CN107522585A - A kind of hydrogenation method for splitting of quinoline kind axle chirality compound - Google Patents

A kind of hydrogenation method for splitting of quinoline kind axle chirality compound Download PDF

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CN107522585A
CN107522585A CN201610446190.9A CN201610446190A CN107522585A CN 107522585 A CN107522585 A CN 107522585A CN 201610446190 A CN201610446190 A CN 201610446190A CN 107522585 A CN107522585 A CN 107522585A
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substrate
racemic
quinolines
phosphoric acid
compound
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CN107522585B (en
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周永贵
王杰
陈木旺
孙蕾
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Dalian Institute of Chemical Physics of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • 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
    • 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
    • C07D215/06—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 having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • 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
    • C07D215/16—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 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 ring carbon atoms
    • C07D215/20—Oxygen atoms
    • 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

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

Abstract

A kind of hydrogenation method for splitting of quinoline kind axle chirality compound, what it was used is chiral phosphoric acid, the transfer hydrogenation system of Hantzsch esters.Quinoline kind axle chirality compound (enantiomeric excess is up to 99%), and tetrahydroquinoline kind axle chirality compound (enantiomeric excess is up to 97%) can be obtained by this method, coefficient is split and can reach S=209.The present invention can realize that catalysis is split, and operation is simple, and catalyst commercially available, mild condition, energy consumption is low, and environment-friendly and fractionation coefficient is high, and yield is good.

