cas 486460-23-5, Sitagliptin N-Boc IMpurity

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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 0065-0067

(2021/11/14)

Process for preparing sitagliptin
The present technology relates to a method for manufacturing sitagliptin, which is a representative drug among DPP-4 inhibitors which are drugs used for the treatment of diabetes. The method of the present invention uses CDI for the condensation reaction of specific compounds, and through a specific subsequent process, high-purity sitagliptin phosphate monohydrate can be manufactured in a high yield. In particular, the manufacturing method of the present invention is suitable for mass production.
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Paragraph 0049-0051

(2021/06/01)

Synthesis method of sitagliptin free alkali
The invention belongs to the field of organic chemistry, and particularly discloses a synthesis method of sitagliptin free alkali. The synthesis method comprises the following specific steps: (1) dissolving (3R)-N-tert-butyloxycarbonyl-3-amino-4-(2,4,5-trifluorophenyl) butyric acid and organic alkali in an organic solvent, adding a phosphorus-containing condensing agent, then adding 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-alpha]pyrazine hydrochloride to prepare a compound represented by a formula (II); and (2) removing t-butyloxycarboryl from the compound shown in the formula II under the action of acid to obtain a compound I namely sitagliptin free alkali. The method is mild in process reaction condition, easy to control, short in reaction time, free of extraction, simple to operate and beneficial to industrial production, and the process cost is reduced; and the prepared compound shown in the formula I is high in yield, high in purity and free of heavy metal residues.
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Paragraph 0024; 0042-0053; 0060-0069

(2021/07/17)

Synthesis method of sitagliptin free alkali and sitagliptin phosphate monohydrate
The invention relates to a synthesis method of sitagliptin free alkali and sitagliptin phosphate monohydrate. According to the method, dry HOBt is removed or changed into HOBt hydrate, a solvent DMF is removed in the process, and a simple solvent easy to recover is used in the production process, so that the production cost is reduced, and the reaction safety is improved. According to the invention, with the in-situ process from a compound represented by a formula 2 to a compound represented by a formula 6, the yield can be improved, the operation steps can be reduced, and the methanol or isopropanol IPA is replaced with other solvents so as to avoid the generation of impurities represented by a formula 7, a formula 8 and a formula 9, such that the product purity and the yield can be substantially improved, and the HPLC purity of the sitagliptin free alkali is more than 99%.
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Paragraph 0030-0031; 0035-0043; 0046-0050

(2021/07/24)

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)

Preparation method of tert-butyloxycarbonyl-sitagliptin
The invention discloses a preparation method of tert-butyloxycarboryl-sitagliptin. The preparation method comprises the following steps: taking BOC-(R)-3-amino-4-(2, 4, 5-trifluorophenyl) butyric acidas a main raw material; under condition of adjustment by alkalinity, adding acyl chloride, carrying out a reaction at -20 to 50 DEG C for 1 to 10 h, adding 3-trifluoromethyl-5, 6, 7, 8-tetrahydro-1,2, 4-triazolo[4, 3-a] pyrazine hydrochloride at the temperature of -20 to 50 DEG C for 1 to 10 h, adding water at the temperature, carrying out stirring crystallization, carrying out filtering and carrying out drying. The method has the advantages of reasonable reaction steps, mild reaction conditions, fewer side reactions, simple and convenient post-treatment, safety and environmental protection;the yield of synthesized tert-butyloxycarboryl-sitagliptin is high and can reach 92% or above, and the purity of a finished product is also high and can reach 99.5% or above.
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Paragraph 0029

(2020/05/05)

PROCESSES FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
The present application relates to improved processes for the preparation of Sitagliptin and pharmaceutically acceptable salts thereof. The present application also relates to the improved crystallization process for the preparation of Sitagliptin Phosphate. The present application also relates to the improved crystallization process for the preparation of Sitagliptin Hydrochloride monohydrate.
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Page/Page column 15; 17-18

(2020/06/19)

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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(2019/07/04)

