cas 486460-00-8, BOC-(R)-3-AMINO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYRIC ACID

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Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore
(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.
p. 205 - 209
(2006)
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Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin
Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75–92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)- and (S)-1-phenylethylamines, the partially enantioenriched (R)- and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided >99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.
Sudhakaran, Shana,Shinde, Prasad G.,Aratikatla, Eswar K.,Kaulage, Sandeep H.,Rana, Priksha,Parit, Ratan S.,Kavale, Dattatry S.,Senthilkumar, Beeran,Punji, Benudhar
supporting information

(2021/12/09)

Synthesis of (?)-(R)-Sitagliptin by RhI-Catalyzed Asymmetric Hydroamination
We report of a concise synthesis of (R)-sitagliptin monophosphate – a drug predominantly applied in the treatment of type 2 diabetes. Utilizing our recently developed RhI-catalyzed hydroamination of allenes for the stereoselective construction of the inherent chiral amino function, a new approach to (R)-sitagliptin monophosphate on a 3.5 mmol scale was established.
Berthold, Dino,Breit, Bernhard
p. 6247 - 6249
(2021/09/25)

Preparation method of chiral 4 - aryl - β β-amino acid derivative
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 0056-0058

(2021/11/14)

Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione
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; 0091

(2020/05/02)

Preparation method of 1,3-dicarbonyl compound and intermediate of the 1,3-dicarbonyl compound
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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Paragraph 0092-0093; 0096

(2020/05/02)

Synthesis of (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal Synthesis of Sitagliptin Phosphate
An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β-amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc-amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.
Achanta, Srinivas,Bandichhor, Rakeshwar,Chaudhari, Pramod S.,Cobley, Christopher J.,Dahanukar, Vilas,Llewellyn-Beard, Fiona,Sreenivasulu, Kurella,Sud, Abhishek
(2020/05/08)

AN IMPROVED PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES
The present invention relates to a process for the preparation of novel intermediates useful for the preparation of Sitagliptin or its pharmaceutically acceptable salts. The present invention relates to an efficient process for the preparation of Sitagliptin intermediates. The present invention relates to an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.
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(2020/05/29)

BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and preparation method thereof
The invention provides a sitagliptin phosphate important intermediate BOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and a preparation method and preparation thereof. TheBOC-(R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid condensation impurity and the preparation method thereof have important significance for the following industrial production of bulk drugs.
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Paragraph 0101-0103; 0106-0109

(2019/07/04)

Method for synthesizing sitagliptin and intermediate thereof through biological catalysis
The invention provides a method for synthesizing sitagliptin and an intermediate thereof through biological catalysis, and particularly provides compounds as shown in formula I and a formula II, or pharmaceutically acceptable salt thereof, polypeptide capable of synthesizing a compound as shown in the formula I to produce a compound as shown in the formula II, nucleic acid coding the polypeptide,and a vector and a cell containing the nucleic acid. In addition, the invention further provides a method for producing the compound as shown in the formula II and sitagliptin through the polypeptideand the compound as shown in the formula I, and a preparation method for preparing the polypeptide.
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Paragraph 0145; 0175; 0176; 0177; 0179

(2018/10/11)

Practical asymmetric synthesis of Sitagliptin phosphate monohydrate
Optically pure sitagliptin phosphate monohydrate is efficiently and practically synthesized through a chiral hemiacetal as the key intermediate in 54% overall yield starting from (E)-4-(2,4,5-trifluorophenyl)but-2-enal and N-boc-protected hydroxylamine. The chiral hemiacetal fragment is constructed by a tandem aza-Michael/hemiacetal reaction catalyzed by an organocatalyst and the influence of acidity of Br?nsted acid on tandem aza-Michael/hemiacetal reaction is researched in detail.
Gao, Haoling,Yu, Jiangang,Ge, Chengsheng,Jiang, Qun
(2018/06/29)

Preparation method of sitagliptin intermediate
The invention discloses a preparation method of a sitagliptin intermediate and belongs to the field of medicine synthesis. The invention provides a preparation method of a compound 2; the compound 2 is prepared without the need of a catalyst and a resolving agent which have a high price and harsh low-temperature conditions, so that the cost is reduced to the great extent; the preparation method has the advantages of simple technology, high purity and high yield and is suitable for mass production.
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(2018/04/01)

Chiral synthesis method for chiral beta-amino acid and synthesis method for medicinal intermediate
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 0077; 0078; 0079; 0080

(2018/01/11)

Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities
The invention discloses sitagliptin phosphate impurities, a method for preparing the same and application of the sitagliptin phosphate impurities. The sitagliptin phosphate impurities are sitagliptin phosphate impurities A, sitagliptin phosphate impurities B and sitagliptin phosphate impurities C. The relevant sitagliptin phosphate impurities, the method and the application have the advantage of important monitoring significance on industrial production of sitagliptin phosphate crude medicines.
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Paragraph 0040

(2017/05/26)

Purpose of compound for preparing Sitagliptin and Sitagliptin preparation method
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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Paragraph 0039; 0040

(2017/10/31)

Application of asymmetric conjugate addition reaction in synthesis of Imigliptin intermediate compound
The invention provides a synthesis method of a compound in a Formula (1), i.e., an Imigliptin intermediate compound. The synthesis method comprises the following steps: taking a compound in a Formula (2) as an initial raw material, and performing a series of reactions to finally obtain the compound in the Formula (1), i.e., the Imigliptin intermediate compound, wherein the reactions are as shown in the specification. Compared with too many steps and a complex synthesis process in Imigliptin intermediate compound synthesis in the prior art, the synthesis method provided by the invention is simple and easy to implement, low in cost, high in yield and favorable in product quality, thereby being suitable for large-scale industrial production.
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Paragraph 0016

(2018/03/28)

A west he row sandbank intermediate preparation method
The invention discloses a preparation method for a sitagliptin intermediate and belongs to the field of drug synthesis. The preparation method comprises the following steps: (1) carrying out a ring-opening reaction: carrying out Grignard reaction on 2,4,5-trifluorobromobenzene and a Grignard reagent RMgX in a medium of tetrahydrofuran and methyl tertiary-butyl ether at (-20) DEG C to 50 DEG C by taking cuprous chloride as a catalyst, wherein R2 is isopropyl and X is halogen, and then carrying out the ring-opening reaction on the generated compound and a compound shown in a formula 3 to obtain a compound shown in a formula 4; and (2) carrying out an oxidizing reaction: carrying out the oxidizing reaction on the compound shown in the formula 4 and potassium permanganate in an acetone medium, quenching and neutralizing the product by using reducing agents sodium sulfite and sodium hydrogen sulfite, and extracting the product by methyl tertiary butyl ether to obtain the sitagliptin intermediate. The method is low in cost, high in yield, mature in process and suitable for industrial production.
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Paragraph 0071; 0072; 0074; 0082

(2017/08/25)

Synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid
The invention relates to a synthesis method of chiral N-Boc-3-amino-4-aryl-butyric acid. The method is as below: 1, conducting a cross metathesis reaction, an asymmetric conjugate addition reaction and an oxidation reaction on starting materials including an allyl aromatic compound and crotonaldehyde by a continuous reaction one-pot method to synthesize an N-Boc-3-aryl methyl-5-oxo isoxazole intermediate; or conducting an asymmetric conjugate addition reaction and an oxidation reaction on a starting material (E)-4-aryl-2-crotonaldehyde by a continuous reaction one-pot method to synthesize an N-Boc-3-aryl methyl-5-oxo isoxazole intermediate; and 2, subjecting (3R)-N-Boc-3-aryl methyl-5-oxo isoxazole intermediate by high-pressure hydrogenation to directly prepare the chiral N-Boc-3-amino-4-aryl-butyric acid. The synthesis method provided by the invention has the advantages of simple operation, mild reaction conditions, target product yield reaching 60-69%, and ee value of the target product reaching as high as 96%. The synthetic route has industrialization prospect.
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Paragraph 0032; 0033; 0034; 0035; 0045

(2017/08/28)

Novel preparation method for anti-type-II-diabetes drug sitagliptin
The invention discloses a novel preparation method for an anti-type-II-diabetes drug sitagliptin. According to the invention, trifluorobenzene with a cheaper price is used as a fluorization reagent and a starting raw material and a basic skeleton of sitagliptin is successfully synthesized through effective acylation of trifluorobenzene and L-aspartic acid; a synthesis route in the invention, from starting raw material and final product, is completely different from schemes disclosed in the prior art; the route is optimized, and easily-available natural L-aspartic acid is used as a chiral source for successful synthesis of an optically pure sitagliptin product; the problems of asymmetric catalysis and complex splitting in the prior art are overcome; the method also effectively overcomes the problem of low yield of the basic skeleton of sitagliptin synthesized via Friedel-Crafts acylation of trifluorobenzene and improves yield; the method is lower in cost, more convenient to operate and more suitable for industrial production; and compared with the prior art, the method is simpler in the synthesis route and better in operability.
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Paragraph 0022; 0023; 0024

