CN104860939A - Cinchona alkaloids compound and preparation method thereof - Google Patents

Cinchona alkaloids compound and preparation method thereof Download PDF

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Publication number
CN104860939A
CN104860939A CN201510167980.9A CN201510167980A CN104860939A CN 104860939 A CN104860939 A CN 104860939A CN 201510167980 A CN201510167980 A CN 201510167980A CN 104860939 A CN104860939 A CN 104860939A
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compound
reaction
preparation
formula
mol ratio
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廖霞俐
张伟
任玉峰
杨健
杨波
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Kunming University of Science and Technology
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Kunming University of Science and Technology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D453/00Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18Bridged systems

Abstract

The invention discloses a cinchona alkaloids compound with a new macrocyclic structure, and a preparation method thereof. The cinchona alkaloids compound is prepared with cinchona alkaloids quinidine as a substrate. According to the preparation method, quinidine is subjected to a halogen cyclization reaction, such that the new macrocyclic structure is obtained. Related derivatives can be obtained through the changes on the C11-locus. The cinchona alkaloids compound provided by the invention can be used as a novel chiral catalyst or a ligand. The preparation method is simple, and yield is high.

Description

A kind of cinchona alkaloid compound and preparation method thereof
Technical field
The invention belongs to organic chemistry filed, be specifically related to a kind of to there is cinchona alkaloid compound of new macrocyclic structure and preparation method thereof.
Background technology
Quinine (Cinchona alkaloids) is the natural alkaloid that a class is found in Peruvian bark bark and Gen Pi, mainly comprises quinine, Quinidine, cinchonine and cinchonine and determines.Quinine has important biological activity, as heat resistanceheat resistant, antimalarial etc., is once used widely.Meanwhile, quinine is applied to various catalyzed reaction particularly in asymmetry catalysis as a kind of important catalyzer and part in chemosynthesis.Due to the chiral molecules structure of the uniqueness that this compounds has, the various catalyzer designed for parent with it, all achieve outstanding progress in fields such as chiral primary amine catalysis, thiocarbamide catalysis, base catalysis and phase-transfer catalysiss in recent years.
But, focus mostly in converting its certain group to the structure of modification that quinine carries out, quaternized etc. in the substitution reaction on such as 9-position hydroxyl, rubane nitrogen-atoms, and the transformation of its skeleton structure particularly rubane seldom related to.Therefore, its skeleton structure is transformed, obtain novel cinchona alkaloid compound for enriching the type of such catalyzer and expanding its range of application and there is important Theory and applications be worth.
Summary of the invention
The object of the present invention is to provide a kind of cinchona alkaloid compound with new macrocyclic structure, its structural formula is such as formula shown in I:
Wherein, R is the corresponding compd A of I(), the corresponding compd B of H() or the corresponding Compound C of OH().
In the present invention, the preparation of compd A is obtained by the synthesis of halogen cyclization, be dissolved in anhydrous acetonitrile by Quinidine, then salt of wormwood is added, add iodine under ice bath and stir 3 ~ 4 h, after TLC detection reaction terminates, react with the cancellation of hyposulfurous acid sodium water solution, aqueous phase dichloromethane extraction 3 ~ 4 times, merge organic phase, after using water and saturated common salt water washing successively, dry, filter, evaporated under reduced pressure, purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=40/1 ~ 7/1, v/v) compound that R is I is obtained, wherein Quinidine, salt of wormwood, the mol ratio of iodine is 1:3:3 ~ 1:4:4,