Preparation Method Camphorsulfonic acid Salt of Sitagliptin
The present invention provides a method for manufacturing a camsylate salt of sitagliptin and the camsylate salt manufactured by a manufacturing method thereof. The manufacturing method of the present invention has a simple manufacturing process, thereby being able to synthesize a sitagliptin camsylate salt economically in terms of time and/or cost. Therefore, it is possible to be usefully applied for mass production.COPYRIGHT KIPO 2019
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Paragraph 0043-0044

(2019/10/22)

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas
Carboxylic acids and their corresponding carboxylate anions are generally utilized as Br?nsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Br?nsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.
Hayama, Noboru,Kuramoto, Ryuta,F?ldes, Tamás,Nishibayashi, Kazuya,Kobayashi, Yusuke,Pápai, Imre,Takemoto, Yoshiji
supporting information
p. 12216 - 12225
(2018/09/25)

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)

A west he row sandbank chiral intermediate and asymmetric synthesis method
The invention relates to a sitagliptin chiral intermediate and an asymmetric synthesis method thereof. The asymmetric synthesis method comprises the steps: with 2,4,5-trifluorophenyl acetic acid as a starting material, carrying out a reduction reaction to obtain 2-(2,4,5-trifluorophenyl)ethanol, then carrying out a reaction with an oxidant, carrying out condensation of the product without separation and (R)-(+)-tert-butyl sulfinamide to obtain corresponding acetal, carrying out a reaction of the obtained product with dialkyl malonate to obtain a key chiral intermediate, hydrolyzing to obtain a corresponding organic amine, carrying out a reaction of the amine with caustic alkali and then acidifying to obtain a corresponding carboxylic acid, then carrying out condensation with 3-(trifluoromethyl)-5,6,7,8- tetrahydro-[1,2,4] triazolo[4,3-a]pyrazine hydrochloride to obtain sitagliptin tert-butyl oxanamide, and finally deprotecting with hydrochloric acid to obtain sitagliptin. The yields of all the steps are all higher, the used reagents are all conventional cheap reagents, no expensive chiral catalysts are used, the reaction conditions are quite mild, and the asymmetric synthesis method is suitable for industrialization.
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(2017/08/25)

SITAGLIPTIN INTERMEDIATE, METHOD OF SYNTHESIZING THE SITAGLIPTIN INTERMEDIATE, AND METHOD OF SYNTHESIZING SITAGLIPTIN USING THE SITAGLIPTIN INTERMEDIATE
Disclosed is an intermediate compound of sitagliptin which has a molecular structure represented by chemical formula 1. The use of the intermediate compound of sitagliptin enables production of sitagliptin compounds which are used as dipeptidyl peptidase-4 (DPP-4) inhibitors in a cost effective and eco-friendly manner, without using expensive coupling agents.COPYRIGHT KIPO 2017
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Paragraph 0147; 01484

(2017/11/22)

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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(2017/09/13)

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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(2017/05/26)

A west he row sandbank synthesis of intermediates method
The invention relates to a synthesis method of sitagliptin intermediate compound 7-[(3R)-3-(tert-butoxycarbonyl-amido)-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetralin-3-(trifluoromethyl)-1,2,4-triazole[4,3-a]pyrazol (compound (1)) which is prepared by condensing (R)-3-(tert-butoxycarbonyl-amido)-4-(2,4,5-trifluorophenyl)butyrate and 3-(trifluorophenyl)-5,6,7,8- tetralin-[1,2,4] triazol[4,3-a]pyrazine hydrochloride in the presence of a condensing agent and an acid-binding agent. The method can be used for preparing the high-purity high-yield compound (1) stably, has the advantages of stable process, simplicity and convenience in operation, short reaction time and the like, and is applicable to industrial production.
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Paragraph 0034-0035

(2017/05/26)