(2017/09/13)

Intermediate of Sitagliptin and synthesis method of intermediate
The invention provides an intermediate of Sitagliptin and a synthesis method of the intermediate. The intermediate is the compound of formula (I), and the synthesis method comprises enabling the compound of the formula (3) to react with cyan-containing salt to obtain the compound of the formula (2), and hydrolyzing the compound of the formula (2) by use of alkali. The synthesis method is short in reaction path, the reaction reagent is cheap, and the expensive reagent in the traditional process is avoided to use, the production cost can be effectively lowered, the synthesis time is shortened, and the industrial production is facilitated. The intermediate of the Sitagliptin manufactured by use of the synthesis method is large in yield, high in purity, and in favor of the preparation of high-quality Sitagliptin.
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(2017/07/19)

Glucovance west Geleg sandbank intermediate process for the preparation of amino acid derivatives
The invention discloses a preparation method of a new diabetes drug sitagliptin intermediate aminobenzene butyric acid derivative. The preparation method comprises the following steps of: (1) mixing a compound shown in a formula I with R(+)-alpha-phenethyl and acetic acid to obtain a compound shown in a formula II; (2) mixing the compound shown in the formula II with sodium borohydride and protonic acid or lewis acid to obtain a compound shown in a formula III; (3) mixing the compound shown in the formula III with X to obtain a compound shown in a formula IV; (4) mixing the compound as shown in the formula IV with an inorganic base 1 to obtain a compound shown in a formula V; (5) obtaining a compound shown in a formula VI by the compound shown in the formula V; and (6) mixing the compound shown in the formula VI with an inorganic base 2 to obtain a compound shown in a formula VII.
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(2019/02/02)

Sitagliptin intermediate preparation method
The invention relates to the technical field of organic chemistry and especially relates to a sitagliptin intermediate preparation method. The invention provides a compound with a structure shown in the formula 6. The sitagliptin intermediate shown in the formula 8 and prepared from the compound with a structure shown in the formula 6 has high HPLC purity and an ee value of 99% or more.
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Paragraph 0081-0083

(2017/05/13)

A synthetic west he row sandbank of the new method
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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Paragraph 0070-0071

(2016/12/16)

NOVEL BETA-SULFINAMINO MALONATE DERIVATIVES AND PROCESS FOR PREPARING THE SAME, AND PROCESS FOR PREPARING SITAGLIPTIN USING THE SAME
The present invention relates to beta-sulfinamino malonate derivatives having a high diastereomeric ratio (DR) value manufactured through a stereoselective addition reaction of chiral sulfinyl imine and malonate derivatives, to optically pure Sitagliptin by using the same, and to a method for manufacturing pharmaceutically acceptable salt thereof. According to the present invention, the method is capable of manufacturing novel beta-sulfinamino malonate derivatives which are intermediate in the manufacture of Sitagliptin, with high optical purity and high yields without using a solvent under mild conditions, and ultimately manufacturing optically pure Sitagliptin in an efficient manner by using the same.COPYRIGHT KIPO 2016
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(2021/06/22)

Preparation method of Sitagliptin midbody of beta-amino acid
The invention discloses a preparation method of a Sitagliptin midbody of beta-amino acid. The method comprises the following steps of 2,4,5-fluorobenzene acetaldehyde 2, L-benzedrine alcohol and tributyl allyl tin alkanes perform asymmetrical allylation reaction under the effect of a catalyst A to obtain a compound 3; the compound 3 is oxidized to remove chiral auxiliary radials to obtain a compound 4; the compound 4 is subjected to amino radial protection to obtain a compound 5; the compound 5 is subjected to double-bond oxidation to obtain beta-aminobutyric acid 1. The method provided by the invention has the advantages that the raw materials are cheap and can be easily obtained; the reaction route is short; the operation is simple and convenient; the reaction conditions are mild; no special requirements exist on the equipment; the yield is high; the selectivity is high; good industrial application and economic values are realized.
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Paragraph 0074-0075

(2018/02/04)

Substrate screening of amino transaminase for the synthesis of a sitagliptin intermediate
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
p. 4660 - 4664
(2016/07/15)

