substituted β-amino acids in good yields and excellent enantioselectivity. The chiral ligands are inexpensive and can be quantitatively recycled. The procedure was used for the preparation of anti-diabetic drug sitagliptin.
- Zhou, Shengbin,Wang, Jiang,Chen, Xia,Acena, Jose Luis,Soloshonok, Vadim A.,Liu, Hong
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supporting information
p. 7883 - 7886
(2014/08/05)
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- SITAGLIPTIN INTERMEDIATE COMPOUNDS, PREPARATION METHODS AND USES THEREOF
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Sitagliptin intermediate compounds of formula (f) and methods of preparation and use thereof are disclosed. Compounds of formula (f) are prepared by the following steps: compounds of formula (a) are subjected to electrophilic reaction with benzyl halides to form compounds of formula (b), which then react with compounds of formula (i) to form novel compounds of formula (e). Gignard agents formed from 2,4,5-trifluoro brmobenzene and magnesium metal react with compounds of formula (e) to afford compounds of formula (f), which are novel intermediates for the preparation of Sitagliptin intermediates of formula (g). Compounds of formula (f) are subjected to reduction by Pd/C, debenzylation, substitution of protecting group to form compounds of formula (g). Compounds of formula (a), (b), (i), (e), (f), and (g) have the following structures, in which R is protecting group of carboxyl and R2 is (substituted) hydrocarbyl.
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Paragraph 0068
(2013/03/26)
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- METHOD FOR MANUFACTURING DIPEPTIDYL PEPTIDASE-IV INHIBITOR AND INTERMEDIATE
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The present invention relates to an improved method for manufacturing dipeptidyl peptidase-IV inhibitor and intermediate. The present invention allows reduction of production costs by reacting low cost reagents, improves yield and is adaptable for mass production.
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Page/Page column 7-8
(2012/02/01)
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- Synthesis, biological assay in vitro and molecular docking studies of new imidazopyrazinone derivatives as potential dipeptidyl peptidase IV inhibitors
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A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)- hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan- 2-amine fumaric acid (17h, IC50 = 78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h.
- Zhu, Yanyun,Xia, Shuang,Zhu, Mingjie,Yi, Weiyin,Cheng, Jiagao,Song, Gonghua,Li, Zhong,Lu, Peng
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experimental part
p. 4953 - 4962
(2010/11/18)
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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 59
(2010/11/05)
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- Improved enzymatic syntheses of valuable β-arylalkyl-β-amino acid enantiomers
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The enantioselective (E~ 200) Burkholderia cepacia-catalysed hydrolyses of β-amino esters with H2O (0.5 equiv.) in t-BuOMe or in i-Pr2O at 45 °C are described. The enantiomers of biologically relevant β-arylalkyl-substituted β-amino acids, and especially (R)-3-amino-3-(2,4,5-trifluorophenyl)butanoic acid, the intermediate of the new antidiabetic drug sitagliptine, were prepared with high enantiomeric excesses (ee≥96%) and in good yields (≥42%). The Royal Society of Chemistry 2010.
- Tasnadi, Gabor,Forro, Enik,Fueloep, Ferenc
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experimental part
p. 793 - 799
(2010/06/20)
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- Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore
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(3R)-3-[N-(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid 7a has been synthesized by an asymmetric hydrogenation of enamine ester 3 using chiral ferrocenyl ligands I and II in conjunction with [Rh(COD)Cl] 2. The direct reduction of 3 provides amino ester 1b in 93% ee, which was isolated as an (S)-camphorsulfonic acid salt to upgrade the enantiomeric excess to >99%. A more concise approach was developed involving the in situ protection of 1b using di-tert-butyldicarbonate. This approach provided the desired N-Boc amino ester 7b directly from the hydrogenation with 97% ee, which was upgraded to >99% ee upon crystallization.
- Kubryk, Michele,Hansen, Karl B.
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p. 205 - 209
(2007/10/03)
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