A process for preparing phosphoric acid sitagliptin-free method of inhibiting I
The present invention relates to a method for preparing an anhydrous crystal form I of sitagliptin phosphate. The method comprises: crystallizing by stirring a suspension of sitagliptin phosphate solid at a crystallization temperature, then separating the crystallized crystals, washing, and drying so as to obtain an anhydrous crystal form I of the sitagliptin phosphate, wherein the solvent for the suspension of the sitagliptin phosphate solid is selected from acetone or acetonitrile, or the solvent for the suspension of the sitagliptin phosphate solid is selected from a mixture of a C1-4 alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water. A single crystal form of sitagliptin phosphate in an anhydrous crystal form I can be prepared by the method of the present invention. The method facilitates the control of product quality and the establishment of a quality standard, and has advantages such as a simple and convenient crystallization process, mild reaction conditions, and a high product yield without a high temperature reaction for a long time.
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Paragraph 0066; 0068

(2018/11/03)

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)

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin
In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (?)-(R)-sitagliptin.
Bae, Han Yong,Kim, Mun Jong,Sim, Jae Hun,Song, Choong Eui
supporting information
p. 10825 - 10829
(2016/09/03)

For preparing sitagliptin intermediate and its preparation method and application (by machine translation)
The invention relates to the field of organic chemistry, in particular to a process for preparing a sitagliptin intermediate and its preparation method and application, the intermediate A has the following structure: Wherein R is hydrogen atom or (by machine translation)
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(2017/06/02)

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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(2016/12/16)

NOVEL INTERMEDIATES FOR PREPARING DPP-IV INHIBITORS, PREPARING METHOD THEREOF AND PREPARING METHOD OF DPP-IV INHIBITORS USING THE SAME
Disclosed are novel intermediates for use in preparing DPP-IV inhibitors, methods for preparing the same, and methods for preparing DPP-IV inhibitors using the same. Using the novel intermediates of the present invention, highly pure DPP-IV inhibitors can be produced in a simple and economical manner at a high yield.
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Paragraph 198-202

(2017/01/02)

Improved method of sitagliptin
The present invention relates to an improved method for manufacturing sitagliptin, comprising a step of preparing N-Boc protected sitagliptin using diphenyl phosphite suitable for mass production as a reagent and a deprotection step.
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Paragraph 0057; 0058; 0059; 0060

(2017/06/02)

Boronic acid-DMAPO cooperative catalysis for dehydrative condensation between carboxylic acids and amines
Arylboronic acid and 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO) cooperatively catalyse the dehydrative condensation reaction between carboxylic acids and amines to give the corresponding amides under azeotropic reflux conditions. This cooperative use is much more effective than their individual use as catalysts, and chemoselectively promotes the amide condensation of (poly)conjugated carboxylic acids. The present method is practical and scalable, and has been applied to the synthesis of sitagliptin and a drug candidate.
Ishihara, Kazuaki,Lu, Yanhui
p. 1276 - 1280
(2016/02/05)

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 0213

(2015/12/30)

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATE
The present invention provides a process for the preparation of sitagliptin. The present invention also provides a process for the preparation of tert-butyl [(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-yl]carbamate, an intermediate of sitagliptin.
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Page/Page column 10

(2015/12/08)

PROCESS FOR THE PREPARATION OF SITAGLIPTIN PHOSPHATE
The present invention relates to a method for the preparation of sitagliptin phosphate and sitagliptin phosphate anhydrous of Formula (I′) and monohydrate of Formula (I),
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Paragraph 0108; 0109

(2015/03/31)

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND INTERMEDIATE COMPOUNDS
There is provided a process for the preparation of sitagliptin or a pharmaceutically acceptable salt thereof, and a process for the preparation of intermediate compounds useful in the preparation of sitagliptin. In particular, there is provided a process comprising condensing 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid of formula (II) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine of formula (III) or a salt thereof in presence of a catalyst to obtain (R)-tert-butyl-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-yl-carbamate of formula (IV) or a pharmaceutically acceptable salt thereof. The catalyst is represented by the compound of formula (V). Compound of formula (IV) or its pharmaceutically acceptable salt obtained may be deprotected to obtain a compound of formula (I).
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Paragraph 0077; 0078