Chiral Lewis Base-Catalyzed, Enantioselective Reduction of Unprotected β-Enamino Esters with Trichlorosilane
Catalytic asymmetric reduction of N-unsubstituted β-enamino esters represents a major challenge for asymmetric catalysis. In this paper, the first organocatalytic system that could be used for the asymmetric hydrosilylation of N-unsubstituted β-enamino esters has been developed. Using N-tert-butylsulfinyl-L-proline-derived amides and L-pipecolinic acid-derived formamides as catalyst, a broad range of β-aryl- and β-alkyl-substituted free β-amino esters could be prepared with high yields and enantioselectivities. The practicality was illustrated by the gram-scale asymmetric synthesis of ethyl (R)-3-amino-3-phenylpropanoate and isopropyl (S)-3-amino-4-(2,3,5-trifluorophenyl)butanoate. The resulting product can be smoothly transformed to the FDA approved medicines dapoxetine and sitagliptin in a short synthetic route.
Ye, Jianheng,Wang, Chao,Chen, Lin,Wu, Xinjun,Zhou, Li,Sun, Jian
supporting information
p. 1042 - 1047
(2016/04/19)

TETRAHYDRO-IMIDAZO[1,5-A]PYRAZINE DERIVATIVES SALTS, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
The present invention relates to (R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid pharmaceutical salts, methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as a dipeptidyl peptidase IV inhibitor.
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(2016/10/08)

Method for synthesizing sitagliptin intermediate
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 0057; 0058; 0059

(2016/10/24)

BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-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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Paragraph 0179

(2015/12/30)

A concise enantioselective synthesis of (R)-selegiline, (S)-benzphetamine and formal synthesis of (R)-sitagliptin via electrophilic azidation of chiral imide enolates
A concise and high yielding enantioselective synthesis of (R)-selegiline, an anti-Parkinson's drug, (S)-benzphetamine, an anti-obesity agent, and (S)-sitagliptin, an anti-diabetic drug has been described starting from commercially available starting materials employing Evans' electrophilic azidation of chiral imide enolates as a key chiral inducing step, which proceeds in a highly diastereoselective manner (>99%).
Dey, Soumen,Sudalai, Arumugam
p. 67 - 72
(2015/02/02)

Efficient stereocontrolled synthesis of sitagliptin phosphate
The synthesis of sitagliptin phosphate 1, a novel DPP-IV inhibitor for the treatment of type 2 diabetes mellitus has been accomplished starting from the chiral synthon (1,4-bis[(R)-1-phenylethyl]piperazine-2,5-dione) 2, involving highly stereocontrolled (>98%) alkylation as a key step, in a good overall yield of 50% over six steps.
Subbaiah,Haq, Wahajul
p. 1026 - 1030
(2014/08/18)

Chemical kinetic resolution of unprotected β-substituted β-amino acids using recyclable chiral ligands
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
supporting information
p. 7883 - 7886
(2014/08/05)

SITAGLIPTIN INTERMEDIATE COMPOUNDS, PREPARATION METHODS AND USES THEREOF
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 0070; 0037

(2013/03/26)

SITAGLIPTIN INTERMEDIATE COMPOUNDS, PREPARATION METHODS AND USES THEREOF
The invention relates to Sitagliptin intermediate compounds of formula (f), preparation methods and uses thereof. The compound 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 bromobenzene and magnesium metal react with compounds of formula (e) to afford compounds of formula (f), which are novel intermediate compounds for the preparation of Sitagliptin intermediates of formula (g). The compound of formula (f) was subjected to reduction by Pd/C, debenzylation, substitution of protecting group to form the compounds of formula (g). The mentioned compounds have the following structures, wherein, R is the protecting group of carboxyl, R2 is (substituted) hydrocarbyl.
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Paragraph 0034

(2013/03/26)

INTERMEDIATES OF SITAGLIPTIN AND PREPARATION PROCESS THEREOF
Disclosed are intermediates of Sitagliptin, a preparation process thereof, and a process for synthesizing Sitagliptin using these intermediates. Sitagliptin is synthesized by using chiral amino compounds as a raw material, without having to build a chiral center with a chiral asymmetric catalytic hydrogenation, and high-pressure hydrogenation is avoided.
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(2013/11/05)

Efficient synthesis of sitagliptin phosphate, a novel DPP-IV inhibitor, via a chiral aziridine intermediate
Sitagliptin phosphate, a novel DPP-IV inhibitor of T2DM, has been synthesized via 12 linear steps, in an overall yield of 26%. The key step is the coupling reaction of 2,4,5-trifluorophenylmagnesium bromide with a chiral aziridine derivative, which was prepared from l-homo-serine by simple steps.
Pan, Xianhua,Li, Xiaojun,Lu, Qingling,Yu, Wansheng,Li, Weijin,Zhang, Qunhui,Deng, Fei,Liu, Feng
p. 6807 - 6809
(2013/11/19)

