EP3041824A1 - Procédé de préparation d'amines et d'alcools chiraux cycliques par arylation catalytique intramoléculaire de substrats d'acide boronique, d'ester aldéhydes et d'imine - Google Patents

Procédé de préparation d'amines et d'alcools chiraux cycliques par arylation catalytique intramoléculaire de substrats d'acide boronique, d'ester aldéhydes et d'imine

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Publication number
EP3041824A1
EP3041824A1 EP14772447.0A EP14772447A EP3041824A1 EP 3041824 A1 EP3041824 A1 EP 3041824A1 EP 14772447 A EP14772447 A EP 14772447A EP 3041824 A1 EP3041824 A1 EP 3041824A1
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EP
European Patent Office
Prior art keywords
chiral
process according
formula
catalyst
previous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP14772447.0A
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German (de)
English (en)
Inventor
Anthony Burke
Carolina SILVA MARQUES
Daniela Alexandra SILVA PEIXOTO
Hugo Ricardo MATOS VIANA
Albertino João BRITO GOTH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universidade de Evora
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Universidade de Evora
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present application refers to a catalytic intramolecular arylation process to afford cyclic chiral alcohols or amines.
  • Cyclic chiral amines and alcohols are a renowned group of organic molecules, due to the fact that many show important biological activity.
  • Current industrial methods for preparing such molecules are limited to asymmetric hydrogenations , which reduce structural diversity in the target compound, and entail significant infra-structure investment for large-scale production.
  • cyclic chiral amines and alcohols have been shown to be biologically active. 45% of molecules that chemists are developing into drugs contain a chiral amine unit (Ritter, 2013), and many of these chiral amines in turn are cyclic, well known examples include: rivastagimine, rasagline, sertraline, indatraline (Hyttel and Larsen, 1985) cetirizine and cromakilm etc.
  • cyclic alcohol unit cycloalkanol
  • some examples include, compound PH46A which is currently under clinical trials for inflammatory bowel diseases (Business concentrate C&EN, 2013), 4-hydroxy-l-tetralone, which is a natural products obtained from Ampelocera edentula showing activity against cutaneous leishmaniasis (Fournet et al . , 1994), this unit is also present in a variety of other natural products like: catalponol and epicatalponol (Inouye et al . 1975), isocatalponol (Briekskorn and Pohlmann, 1975) junglanoside A (Liu et al . 2004) and isohinanolone (Anh et al . 1997) .
  • Enzymatic transamination has been used for the synthesis of ( S) -rivastigmine (Fuchs et al . 2012) .
  • an advanced ketone intermediate using the D-transaminase from Paracoccus denitrificans.
  • Biotransformation processes are becoming more and more frequent for accessing new drug compounds, but issues such as reactor dilution, and the limited enantiospecifity of enzymes (generally only give one of the enantiomers, of an enantiomeric pair) make such methods less advantagous .
  • Rhodium catalysts have also been used for the same purpose, a Rh-bisphosphine catalyst was used in an asymmetric intramolecular hydroarylation of ketones in 2012 (Sarpong and Gallego, 2012) .
  • Rh- complexes based on chiral sulfinamide-alkene, TADDOL- derived phosphoramidite and diene ligands for the intramolecular arylation of ketones (including hindered ketones) to give 5-, 6- and 7-membered aza-, oxocycloalkanols with very good enantioselectivities (Low et al. 2012) .
  • the present invention provides a new efficient catalytic process which involves the cyclization of a novel catalytic intramolecular arylation process that involves boronic acid or ester aldehydes and imines to afford cyclic alcohols or amines.
  • this invention provides a procedure for the preparation of important biologically active molecules, for instance those used for the treatment of neurodegenerative diseases, such as Alzheimer's (Rivastagimine) , Parkinson's (Rasagline) , Depression (Sertraline, (+) -indatraline) , as well as in inflammatory disorders (Cetirizine) , inflammatory bowel diseases (PH46A) and other chronic diseases such as congenital heart failure (Cromakilm) , cancer and various infectious diseases as well.
  • neurodegenerative diseases such as Alzheimer's (Rivastagimine) , Parkinson's (Rasagline) , Depression (Sertraline, (+) -indatraline) , as well as in inflammatory disorders (Cetirizine) , inflammatory bowel diseases (PH46A) and other chronic diseases such as congenital heart failure (Cromakilm) , cancer and various infectious diseases as well.
  • the reaction yields are good and the obtained enantioselectivities are promising.