In the present invention, use reductive agent to carry out de-hydroiodination to compd A to obtain, be dissolved in dried toluene by compd A, then reductive agent reduction treatment is used, after TLC monitoring reaction terminates, evaporated under reduced pressure, purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=9/1 ~ 4/1, v/v) compd B is obtained after, reductive agent reduction treatment refers to Pd/C-hydrogen reducing or tri-butyl tin hydride/Diisopropyl azodicarboxylate reduction, when wherein adopting tri-butyl tin hydride/Diisopropyl azodicarboxylate reduction, reaction conditions is 110 ~ 120 DEG C of back flow reaction 24 h, compd A, tri-butyl tin hydride (n-Bu 3snH), the mol ratio of Diisopropyl azodicarboxylate (AIBN) is 1:2:0.4 ~ 1:2:0.5, when adopting Pd/C-hydrogen reducing, at room temperature react 10 ~ 12 h, compd A and Pd/C(palladium carbon) the mixture of mol ratio to be 3.2:1 ~ 3.5:1(Pd/C be palladium and gac, activeconstituents is palladium, mass percentage is 10%, calculates with the gauge of the palladium contained in palladium carbon).
In the present invention, the preparation of Compound C is by carrying out the substitution reaction of compd A, namely under condition of ice bath, lithium aluminum hydride is added in dried tetrahydrofuran (THF) and mix, then compd A is added, question response becomes not too acutely and moves to stirred at ambient temperature reaction 2 ~ 3 h, after TLC monitoring reacts completely, add the sodium hydroxide solution cancellation reaction that mass percent concentration is 15%, filter, extraction, extract is through silica gel column chromatography (trichloromethane/methyl alcohol=7/1 ~ 4/1, v/v) Compound C is obtained after purifying, wherein the mol ratio of compd A and lithium aluminum hydride is 1:10 ~ 1:15.
The advantage of the inventive method and technique effect: present method with a kind of common quinine Quinidine for raw material, utilize simple, easy-operating reactions steps, can obtain a kind of cinchona alkaloid compound with novel macrocyclic structure, this compound can be used as chiral catalyst and part is applied in organic synthesis.
Accompanying drawing explanation
Fig. 1 is the mass spectrum of compd A in the present invention;
Fig. 2 is the mass spectrum of compd B in the present invention;
Fig. 3 is the mass spectrum of Compound C in the present invention.
Embodiment
Further method described in the present invention is described below by embodiment; but scope does not limit by embodiment; the reagent that the reagent used in the present embodiment is conventional commercial reagent if no special instructions or prepares according to a conventional method, the method for use is ordinary method if no special instructions.
Embodiment 1: structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is I.
The preparation method of above-claimed cpd is as follows:
Take Quinidine 50 mg(0.154 mmol, 1 eq) be placed in the single port bottle of 25 mL, add 10 mL anhydrous acetonitriles to dissolve, 63.8 mg salt of wormwood (0.46 mmol are added again in solution, 3 eq), iodine 116.7 mg(0.46 mmol is added under ice bath, 3 eq), mixture stirs 3 hours under ice bath, after TLC detection reaction terminates, react with the cancellation of hyposulfurous acid sodium water solution, aqueous phase 30 mL dichloromethane extraction three times, merge organic phase, after using water and saturated common salt water washing successively, anhydrous magnesium sulfate drying, filter, evaporated under reduced pressure, purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=10/1, v/v), obtain faint yellow waxy solid product and be compd A (Fig. 1).
Embodiment 2: structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is I.
The preparation method of above-claimed cpd is as follows:
Take Quinidine 50 mg(0.154 mmol, 1 eq) be placed in the single port bottle of 25 mL, add 10 mL anhydrous acetonitriles to dissolve, 85.7mg salt of wormwood (0.62 mmol is added again in solution, 4eq), iodine 157.4 mg(0.62 mmol is added under ice bath, 4eq), mixture stirs 4 hours under ice bath, after TLC detection reaction terminates, react with the cancellation of hyposulfurous acid sodium water solution, aqueous phase 30 mL dichloromethane extraction 4 times, merge organic phase, after using water and saturated common salt water washing successively, anhydrous magnesium sulfate drying, filter, evaporated under reduced pressure, purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=20/1, v/v), obtain faint yellow waxy solid product and be compd A.