INTERMEDIATES OF SITAGLIPTIN AND PREPARATION PROCESS THEREOF
Disclosed are intermediates of Sitagliptin, a preparation process thereof, and a process for synthesizing Sitagliptin using these intermediates. Sitagliptin is synthesized by using chiral amino compounds as a raw material, without having to build a chiral center with a chiral asymmetric catalytic hydrogenation, and high-pressure hydrogenation is avoided.
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(2013/10/22)

A NOVEL PROCESS FOR THE PREPARATION OF SITAGLIPTIN
The present invention is directed to a process for the preparation of enantiomerically enriched β-amino acid derivatives which are important chiral building blocks and intermediates in pharmaceuticals. More specifically, the invention pertains to a novel process for practically convenient and economically producing enantiomerically enriched β-amino acid derivatives which are useful for the synthesis of amide inhibitors of dipeptidyl peptidase IV like Sitagliptin, which have been used to treat type 2 diabetes.
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(2013/08/15)

SITAGLIPTIN SYNTHESIS
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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(2012/05/07)

Process for the production of sitagliptin
The present invention is directed to a process for the preparation of Sitagliptin, having formula (I)
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Page/Page column 10-11

(2012/03/26)

SITAGLIPTIN INTERMEDIATES, PREPARATION METHODS AND USES THEREOF
The present invention relates to Sitagliptin intermediate and preparation method and use thereof. The method comprises reacting compound of formula (II) and trifluorobromobenzene with a Grignard reagent by a Grignard reaction to obtain a compound of formula (I). Compound of formula (I) is a new intermediate compound for the synthesis of Sitagliptin. Compound of formula (I) can be easily used for preparing another important intermediate compound of formula (V) for the synthesis of Sitagliptin. The structures of the compounds mentioned above are as the following:
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Page/Page column 7

(2012/07/27)

SITAGLIPTIN INTERMEDIATES, PREPARATION METHODS AND USES THEREOF
The present invention relates to Sitagliptin intermediate and preparation method and use thereof. The method comprises reacting compound of formula (II) and trifluorobromobenzene with a Grignard reagent by a Grignard reaction to obtain a compound of formula (I). Compound of formula (I) is a new intermediate compound for the synthesis of Sitagliptin. Compound of formula (I) can be easily used for preparing another important intermediate compound of formula (V) for the synthesis of Sitagliptin. The structures of the compounds mentioned above are as the following:
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Page/Page column 9

(2012/08/08)

METHOD FOR MANUFACTURING DIPEPTIDYL PEPTIDASE-IV INHIBITOR AND INTERMEDIATE
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 9

(2012/02/01)

METHOD FOR PREPARING DIPEPTIDYL PEPTIDASE-IV INHIBITOR AND INTERMEDIATE
The present invention relates to an improved method for preparing dipeptidyl peptidase-IV inhibitor and intermediate. The present invention is able to reduce preparation costs by using low cost reagents on reaction and is able to be used in mass production by improving yield.
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(2012/02/01)

SALTS OF TETRAHYDROIMIDAZO Y1,5-A¨PYRAZINE DERIVATIVES, PREPARATION METHODS AND PHARMACEUTICAL USE THEREOF
Pharmaceutical salts of (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-formic acid, their preparation methods, compositions containing the said pharmaceutical salts and their use as medicaments, especially as dipeptidyl peptidase IV (DPP-IV) inhibitors are disclosed.
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(2012/02/04)

TETRAHYDRO-IMIDAZO[1,5-a]PYRAZINE DERIVATIVES SALTS, PREPARATION METHODS AND MEDICINAL USE THEREOF
Pharmaceutically acceptable salts of (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-formic acid, their preparation methods, compositions containing the said pharmaceutical salts and their use as medicaments, especially as dipeptidyl peptidase IV (DPP-IV) inhibitors are disclosed.
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(2012/03/27)

PROCESS FOR PREPARING R-BETA-AMINO PHENYLBUTYRIC ACID DERIVATIVES
Disclosed is a process for preparing single enantiomers of beta-amino phenylbutyric acid derivatives and pharmaceutically acceptable salts thereof, which affords the desired compounds having special optical configuration. The process comprises a step of chemical synthesis and a step of resolving the optical isomers of beta-amino phenylbutyric acid derivatives with a resolving agent. The resolving step comprises reacting the optical isomers with resolving agents, such as di-para-toluoyl-L-tartaric acid and di-para-toluoyl-D-tartaric acid. The obtained R-beta-amino phenylbutyric acid derivatives (I) have high optical purity, and the total yield of the accumulative resolution of the laevo and the dextro isomer is up to above 70%.
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(2011/06/23)

