WO2015189862A1 - Amines chirales, procédé pour leur préparation et leur utilisation - Google Patents

Amines chirales, procédé pour leur préparation et leur utilisation Download PDF

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Publication number
WO2015189862A1
WO2015189862A1 PCT/IN2015/050040 IN2015050040W WO2015189862A1 WO 2015189862 A1 WO2015189862 A1 WO 2015189862A1 IN 2015050040 W IN2015050040 W IN 2015050040W WO 2015189862 A1 WO2015189862 A1 WO 2015189862A1
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amino
phenyl
nitro
chiral
compound
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PCT/IN2015/050040
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WO2015189862A4 (fr
Inventor
Nabin Chandra Barua
Bishwajit SAIKIA
Preetismita BORAH
Gakul Baishya
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Council Of Scientific & Industrial Research
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Publication of WO2015189862A1 publication Critical patent/WO2015189862A1/fr
Publication of WO2015189862A4 publication Critical patent/WO2015189862A4/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to chiral amine and a process for preparation thereof.
  • the present invention also relates to a one pot route process for the synthesis of chiral amino group compounds by the reduction of nitro olefins using chiral ligand.
  • the present invention particularly relates to a series of compounds containing chiral amino group that is used for the synthesis of Sitagliptin. More particularly, the present invention relates to the use of said compounds for the synthesis of potent antidiabetic drug Sitagliptin (a DPP-IV inhibitor).
  • Chiral amines have proven to be powerful pharmacophores for defining new pharmaceutical drugs.
  • Chiral primary amines are currently the reliable building blocks that chemists often turn to during the synthetic planning of an alkaloid, while medicinal chemists require them because they hold greater diversification potential verses secondary or tertiary chiral amine building blocks development of drug candidates.
  • the cinchona alkaloids were the first chiral amines to be used in asymmetric catalysis.
  • Chiral amines represent a powerful and useful means of accomplishing chemical transformations. Their diverse range of activity allows them to function as acids/bases, nucleophiles, and chiral promoters.
  • Enantiomerically pure amines play an important role in stereoselective organic synthesis. They are used as resolving agents, chiral auxiliaries and as building blocks in pharmaceuticals and other important bioactive molecules. They are frequently used as synthons for the preparation of various pharmaceutically active substances and agrochemicals, or as resolving agents for chiral acids.
  • a-Amino acids such as L-proline constitute a special class of chiral amines and are composing the main part of the chiral pool. The use of these compounds in enantioselective synthesis of pharmaceuticals, agrochemicals and several interesting natural products has been complied.
  • ⁇ -Amino Acids are components of many bioactive natural and synthetic products, such as the antitumor agents Taxol and cryptophycin, the msecticidal and antifungal agent jasplakinolide and arninopeptidase inhibitor bestatin. Synthetic ⁇ -Amino acids are also precursors of bioactive ⁇ -lactams. Reference may be made to following prior arts for the utilization of ⁇ -Amino Acids: a) Wam,M.C.;Taylor,H.L,;Wall,M.E
  • the main object of the present invention is to provide a one pot route process for the synthesis of chiral amino group compounds by the reduction of nitro olefins using chiral ligand.
  • Another object of the present invention relates to series of compounds containing chiral amino group that is used for the synthesis of Sitagliptin
  • Still another object of the present invention is to use the said compounds for the synthesis of potent antidiabetic drug Sitagliptin (a DPP-IV inhibitor).
  • Yet another object of the present invention is to provide a process for the preparation of (3R)-3-amino-l-[3 rifluoromethyl)-5,6-dihydro-[l,2,4]-triazolo-[4,3-(x]-pyrazine-7(8H)- yl]-4-(2,4,5-trifluorophenyl)-butane-l-one and intermediates thereof.
  • the present invention provides a process for the synthesis of chiral amines by the reduction of nitro olefins using chiral ligand wherein the said process comprises of following steps :- a) mixing under stirring anhydrous copper (II) fluoride, Josiphos catalyst in toluene for about 60-90 minutes followed by addition of PMHS, phenyl silane, water, and a nitro olefin having formula I with vigorous stirring, (formula I),
  • R COOMe, COOEt, or COO3 ⁇ 4u
  • step a) stirring the solution obtained in step a) for a time period in the range of 10-12 h, adding phenyl silane and continuing stirring for a time period in the range of 3-4 h; c) adding TBAF solution prepared in THF to the solution obtained in step b), stirring for a time period in the range of about 1-2 hour; d) adding water to the solution obtained in step c), extracting and drying with ether and Na 2 S0 4 and purifying the residue to obtain chiral amines having formula II and chiral nitro compounds having formula III, (formula II)
  • step f) adding HC1 dropwise to the solution of compound (formula II) obtained in step e) at a temperature of 25 to 27 °C and heating the mixture at reflux for a time period of 6 to 7 h followed by cooling to obtain compound having formula (IV) formula (IV).