Embodiment 3: structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is H.
The preparation method of above-claimed cpd is as follows:
Take 50 mg(0.11 mmol, 1 eq) above-claimed cpd A, be placed in the single port flask of 25 mL, the toluene adding 10 mL dryings dissolves, under agitation slowly be added dropwise to tri-butyl tin hydride 62 mg(0.22 mmol, 2 eq) and Diisopropyl azodicarboxylate 7 mg(0.044 mmol, 0.4 eq), heat 120 DEG C of back flow reaction 24 hours, after TLC monitoring reaction terminates, evaporated under reduced pressure, purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=4/1, v/v), obtain faint yellow solid and be compd B (Fig. 2).
Compd B can as the catalyzer of N-Nitrosoaldol reaction, and specific examples is as follows:
In the reaction flask of 25 mL, add nitrosobenzene (107 mg, 1 mmol), then add the CHCl of 4mL 3, be stirred well to dissolving, then add the cyclohexyl ketone (10 times of equivalents) of compd B (16.2 mg, 0.05 mmol) and 1mL, after reacting 2 h under room temperature, use saturated NH 4the cancellation of Cl solution is reacted, and aqueous phase is extracted with ethyl acetate 3 times, and merge organic phase, with anhydrous magnesium sulfate drying, evaporated under reduced pressure solvent, crude product purification by silica gel column chromatography (ethyl acetate and hexane system) obtains 182.4 mg, yield 89%.
Embodiment 4: structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is H.
The preparation method of above-claimed cpd is as follows:
Take 50 mg(0.11 mmol) above-claimed cpd A, be placed in the single port flask of 25 mL, the toluene adding 10 mL dryings dissolves, under agitation add Pd/C(36.4 mg, the mass content of palladium is 10%, 0.034 mmol), in reaction system, pass into hydrogen, 12 h are reacted under room temperature, after TLC monitoring reaction terminates, evaporated under reduced pressure, purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=7/1, v/v), obtain faint yellow solid and be compd B.
Embodiment 5: structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is OH.
The preparation method of above-claimed cpd is as follows:
Take lithium aluminum hydride 42 mg(1.1 mmol, 10 eq), be placed in 25 mL single port flasks, under ice cooling, 4, anhydrous tetrahydro furan 10 mL is added dropwise to wherein with dropping funnel, and stirring makes it abundant mixing, then 50 mg(0.11 mmol are got, 1 eq) compd A, dissolve with 5 mL anhydrous tetrahydro furans, slowly reaction solution is instilled under ice bath, and continue to be stirred under ice bath no longer acutely, react 2 hours under moving to room temperature, TLC monitors reaction after substrate complete reaction, instillation adds the sodium hydroxide solution that mass percent concentration is 15% wherein, treat that solution becomes clarification by muddiness, filter by it, after filtrate reduced in volume, extraction into ethyl acetate, and by extract with purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=7/1), obtain white powdery solids and be Compound C (Fig. 3).
Embodiment 6: structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is OH.
The preparation method of above-claimed cpd is as follows:
Take lithium aluminum hydride 62.7mg(1.65 mmol, 15 eq), be placed in 25 mL single port flasks, under ice cooling, 4, anhydrous tetrahydro furan 10 mL is added dropwise to wherein with dropping funnel, and stirring makes it abundant mixing, then 50 mg(0.11 mmol are got, 1 eq) compd A, dissolve with 5 mL anhydrous tetrahydro furans, slowly reaction solution is instilled under ice bath, and continue to be stirred under ice bath no longer acutely, react 3 hours under moving to room temperature, TLC monitors reaction after substrate complete reaction, instilling mass percent concentration is wherein the sodium hydroxide solution of 15%, treat that solution becomes clarification by muddiness, filter by it, after filtrate reduced in volume, extraction into ethyl acetate, and by extract with purification by silica gel column chromatography (eluent: trichloromethane/methyl alcohol=4/1), obtain white powdery solids and be Compound C.