Description

A kind of hydrogenation method for splitting of quinoline kind axle chirality compound
Technical field
Realize what quinoline kind axle chirality compound was split by the acid catalyzed transfer hydrogenation of chiral phosphorus the present invention relates to a kind of Method.
Background technology
Axial chirality compound occupies very important status (bibliography one in organic synthesis and commercial Application：(a) Bringmann,G.；Gulder,T.；Gulder,T.A.M.；Breuning,M.Chem.Rev.2011,111,563.(b) Kozlowski,M.C.；Morgan,B.J.；Linton,E.C.Chem.Soc.Rev.2009,38,3193.(c)Tang,W.； Zhang,X.Chem.Rev.2003,103,3029.).Therefore, synthesis axial chirality compound has great importance.However, mesh The preceding method for obtaining axial chirality compound is mainly to pass through traditional chemical resolution, cross-coupling, oxidative coupling, desymmetrization, Dynamic Kinetic Resolution, the methods of Kinetic Resolution.And be directed to for the method for Kinetic Resolution, mainly using bromination, Carbon-hydrogen bond activation, it is acylated, the methods of reduction amination.(bibliography two：(a)Miyaura,N.；Suzuki, A.Chem.Rev.1995,95,2457.(b)Broutin,P.E.；Colobert,F.Org.Lett.2003,5,3281.(c) Mulrooney,C.A.；Li,X.；DiVirgilio,E.S.；Kozlowski,M.C.J.Am.Chem.Soc.2003,125, 6856.(d)Guo,Q.-X.；Wu,Z.-J.；Luo,Z.-B.；Liu,Q.-Z.；Ye,J.-L.；Luo,S.-W.；Cun,L.-F.； Gong,L.-Z.J.Am.Chem.Soc.2007,129,13927.(e)Gao,D.-W.；Gu,Q.；You,S.-L.ACS Catal.2014,4,2741.(f)Ma,G.；Deng,J.；Sibi,M.P.Angew.Chem.Int.Ed.2014,53,11818. (g)Lu,S.；Poh,S.B.；Zhao,Y.Angew.Chem.Int.Ed.2014,53,11041.).It is real by hydrogenated aromatic heterocycle There is presently no report for the method that existing axial chirality compound is split.
Transfer hydrogenation is as a kind of gentle hydro genation system (bibliography three：(a)Rueping,M.；Antonchick, A.P.；Theissmann, T.Angew.Chem.Int.Ed.2006,54,3683.), energy consumption is low, and environment-friendly, Wo Menshe Can think by realizing the fractionation of axial chirality compound to the method for aromatic heterocycle transfer hydrogenation.
The content of the invention
It is an object of the invention to provide a kind of transfer hydrogenation by aromatic heterocycle to realize quinolines racemic axial chirality The method that compound is split.Present invention practicality easy to operate, coefficient height is split, yield is good, and energy consumption is low and reaction has environment friend The advantages that good.
To achieve the above object, technical scheme is as follows：
The present invention is hydrogen source with chiral phosphoric acid catalyst, Hantzsch esters, realizes quinolines racemic axial chirality compound Hydrogenation split, reaction equation and condition are as follows：
In formula：
Temperature：30-60℃；
Pressure：Normal pressure；
Solvent：Organic solvent；
Time：20-24 hours；
Hydro genation system：Chiral phosphoric acid (CPA), HEH (Hantzsch esters)；
The R1, R2, R3, R4, R5For C1-C10 alkyl, C1-C10 alkoxy, phenyl and the phenyl ring containing substituent, Substituent on phenyl ring is-CH3、-OCH3In a kind of substituent；
Ar in described chiral phosphoric acid (CPA) is the phenyl ring of phenyl and substituted base, or-SiPh3。
Reactions steps are：
Under nitrogen protection, substrate quinolines racemic axial chirality compound and chiral phosphoric acid are added in reaction bulb (in formula 1 Substrate dosage 5%), Hantzsch esters (1.2eq. of substrate dosage in formula 1), add 3.0 milliliters of dichloromethane, react 20- 24 hours.Directly column chromatography for separation can obtain pure axial chirality substrate and product after rotation removes solvent.
Substrate quinolines racemic axial chirality compound and the mol ratio of Hantzsch esters are 1 in reaction:1.2, substrate quinoline The molar ratio of quinoline class racemic axial chirality compound and catalyst is 20:1.Reaction organic solvent used is benzene, dichloromethane Alkane, 1,4- dioxane, methanol, tetrahydrofuran.
When substrate quinolines racemic axial chirality compound amount is 0.1-0.15mmol, the dosage of organic solvent is 2.0-3.0 milliliter；
Generally, when substrate quinolines racemic axial chirality compound amount is 0.15mmol, the dosage of organic solvent is 3.0 milliliter；When substrate quinolines racemic axial chirality compound amount is 0.1mmol, the dosage of organic solvent is 2.0 millis Rise.
The catalyst chiral phosphoric acid and organic solvent are commercially available and without any processing, and Hantzsch esters can To be obtained by cheap diketone, ammonium acetate and formalin one-step synthesis.
The present invention has advantages below
1. reactivity and enantioselectivity are high, and it is high to split coefficient.
2. various quinoline kind axle chirality compounds and tetrahydroquinoline kind axle chirality compound can be obtained.
3. catalyst commercially available, operation is easy.
4. reaction condition is gentle, energy consumption is low.
Embodiment
The present invention is described in detail below by embodiment, but the present invention is not limited to following embodiments.
Embodiment 1：The optimization of condition
Under nitrogen protection, substrate quinolines racemic axial chirality compound (0.1mmol) and chirality are added in reaction bulb Phosphoric acid (5mol% of substrate dosage in formula 1), Hantzsch esters (1.2eq. of substrate dosage in formula 1), 3.0 milliliters of addition are molten Agent, react 20-24 hours.Directly column chromatography for separation can obtain pure axial chirality substrate and product after rotation removes solvent.Reaction equation and tool Body structure is as follows：
Conversion ratio (C) is the theoretical yield calculated according to the enantiomeric excess (ee) of recovery raw material and product, and recovery is former The enantiomeric excess (ee) of material and product is determined with Chiral liquid chromatography (HPLC), splits coefficient (S) by formula S=ln [(1-C) (1-ee1)]/ln[(1-C)(1+ee1)], C=ee1/(ee1+ee2) be calculated.Refer to table 1.
The optimization that the quinoline kind axle chirality hydrogenation of compounds of table 1. is splita
aConditions:1 (0.1mmol), CPA (5.0mol%), HEH (0.12mol), solvent (2.0mL), 30 ℃,20-24hb Determined by HPLC.cS=ln [(1-C) (1-ee1)]/ln[(1-C)(1+ee1)], C=ee1/(ee1 +ee2).
Embodiment 2：Transfer hydrogenation splits various quinoline kind axle chirality compoundsa
Under nitrogen protection, substrate quinolines racemic axial chirality compound (0.15mmol) and chirality are added in reaction bulb Phosphoric acid (5mol% of substrate dosage in formula 1), Hantzsch esters (1.2eq. of substrate dosage in formula 1), add 3.0 milliliters of dichloros Methane, react 20-24 hours.Directly column chromatography for separation can obtain pure axial chirality substrate and product after rotation removes solvent.Reaction equation is such as Under：
Yield (yield) is separation yield, and the enantiomeric excess (ee) for reclaiming raw material and product uses Chiral liquid chromatography (HPLC) determine, split coefficient (S) and be calculated by formula.See formula 1.
The transfer hydrogenation of formula 1. splits various quinoline kind axle chirality compoundsa
The present invention successfully realizes the fractionation of quinolines racemic axial chirality compound using transfer hydrogenation, can obtain quinoline Kind axle chirality compound (enantiomeric excess is up to 99%), and (enantiomeric excess is reachable for tetrahydroquinoline kind axle chirality compound 97%), split coefficient and can reach S=209.The present invention can realize that catalysis is split, and operation is simple, and catalyst business can , mild condition, energy consumption is low, environment-friendly and fractionation coefficient is high, and yield is good.