  • the ratio of the Josiphos catalyst and CuF 2 used in step a) is 1: 1.
  • the present invention also provides a chiral amines prepared by the aforesaid process.
  • the percent yield of the chiral amine obtained is in the range of 85 to 88%.
  • the representative compounds prepared by the aforesaid process comprises of:- a) 3- -Amino-4- b) 3- -Amino-4- c) 3- -Amino-4- d) 3- -Amino-4- e) 3- -Amino-4- f) 3- -Amino-4- g) 3- -Amino-4- h) 3- -Amino-6- i) 3- -Amino-4-
  • the present invention also provides a process of preparing compound of formula I, by comprising dissolving compound of formula (V) in a solvents selected from DCM, DMF, toluene, ethyl acetate and a basic alumina followed by stirring at a temperature in the range of 25 to 27 °C for a time period in the range of 1 to 2 hours, purifying the product to obtain compound of the formula I, formula V,
  • R COOMe, COOEt, or COO3 ⁇ 4u
  • the present invention provides a process for preparation of sitagliptin using chiral amine wherein the process steps comprising: - a) dissolving compound (6) in solvents selected from DCM, DMF, toluene and ethyl acetate and in a basic alumina followed by stirring at a temperature in the range of 25 to 27 °C for a time period in the range of 1 to 2 hours, purifying the product to obtain compound (7a), b) mixing under stirring anhydrous copper (II) fluoride, Josiphos catalyst in toluene for 60 minutes followed by addition of PMHS, phenyl silane, water, nitro olefin with vigorous stirring,
  • step c) stirring the solution obtained in step b) for a time period of 12 h, adding phenyl silane and continuing stirring for a time period of 4 h, d) adding TBAF solution prepared in THF to the solution obtained in step c), stirring for a time period of about 1 hour,
  • step d adding water to the solution obtained in step d), extracting and drying with ether and Na 2 S0 4 and purifying the residue with flash chromatography to obtain chiral amines (8a),
  • step f) adding HC1 dropwise to the solution of compound (8a) obtained in step f) at a temperature of 25 to 27 °C and heating the mixture at reflux for a time period of 6 to 7 h followed by cooling to obtain compound (10), g) reacting 3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ajpyrazine, acid with compound (10) in the presence of solvents selected from ethanol, NMM and HOBt followed by cooling the contents and adding EDC, h) stirring the reaction mixture obtained in step g) at a temperature of 25 to 27 °C for a time period of 3 to 4 hr followed by addition of water, and i) isolating the product obtained in step h) via extractive workup with methanol (3 x 15 mL) and concentrated in vacuo followed by purification using chromatographic methods to obtain Sitagliptin.
  • chiral amine used is obtained from vinyl nitro compounds using Josiphos catalyst to obtain sitagliptin.
  • Scheme 1 Synthesis of chiral amino ester part of Sitagliptin. Reagents and conditions: (a) CH 3 NO 2 , NaOH, MeOH, rt; (b) NaBH 4 , CHC1 3 , Silica gel, z-PrOH, rt; (c) Ethyl gly oxalate, DBU, rt; (d) Ac 2 0, I 2 , rt; (e) Basic alumina, DCM, rt; (f) Josiphos catalyst, phenylsilane, PMHS, CuF 2 , rt; (g) H 2 , Pd-C, ethyl acetate, rt.
  • Scheme 2 Synthesis of different analogues chiral amino ester part of Sitagliptin. Reagents and conditions: (a) Josiphos catalyst, phenyl silane, PMHS, CuF 2 , rt; (b) H 2 , Pd-C, ethyl acetate, rt.
  • FIG. 1 Structures of Compounds synthesized.
  • Reagents and conditions (a) 2M HCl, reflux; (b) 3-Trifluoromethyl-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazine (A), EDC, Cat. HOBt, NMM, ethanol, rt.
  • the problem which the present invention proposes to solve is to obtain a novel route for the synthesis of chiral amine from vinyl nitro compound and its application for the synthesis of novel DPP IV inhibitor Sitagliptin.
  • Chiral amines (1°, 2° & 3°) are important target molecules owing to their extensive use and importance as potent pharmacophores.
  • Compounds containing chiral amine moiety is more active and plays a prominent role in biological activity.
  • it is a highly efficient route in bond formations among diverse building blocks for chemical synthesis.