Claims (4)

1. structural formula is such as formula the cinchona alkaloid compound shown in I:
Wherein, R is I, H or OH.
2. the preparation method of cinchona alkaloid compound according to claim 1, it is characterized in that: when in formula I, R is I, obtained by the synthesis of halogen cyclization, be dissolved in anhydrous acetonitrile by Quinidine, then salt of wormwood is added, add iodine under ice bath and stir 3 ~ 4 h, after TLC detection reaction terminates, react with the cancellation of hyposulfurous acid sodium water solution, aqueous phase dichloromethane extraction 3 ~ 4 times, merge organic phase, after using water and saturated common salt water washing successively, dry, filter, evaporated under reduced pressure, purifying obtains the compound that R is I, wherein Quinidine, salt of wormwood, the mol ratio of iodine is 1:3:3 ~ 1:4:4.
3. the preparation method of cinchona alkaloid compound according to claim 1, it is characterized in that: when in formula I, R is H, use reductive agent to carry out de-hydroiodination to the compound that R is I to obtain, be that the compound dissolution of I is in dried toluene by R, then reductive agent reduction treatment is used, after TLC monitoring reaction terminates, evaporated under reduced pressure, obtains the compound that R is H after purifying; Wherein, reductive agent reduction treatment refers to tri-butyl tin hydride/Diisopropyl azodicarboxylate reduction or Pd/C-hydrogen reducing, when adopting tri-butyl tin hydride/Diisopropyl azodicarboxylate reduction, the mol ratio of the compound of reaction conditions to be 110 ~ 120 DEG C of back flow reaction 24 h, R be I, tri-butyl tin hydride, Diisopropyl azodicarboxylate is 1:2:0.4 ~ 1:2:0.5; When adopting Pd/C-hydrogen reducing, at room temperature react 10 ~ 12 h, R is the compound of I and the mol ratio of Pd/C is 3.2:1 ~ 3.5:1.
4. the preparation method of cinchona alkaloid compound according to claim 1, it is characterized in that: when in formula I, R is OH, carry out substitution reaction to the R compound that is I to obtain, namely under condition of ice bath, lithium aluminum hydride is added in dried tetrahydrofuran (THF) and mix, then the compound that R is I is added, question response becomes not too acutely and moves to stirred at ambient temperature reaction 2 ~ 3 h, after TLC monitoring reacts completely, add the sodium hydroxide solution cancellation reaction that mass percent concentration is 15%, filter, extraction, extract obtains the compound that R is OH after purification by silica gel column chromatography, wherein R is the compound of I and the mol ratio of lithium aluminum hydride is 1:10 ~ 1:15.
CN201510167980.9A 2015-04-10 2015-04-10 Cinchona alkaloids compound and preparation method thereof Pending CN104860939A (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105457675A (en) * 2016-01-20 2016-04-06 大连理工大学 6-hydroxyl quinine quaternary ammonium salt asymmetric phase transfer catalyst, preparation method and application of 6-hydroxyl quinine quaternary ammonium salt asymmetry phase transfer catalyst
CN105498736A (en) * 2016-02-04 2016-04-20 河南科技学院 Chiral stationary phase prepared by taking quinindium-t-butyl carbamate as chirality selector as well as preparation method and application of chiral stationary phase
CN105561959A (en) * 2016-02-04 2016-05-11 河南科技学院 Chiral stationary phase prepared by taking quinine-tertiary butyl carbamate as a chiral selector and preparation method and application of chiral stationary phase
CN105642261A (en) * 2016-02-04 2016-06-08 河南科技学院 Chiral stationary phase prepared with cinchonine-Boc-amide as chiral selector and preparation method and application thereof
CN105732387A (en) * 2016-04-14 2016-07-06 大连理工大学 Novel method for asymmetric alpha-hydroxylation of photo-oxygenation beta-dicarbonyl compound based on C-2' phase transfer catalyst
CN105749890A (en) * 2016-02-04 2016-07-13 河南科技学院 Chiral stationary phase prepared by taking cinchonidine-boc-amide as chiral selector as well as preparation method and application thereof
WO2024034767A1 (en) * 2022-08-11 2024-02-15 고려대학교 산학협력단 Method for producing nitrogen-selective chiral aldol reaction product of nitroso compound using organic chiral catalyst compound

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105457675A (en) * 2016-01-20 2016-04-06 大连理工大学 6-hydroxyl quinine quaternary ammonium salt asymmetric phase transfer catalyst, preparation method and application of 6-hydroxyl quinine quaternary ammonium salt asymmetry phase transfer catalyst
CN105498736A (en) * 2016-02-04 2016-04-20 河南科技学院 Chiral stationary phase prepared by taking quinindium-t-butyl carbamate as chirality selector as well as preparation method and application of chiral stationary phase
CN105561959A (en) * 2016-02-04 2016-05-11 河南科技学院 Chiral stationary phase prepared by taking quinine-tertiary butyl carbamate as a chiral selector and preparation method and application of chiral stationary phase
CN105642261A (en) * 2016-02-04 2016-06-08 河南科技学院 Chiral stationary phase prepared with cinchonine-Boc-amide as chiral selector and preparation method and application thereof
CN105749890A (en) * 2016-02-04 2016-07-13 河南科技学院 Chiral stationary phase prepared by taking cinchonidine-boc-amide as chiral selector as well as preparation method and application thereof
CN105732387A (en) * 2016-04-14 2016-07-06 大连理工大学 Novel method for asymmetric alpha-hydroxylation of photo-oxygenation beta-dicarbonyl compound based on C-2' phase transfer catalyst
CN105732387B (en) * 2016-04-14 2019-03-05 大连理工大学 The method of novel C -2` phase transfer catalyst photooxidation beta-dicarbonyl compound asymmetry 'alpha '-hydroxylation
WO2024034767A1 (en) * 2022-08-11 2024-02-15 고려대학교 산학협력단 Method for producing nitrogen-selective chiral aldol reaction product of nitroso compound using organic chiral catalyst compound

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