  • the reaction is atom- economically, sustainable and its principle advantage is its inherent capacity for product structural diversity generation, and thus has immense potential for preparing multiple-libraries of interesting and useful biologically active molecules.
  • the boronic acid or ester aldehydes and imine substrates used in the process are prepared from simple commercial raw materials by efficient processes, some of which are catalytic themselves (for example, the borylation step) .
  • the cyclization reactions can be run at temperatures of between 0°C and 100°C using a variety of chiral catalysts or non-chiral catalysts and enantioselectivities of up to 80% could be achieved.
  • the present application describes a novel process for the catalytic intramolecular arylation of the substrates of formula (I) and formula (II) for the preparation of the products of formula (VI) and formula (VII), respectively, comprising the use of a suitable metal catalyst, wherein the reaction is conducted by adding the preformed catalyst or by forming the catalyst in situ, from a pre-catalyst and a ligand, in the presence of a base.
  • the preformed catalyst is prepared by adding the ligand to the pre-catalyst in a suitable dry solvent, under an inert atmosphere and allowing the mixture to stir up to 24h, in a temperature range from 20 to 100°C.
  • the pre-catalyst used is selected from the group comprising catalysts Rh based, Ru based, Pd based, Copper based, cobalt based and iron based.
  • reaction solvent used is selected from the group comprising: THF, diethyl ether, dioxane, dichloromethane, chloroform, DMF, DMA and NMP .
  • the ligand used is a chiral or a non-chiral ligand.
  • the chiral ligand is selected from the group comprising chiral diphosphane, diphosphorous and monophosphane type ligands, comprising P,N types ligands, chiral NHCs and dienes, chiral sulfinamide-alkene ligands and oxazoline based ligands.
  • the non-chiral ligand is selected from the group comprising achiral bi-phosphanes and derivatives.
  • the reactions are run under an inert atmosphere (e.g. under dry nitrogen or argon) .
  • reaction temperature ranges between the room temperature and 100°C.
  • the present application provides a catalytic intramolecular arylation process that involves boronic acid or ester aldehydes and imine substrates to afford cyclic chiral alcohols or amines (Scheme 1) .
  • the substrates can be described by the formulae (I) and (ID , in which
  • X represents CH or N and its position can vary from position-2, -3, -4 or -5,
  • Y can be, CR 2 2 or 0, NR 2 (where R 2 represents a hydrogen, a saturated alkyl, or cycloalkyl group, or an aryl group) , COZ (where Z can be NHR 2 or NR 2 2 , 0, or S) the position of Y can vary along the side chain where it is present,
  • R represents a hydrogen, or a saturated or unsaturated alkyl, or cycloalkyl group, or an aryl group, and there can be up to four (4) of these substituents present in any one molecule, as well as representing a fused cyclic system (either aliphatic or aromatic) on any of the open faces of the main aromatic unit (benzene or pyridine ring) ,
  • R 1 represents a hydrogen, a saturated alkyl, or cycloalkyl group, or an aryl group,
  • R 3 represents an alkyl group or cycloalkyl group
  • R 4 represents either an alkyl or aryl sulfinyl group, an alkyl or aryl sulfonyl group, an alkyl or aryl ester group, an alkyl or aryl phosphinoyl group, a 2-, 4- or 6- chloropyridyl group or a alkyl or arylsulfamoyl group (Crampton et al . , 2013) and it can be also chiral and enantiopure (Weix et al . 2005),
  • R 4 represents a hydrogen, or a saturated or unsaturated alkyl, or cycloalkyl group, or an aryl group.
  • the substrates of formula (I) are obtained from simpler substrates using common literature methods (Viana et al . 2013) (Scheme 1) .
  • Bromide or iodide precursors can be used, with a preference for the cheaper bromides.
  • the best strategy is shown in Scheme 1 .
  • the borylation step can be achieved via literature methods, and generally relies on the use of a Pd catalyst like Pd(OAc) 2 (Miyaura, 2008, Zenk and Partzsch, 2003) .
  • Pd(OAc) 2 Some specific examples are shown in Scheme 2 , starting with o-iodophenol.
  • PCC (2 equiv.), Celite (4 equiv.), dry DCM (0.2M), room temp., 2h under N 2 .
  • Speci f ic examples o f compounds o f formula ( I ) are shown below .
  • the amine containing compounds are obtained via mono- alkylation of appropriate aniline substrates, followed by borylation and then reduction (the order of these steps can be exchanged (Peixoto et al . 2013) ) .
  • Substrates of formula (II) are obtained from substances of formula (III) via azotropic addition of a reagent of formula N3 ⁇ 4R 3 in the presence of a Lewis acid catalysis (for example BF 3 -Et20) using common literature methods (Marques and Burke 2011, Marques 2013, Pettrini and Torregiani, 2007) (Scheme 3) .