  • the incretion mimetic and their related agents, the dipeptidyl peptidase-4 (DPP-IV) inhibitors are becoming important and potential agents in the treatment of type 2 diabetes i.e. the most common form of diabetes.
  • this process is applied to develop a novel route to Sitagliptin, the only DPP-IV inhibitors marketed in India will be an excellent discovery to the diabetologist's armamentarium.
  • the structural complexity and interesting biological activities of this natural product continue to attract the attention of chemists and biologists.
  • the structural characteristic of this natural product is the densely functionalized 3-amino-l-(3-trifluoromethyl-5,6-dihydro-8H[l,2,4]- triazolo-[4,3-a]-pyrazin-7-yl-3-amino-butan-l-one core arranged with a heavily substituted 2,4,5-trifluoro-phenyl ring which makes it a synthetically challenging molecule.
  • the present invention provides a process for the synthesis of chiral amines by the reduction of nitro olefins using chiral ligand wherein the said process comprises of following steps :- a) dissolving compound (6) in solvents selected from DCM, 20mL and basic alumina followed by stirring at a temperature in the range of to 25 to 27 C for a time period in the range of 1 to 2 hours, purifying the product with flash chromatography to obtain compound (7),
  • step b) stirring the solution obtained in step b) for a time period of 12 h, adding phenyl silane and continuing stirring for a time period of 4 h,
  • step d) adding TBAF solution prepared in THF to the solution obtained in step c), stirring for a time period of 1 hours,
  • step d adding water to the solution obtained in step d), extracting and drying with ether and Na 2 S0 4 and purifying the residue with flash chromatography to obtain chiral amines (8) and chiral nitro compounds (9),
  • step f) adding HC1 (other acids) dropwise to the solution of compound (8) obtained in step f) at a temperature of 25 to 27°C and heating the mixture at reflux for a time period of 6 to 7 h followed by cooling to obtain compound (10).
  • a process wherein one pot asymmetric reduction of both olefin and nitro groups of p-nitro-a,P-unsaturated ester to obtain Sitagliptin In another embodiment of the present invention a process wherein the percent yield of the chiral amine obtained is in the range of 85 to 88%. In yet another embodiment of the present invention a process wherein the ratio of the Josiphos catalyst and CuF2 used in step b) is 1 : 1.
  • the solvent used is selected from the group consisting of DCM, DMF, Toluene, ethyl acetate.
  • a process of preparation of sitagliptin using compound 8 wherein the process steps comprising in the following steps :- a) adding 3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine to the compound 10 in the presence of solvents selected from ethanol, NMM and HOBt followed by cooling the contents and adding EDC,
  • step b) stirring the reaction mixture obtained in step a) at a temperature of to 25 to 27 °C for a time period of 3 to 4h followed by addition of water, c) isolating the product obtained in step b) via extractive workup with methanol (3 x 15 mL) and then drying over anhydrous sodium sulphate and concentrated in vacuo followed by purification using flash column chromatography to obtain sitagliptin.
  • chiral amine used is obtained from vinyl nitro compounds using Josiphos catalyst to obtain sitagliptin.
  • Scheme 3 has been performed to complete the synthesis of ?-amino acid part of novel dipeptidyl peptidase-4 inhibitor Sitagliptin.
  • a series of (with different substrate Rl) different chiral amines was synthesized by using the Josiphos catalyst (Scheme 2).
  • the present invention provides (1) the application of a nitro aldol addition reaction for the preparation of ?-nitrostyrene from substituted aromatic and aliphatic aldehydes by performed the reaction using sodium hydroxide as base in methanol, (2) reduction of conjugated double bond with sodium borohydride and silica gel in CHC1 3 and iso-propanol mixture (5: 1) afforded intermediate nitroethane, (3) the compound was subjected to Henry's nitro aldol reaction with ethyl glyoxaldehyde using l,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as base to give 2- nitroalcohol, (4) then, the nitro aldol product was treated with acetic anhydride in presence of molecular iodine as catalyst to give the acetate derivative, (5) elimination of acetic acid from nitro acetate derivative using basic alumina in dichloromethane solvent afforded the nitro
  • the next embodiment of the present invention is to synthesize Sitagliptin 1, the only DPP-IV inhibitor, which is even more demanding (Scheme 4). Ester hydrolysis and peptide coupling completed the synthesis of Sitagliptin.
  • the subject of the present invention is products corresponding to the general formula Ri-X-R, wherein the functional moiety X represents chiral amine part, R represents ester part (EtCOO) and finally Ri represents different substituted aliphatic and aromatic aldehydes.