Claims (6)

1. a kind of hydrogenation method for splitting of quinoline kind axle chirality compound, what it was used is chiral phosphoric acid, and Hantzsch esters turn Hydro genation system is moved, reaction equation and condition are as follows：
In formula：
Temperature：30-60℃；
Pressure：Normal pressure；
Solvent：Organic solvent；
Time：20-24 hours；
Hydro genation system：Chiral phosphoric acid (CPA), HEH (Hantzsch esters)；
The R1, R2, R3, R4, R5For C1-C10 alkyl, C1-C10 alkoxy, phenyl and the phenyl ring containing substituent, phenyl ring On substituent be-CH3、-OCH3In a kind of substituent；
Ar in described chiral phosphoric acid (CPA) is the phenyl ring of phenyl and substituted base, or-SiPh3；Substituent on phenyl ring For 3-CH3C6H4, 4-FC6H4In one kind or two kinds.
2. the method as described in claim 1, it is characterised in that：
Reactions steps are：Under nitrogen protection, substrate quinolines racemic axial chirality compound and chiral phosphorus are added in reaction bulb Sour (5mol% of substrate dosage in formula 1), Hantzsch esters (1.2eq. of substrate dosage in formula 1), add dichloromethane, reaction 20-24 hours；Directly column chromatography for separation can obtain pure axial chirality substrate and product after rotation removes solvent.
3. the method as described in claim 1, it is characterised in that：In reaction substrate quinolines racemic axial chirality compound and The mol ratio of Hantzsch esters is 1:1.2, mole of substrate quinolines racemic axial chirality compound and catalyst chiral phosphoric acid Ratio is 20:1.
4. the method as described in claim 1, it is characterised in that：Reaction organic solvent used is benzene, dichloromethane, 1,4- bis- One or two or more kinds in the ring of oxygen six, methanol, tetrahydrofuran.
5. the method as described in claim 1 or 4, it is characterised in that：
When substrate quinolines racemic axial chirality compound amount is 0.1-0.15mmol, the dosage of organic solvent is 2.0- 3.0 milliliter.
6. method as claimed in claim 1 or 2, it is characterised in that：The reaction equation is quinolines racemic axial chirality chemical combination The transfer hydrogenation of thing is split, and solvent is dichloromethane, and temperature is 30 DEG C, the R of Hantzsch esters4For OCH3, R5For CH2CH2CH3, The Ar of chiral phosphoric acid is C6H5When, the result is optimal.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111170949A (en) * 2018-11-09 2020-05-19 中国科学院大连化学物理研究所 Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation
CN114751866A (en) * 2022-04-28 2022-07-15 南昌航空大学 3,3' -biquinazolinone compound containing N-N chiral axis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001159A (en) * 2014-04-23 2015-10-28 中国科学院大连化学物理研究所 Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105001159A (en) * 2014-04-23 2015-10-28 中国科学院大连化学物理研究所 Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by chiral phosphoric acid

Non-Patent Citations (1)

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Title
GAOYUAN MA等: "Catalytic kinetic resolution of biaryl compounds", 《CHEMISTRY-A EUROPEAN JOURNAL》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111170949A (en) * 2018-11-09 2020-05-19 中国科学院大连化学物理研究所 Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation
CN111170949B (en) * 2018-11-09 2021-07-27 中国科学院大连化学物理研究所 Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation
CN114751866A (en) * 2022-04-28 2022-07-15 南昌航空大学 3,3' -biquinazolinone compound containing N-N chiral axis

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