  • a Lewis acid catalysis for example BF 3 -Et20
  • Scheme 3 common literature methods
  • (II) is obtained from a substance of formula (I) .
  • the substances of formula (I) and (II) can be obtained from the boronic acid/ester acetal with the formula (IV) via simple deprotection/hydrolysis with mineral acids (e.g. aqueous H 2 SO 4 , HC1, phosphoric acid, Dowex resins etc) or aqueous Lewis acids (e.g. T1CI 4 , FeCl 3 , titanium isopropoxide etc) (Peixoto et al . 2013) (Scheme 4) .
  • mineral acids e.g. aqueous H 2 SO 4 , HC1, phosphoric acid, Dowex resins etc
  • aqueous Lewis acids e.g. T1CI 4 , FeCl 3 , titanium isopropoxide etc
  • R 5 represents an alkyl group or cycloalkyl group.
  • substrates of formula (I) are transformed to products of formula (VI) (Scheme 7) using a suitable metal catalyst under the conditions described below, and in the case of (II), a product of formula (VII) (Scheme 7) using a suitable metal catalyst under the conditions described below (Marques and Burke 2011, D.W. low et al . 2012, K. Kurihara 2009) .
  • chiral ligands these were generally commercial chiral diphosphane, or diphosphorous or monophosphane type ligands, including P,N types (like; BINAP and derivatives (including fluorine containing derivatives like DiFluorPhos ) , DIOP, DIPAMP, DioxPhos, DeguPhos, Xylyl-P-Phos , (R) -Phanephos, (R) -ShiP, (R) - SIPHOS, ⁇ R, R) -Chiraphos, C 3 -TunePhos, TangPhos, BINAPINE , BINAPHANE, PhanePhos, Synphos, DuanPhos, Walphos, Josiphos, Naud, SchmalzPhos (Robert et al .
  • P,N types like; BINAP and derivatives (including fluorine containing derivatives like DiFluorPhos ) , DIOP, DIPAMP, Di
  • diphosphine ligands Some of the diphosphine ligands used are listed below:
  • the pre-catalyst that were used were generally: Rh based, like [Rh (C 2 H 4 ) 2 C1] 2, Rh(acac) (C 2 H 4 ) 2 , Rh(acac) (coe) 2 , Rh(acac) (eth) 2 or Rh(NHCs) (Marques and Burke, 2013); Ru based, like, [RuCl 2 (i7 6 -p-cymene) ] 2 , RuCl 3 .xH 2 0, RuCl 2 (PPh 3 ) 3 , [Ru (benzene) Cl 2 ] 2 , [RuCl 2 (COD) ] n or RuNHCs (Marques and Burke, 2012); Pd based, like, Pd-diphosphanes (Marques and Burke, 2010), Pd(OAc) 2 , PEPPSI-iPr catalyst,
  • the pre-formed catalysts are generally prepared by adding the ligand to the pre-catalyst (from 0 . 5 mmol to 1 mmol, in equimolar quantities) in a suitable dry solvent (vide inferior) under an inert atmosphere and allowing the mixture to stir for up to 24 h in a temperature range from 2 0 to 1 00°C.
  • a suitable dry solvent vide inferior
  • the following reaction solvents can be used: THF (with water as co-solvent) , diethyl ether, dioxane (with water as co-solvent), dichloromethane, chloroform, DMF, DMA, NMP .
  • the reactions could be performed with 0.1 to 1 mmol of substrate.
  • the reactions were run under an inert atmosphere (e.g. under dry nitrogen or argon) .
  • the formation of the cyclic amine can also be achieved via forming the activated boronic acid/ester imine substrate in situ from either the aldehyde or acetal precursor.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé catalytique qui implique la cyclisation d'un nouveau procédé d'arylation intramoléculaire catalytique qui implique des substrats d'acide boronique ou d'ester aldéhydes ou d'imines, de formules (I) et (II), pour donner des alcools ou des amines chiraux cycliques de formules respectives (VI) et (VII). La présente invention concerne également la préparation des substrats de formules (I) et (II) à partir de matières premières commerciales simples par des procédés efficaces, certains d'entre eux étant catalytiques.
EP14772447.0A 2013-09-03 2014-09-01 Procédé de préparation d'amines et d'alcools chiraux cycliques par arylation catalytique intramoléculaire de substrats d'acide boronique, d'ester aldéhydes et d'imine Ceased EP3041824A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PT10713913 2013-09-03
PCT/IB2014/064179 WO2015033261A1 (fr) 2013-09-03 2014-09-01 Procédé de préparation d'amines et d'alcools chiraux cycliques par arylation catalytique intramoléculaire de substrats d'acide boronique, d'ester aldéhydes et d'imine

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EP3041824A1 true EP3041824A1 (fr) 2016-07-13

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PT109101B (pt) * 2016-01-22 2020-09-29 Universidade De Évora Novo processo para a preparação de 2-halo-piridinas e analógos 3-substituidos

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IL141690A (en) 2001-02-27 2004-06-20 Isp Finetech Ltd Process for preparation of rasagiline and its salts
WO2009147430A1 (fr) 2008-06-02 2009-12-10 Generics [Uk] Limited Procédé pour la préparation d’amines énantiomériquement pures

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