(2015/07/22)

AMORPHOUS FORM OF SITAGLIPTIN FREE BASE
The present invention provides an amorphous form of sitagliptin free base of Formula (I). The invention further provides a process for preparation of an amorphous form of sitagliptin free base. The process comprises a) providing a solution or suspension of sitagliptin free base in one or more solvents; and b) obtaining the amorphous form of sitagliptin free base by the removal of the solvent.(I)
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Paragraph 0088; 0089

(2015/09/23)

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
p. 7883 - 7886
(2014/08/05)

A METHOD OF PREPARING 3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)BUTANOIC ACID DERIVATIVES
The invention provides a new method of preparing 3-arnino-4-(2,4,5-trifluorophenyl)butanoic acid derivatives of general formula (1), which are mainly useful as advanced intermediates of some dipeptidyl peptidase-4 (DPP-4) inhibitors. Pg is a commonly used protecting group, especially t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl or trifluoroacetyl, and R is NR1R2, wherein R1 and R2 is the same or different substituent, which may be hydrogen, a substituted or unsubstituted C1-6 alkyl, or R1 together with R2 form a substituted or unsubstituted 4-, 5-, or 6-membered heterocyclic containing at least one nitrogen atom, especially a derivative of piperazine. The reaction is carried out using condensation reagent of general formula (3), wherein X is a halide anion, and the reaction is carried out in the environment of a polar organic solvent.
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Page/Page column 10

(2014/06/24)

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND INTERMEDIATE COMPOUNDS
There is provided a process for the preparation of sitagliptin or a pharmaceutically acceptable salt thereof, and a process for the preparation of intermediate compounds useful in the preparation of sitagliptin. In particular, there is provided a process comprising condensing 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II) with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of formula (III) or a salt thereof in presence of a catalyst to obtain (R)-tert-butyl-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-yl-carbamate of formula (IV) or a pharmaceutically acceptable salt thereof. The catalyst is represented by the compound of formula (V). Compound of formula (IV) or its pharmaceutically acceptable salt obtained may be deprotected to obtain a compound of formula (I).
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Page/Page column 16; 17

(2014/03/21)

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)

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)

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)

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
The present invention describes a process for the preparation of sitagliptin or its pharmaceutically acceptable salts of formula (1) comprising the steps of a) condensation of compound of formula (2), wherein R is amino protecting group with compound of formula (3), which may be used in its free base form or in a form of a salt in the presence of a coupling agent and a basic solvent that is N-methylimidazole to obtain the compound of formula (4), and b) deprotection of compound of formula (4) to obtain sitagliptin base that can be further transformed into its pharmaceutically acceptable salt. The process is cost effective, environmentally friendly, inexpensive and easily scaled up to commercial level.
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Page/Page column 13-14

(2013/03/26)

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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(2012/03/26)

PREPARATION METHOD OF INTERMEDIATE OF SITAGLIPTIN
The present invention provides a method which enables the simple, economical and high-yield production which is a key intermediate of antidiabetic drug Januvia.
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Page/Page column 4

(2012/08/07)

AN IMPROVED PROCESS FOR THE SYNTHESIS OF BETA AMINO ACID DERIVATIVES
The present invention is related to an improved process and intermediate(s) for the synthesis of beta amino acid derivatives of formula (I). The compounds of formula I act as DPP-IV inhibitors and are useful in the treatment of Type 2 diabetes
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Page/Page column 37-38

(2012/04/04)