  • the compound 2 is commercially available in the market and purchased from Sigma, Aldrich. Synthesis of jff-nitrostyrene compound [1, 2, 4-trifluoro-5-(2-nitro-vinyl)-benzene] (3):
  • ⁇ -nitrostyrene (3) (5 g, 24.63 mmol) was dissolved in iPrOH (1 g) and CHC1 3 (20 mL) with silica gel (1 g) and to this system sodium borohydride (1.86 g, 49.26 mmol, 2 equv) was added over 1 ⁇ 2 h at 27 °C.
  • Dilute HCL 25 mL was added to decompose the excess NaBH 4
  • the reaction mixture was stirred at 27 °C, and the advancement of the reaction was observed by TLC (1:9, Ethyl acetate/Hexane). When the reaction was completed, the reaction mixture was filtered.
  • Nitroalkane (9) (0.039 g, 0.133 mmol) was dissolved in the ethyl acetate (5 mL) and the solution was added to the resin-10% Pd/C (0.009 g, x mmol) in a 500 mL pyrex glass bottle. After that, the bottle was placed in a parr apparatus and after flushing with argon and hydrogen, hydrogenation was started under pressure (50 psi) for 5 h in 27 °C, without stirring. After completion of the reaction, the resin was filtered off and washed with ethyl acetate (3 x 10 mL).
  • Reagents and conditions (a) 2M HCl, reflux; (b) 3-Trifluoromethyl-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3-a]pyrazine (A), EDC, Cat. HOBt, NMM, ethanol, rt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne la synthèse générale d'une amine chirale à partir de composés vinyliques nitrés à l'aide d'un catalyseur Josiphos. Le procédé est appliqué pour développer une nouvelle voie vers la sitagliptine (un inhibiteur de la DPP-IV).
PCT/IN2015/050040 2014-06-10 2015-06-03 Amines chirales, procédé pour leur préparation et leur utilisation WO2015189862A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106892832A (zh) * 2017-03-14 2017-06-27 珠海联邦制药股份有限公司 一种西格列汀杂质及其制备方法
US10385004B2 (en) * 2015-02-13 2019-08-20 Novartis Ag Process and intermediates for the preparation of NEP inhibitors
CN115403277A (zh) * 2022-07-15 2022-11-29 张文文 一种透明防紫外线玻璃砖及其制备方法

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WO2009064476A1 (fr) * 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Préparation d'un intermédiaire de sitagliptine
WO2010122578A2 (fr) * 2009-04-20 2010-10-28 Msn Laboratories Limited Procédé de préparation de la sitagliptine et de ses intermédiaires
EP2308829A1 (fr) * 2008-07-23 2011-04-13 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation de dérivés de l acide r-bêta-amino phénylbutyrique
EP2594557A1 (fr) * 2009-05-28 2013-05-22 Novartis AG Dérivés aminopropioniques substitués en tant qu'inhibiteurs de néprilysine
WO2013114173A1 (fr) * 2012-01-30 2013-08-08 Smilax Laboratories Limited Nouveau procédé de préparation de sitagliptine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009064476A1 (fr) * 2007-11-13 2009-05-22 Teva Pharmaceutical Industries Ltd. Préparation d'un intermédiaire de sitagliptine
EP2308829A1 (fr) * 2008-07-23 2011-04-13 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation de dérivés de l acide r-bêta-amino phénylbutyrique
WO2010122578A2 (fr) * 2009-04-20 2010-10-28 Msn Laboratories Limited Procédé de préparation de la sitagliptine et de ses intermédiaires
EP2594557A1 (fr) * 2009-05-28 2013-05-22 Novartis AG Dérivés aminopropioniques substitués en tant qu'inhibiteurs de néprilysine
WO2013114173A1 (fr) * 2012-01-30 2013-08-08 Smilax Laboratories Limited Nouveau procédé de préparation de sitagliptine

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WEI ZHU ET AL: "Preparation of syn -[delta]-Hydroxy-[beta]-amino Esters via an Intramolecular Hydrogen Bond Directed Diastereoselective Hydrogenation. Total Synthesis of (3 S ,4a S ,6 R ,8 S )-Hyperaspine", ORGANIC LETTERS, vol. 5, no. 26, 1 December 2003 (2003-12-01), US, pages 5063 - 5066, XP055219698, ISSN: 1523-7060, DOI: 10.1021/ol036097m *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10385004B2 (en) * 2015-02-13 2019-08-20 Novartis Ag Process and intermediates for the preparation of NEP inhibitors
CN106892832A (zh) * 2017-03-14 2017-06-27 珠海联邦制药股份有限公司 一种西格列汀杂质及其制备方法
CN115403277A (zh) * 2022-07-15 2022-11-29 张文文 一种透明防紫外线玻璃砖及其制备方法

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