A PROCESS FOR PREPARING R-BETA-AMINO PHENYLBUTYRIC ACID DERIVATIVES
Disclosed is a process for preparing chiral pharmaceutical intermediates of R-beta-amino phenylbutyric acid derivatives (I) and pharmaceutically acceptable salts thereof, which affords the desired object compounds having special optical configuration by chemosynthesis process comprising resolving the optical isomer mixtures of beta-amino phenylbutyric acid derivatives with resolving agent. This process comprises the resolving step of salification in alcoholic solvent or aquesous solution of alcohol with resolving agent of di-para-toluoyl-L-tartaric acid and di-para-toluoyl-D-tartaric acid. The obtained R-beta-amino phenylbutyric acid derivatives (I) have high optical purity, and the total yield of the accumulative resolution of the laevo and the dextro isomer is up to above 70%. The R-beta-amino phenylbutyric acid derivatives (I) produced by this process can be better used in synthesizing medicament.
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(2011/04/25)

TETRAHYDRO-IMIDAZOY1,5-A¨PYRAZINE DERIVATIVES, PREPARATION METHODS AND MEDICAL USES THEREOF
Tetrahydro-imidazo[1,5-a]pyrazine derivatives of formula ( I ), their preparation methods, pharmaceutical compositions containing the derivatives and uses thereof as medicaments, especially as dipeptidyl peptidase IV inhibitor, wherein the substituents of formula ( I ) are defined as same as the description.
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Page/Page column 18

(2010/10/03)

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF N-ACYLATED-4-ARYL BETA-AMINO ACID DERIVATIVES
A process for producing an enantiomerically enriched, pure or enriched and essentially pure compound of Formula I [structure] wherein the R-, or S-configuration at the stereogenic center is marked with an *, which process hydrogenates an enamide compound of formula III [structure] in an organic solvent in the presence of a transition metal precursor complexed to a chiral phosphine ligand catalyst, wherein Ar is phenyl which is unsubstituted or substituted, R1 and R2 are selected from H, Cl - 8 alkyl, C5 - 12 cycloalkyl, aryl and aryl-C 1 - 2-alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a C4- r member heterocyclic πng system optionally fused with a 5- to 6- member carbocyclic or heterocyclic ring system, and the other substituents are as defined herein.
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Page/Page column 21-22

(2010/08/04)

Chemical Properties

Melting Point: 136-138℃
Boiling Point: 443.1 °C at 760 mmHg
Flash Point:221.8 °C
Density: 1.292 g/cm³
Solubility:Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slig
Storage Temp.:2-8°C
Vapor Pressure: 1.25E-08mmHg at 25°C
Refractive Index: 1.494
PKA: 4.30±0.10(Predicted)
PSA: 75.63000
LogP: 3.40530

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Chemical Properties

Melting Point: 136-138℃

Boiling Point: 443.1 °C at 760 mmHg

Flash Point:221.8 °C

Density: 1.292 g/cm³

Solubility:Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slig

Storage Temp.:2-8°C

Vapor Pressure: 1.25E-08mmHg at 25°C

Refractive Index: 1.494

PKA: 4.30±0.10(Predicted)

PSA: 75.63000

LogP: 3.40530

Global suppliers and manufacturers of 486460-00-8total 236 suppliers on LookChem

Article Database

486460-00-8

Articles about 486460-00-8Total 61 be found

More Articles about upstream products of 486460-00-8

More Articles about downstream products of 486460-00-8

Chemical Properties

Melting Point: 136-138℃

Boiling Point: 443.1 °C at 760 mmHg

Flash Point:221.8 °C

Density: 1.292 g/cm3

Solubility:Chloroform (Slightly), DMSO (Slightly), Ethyl Acetate (Slightly), Methanol (Slig

Storage Temp.:2-8°C

Vapor Pressure: 1.25E-08mmHg at 25°C

Refractive Index: 1.494

PKA: 4.30±0.10(Predicted)

PSA: 75.63000

LogP: 3.40530

Global suppliers and manufacturers of 486460-00-8total 236 suppliers on LookChem

Density: 1.292 g/cm³