PROCESS FOR THE PREPARATION OF A CHIRAL BETA AMINOACID DERIVATIVE AND INTERMEDIATES THEREOF
It comprises a process for the preparation of sitagliptin, or its pharmaceutically acceptable salts, or its solvates, including hydrates, comprising: a) coupling an halo-2,4,5-trifluorobenzene with a compound of formula (IV) to give N-protected sitagliptin; the coupling being carried out via the formation of an organocupric compound of the halo-2,4,5-trifluorobenzene or, alternatively, via the formation of a organozinc compound of a compound of formula (IV); where R1 is hydrogen or an amino protective group; R2 is an amino protective group; or alternatively R1 and R2 taken together form a phtalimido group; X is Br or I; and Y is Br, I or R3SO3- wherein R3 is (C1-C4)- alkyl, phenyl, or phenyl mono- or disubstituted by a (C1-C4)-alkyl radical; b) submitting the N-protected sitagliptin to a deprotection reaction; and c) optionally its conversion into a pharmaceutically acceptable salt. It also comprises new intermediate compounds useful in such preparation process.
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Page/Page column 23

(2010/09/17)

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 23-24

(2010/08/04)

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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Page/Page column 29

(2010/12/17)

The asymmetric synthesis of Sitagliptin, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
An efficient asymmetric synthesis of Sitagliptin, a new DPP-IV inhibitor for the treatment of type 2 diabetes mellitus has been developed. The beta-amino acid fragment of Sitagliptin was prepared by asymmetric Michael addition of the corresponding α, β-unsaturated ester to (R)-(α-methylbenzyl) benzylamine followed by a two-step elaboration to obtain N-boc beta-amino ester. Hydrolysis of the ester and coupling with the triazolopiperazine afforded Sitagliptin after cleavage of the N-boc group and salt formation. The overall yield was 31% over nine steps.
Liu, Feng,Yu, Wansheng,Ou, Wenhua,Wang, Xiaoke,Ruan, Libo,Li, Yiming,Peng, Xijiang,Tao, Xiaohu,Pan, Xianhua
experimental part
p. 230 - 232
(2010/08/04)

PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND ITS INTERMEDIATES
The present invention relates to novel and improved processes for the preparation of Sitagliptin compound of formula (1) and its intermediates.
-
Page/Page column 46-47

(2010/11/05)

PREPARATION OF SITAGLIPTIN INTERMEDIATE
Intermediate compounds in the synthesis of Sitagliptin, 3-amino-4-(2,4,5- trifluorophenyl)but-2-enoic acid alkyl ester, and amino protected-3-amino-4-(2,4,5- trifluorophenyl)but-2-enoic acid alkyl ester, and the stereoselective reduction of these compound to give Synthon I, or the amino-protected Synthon I, are provided.
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Page/Page column 17

(2009/06/27)

(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-amine: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (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-amine (1) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
Kim, Dooseop,Wang, Liping,Beconi, Maria,Eiermann, George J.,Fisher, Michael H.,He, Huaibing,Hickey, Gerard J.,Kowalchick, Jennifer E.,Leiting, Barbara,Lyons, Kathryn,Marsilio, Frank,McCann, Margaret E.,Patel, Reshma A.,Petrov, Aleksandr,Scapin, Giovanna,Patel, Sangita B.,Roy, Ranabir Sinha,Wu, Joseph K.,Wyvratt, Matthew J.,Zhang, Bei B.,Zhu, Lan,Thornberry, Nancy A.,Weber, Ann E.
p. 141 - 151
(2007/10/03)

Chemical Properties

Melting Point: 188-191 °C(Solv: toluene (108-88-3))
Density: 1.46±0.1 g/cm3(Predicted)
Solubility:Chloroform (Slightly, Heated), DMSO (Slightly), Ethyl Acetate (Slightly)
Storage Temp.:Refrigerator
PKA: 11.60±0.46(Predicted)
PSA: 92.84000
LogP: 3.72480

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Chemical Properties

Melting Point: 188-191 °C(Solv: toluene (108-88-3))

Density: 1.46±0.1 g/cm3(Predicted)

Solubility:Chloroform (Slightly, Heated), DMSO (Slightly), Ethyl Acetate (Slightly)

Storage Temp.:Refrigerator

PKA: 11.60±0.46(Predicted)

PSA: 92.84000

LogP: 3.72480

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