CN113980028B - Preparation method of chiral spiro indolone compound - Google Patents

Preparation method of chiral spiro indolone compound Download PDF

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CN113980028B
CN113980028B CN202111283033.8A CN202111283033A CN113980028B CN 113980028 B CN113980028 B CN 113980028B CN 202111283033 A CN202111283033 A CN 202111283033A CN 113980028 B CN113980028 B CN 113980028B
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preparation
hydrogen
indolone
chiral spiro
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CN113980028A (en
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钟芳锐
王丹桂
戴志锋
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Longgang Research Institute Of Zhejiang University Of Technology Co ltd
Huazhong University of Science and Technology
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Huazhong University of Science and Technology
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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
    • C07D487/10—Spiro-condensed systems
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0239—Quaternary ammonium compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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Abstract

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of a chiral spiro indolone compound. The invention provides a simple and efficient method for synthesizing chiral spiro indolone compounds, and has the characteristics of simple and convenient operation, mild conditions, easy enlargement of reaction scale, cheap and easy preparation of catalyst, high yield and stereoselectivity and the like.

Description

Preparation method of chiral spiro indolone compound
Technical Field
The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of chiral spiro indolone compounds.
Background
Chiral spiro indolone compounds are widely present in natural products and drug molecules, and have abundant drugs and biological activities, such as anticancer, anti-HIV, anti-malaria and other activities, so the chiral spiro indolone compounds have important application values, and chemists are actively researching novel methods for efficiently constructing chiral frameworks. For example, lewis acid catalyzed 1, 3-dipolar cycloaddition of 3-alkenyl indolinones to azomethine ylides build 3,3' -pyrrolidine spirocyclic indolinone backbones; nucleophilic phosphine catalyzed cyclization reaction to construct 3-cyclopentene spiro indolone derivative. Despite the great progress made in their synthesis, there has been no report to date on the construction of such compounds by intramolecular asymmetric oxidative coupling.
In recent years, a chiral catalytic system combining chiral iodide salt and peroxide has made a certain progress in carbonyl alpha-oxidative coupling reaction, but no report on preparation of chiral spiro indolone compounds by chiral quaternary ammonium iodide salt catalytic oxidative coupling reaction has been provided so far. Under the background, the development of a novel method for synthesizing the chiral spiro indolone derivative by catalytic oxidation of the chiral iodide salt is of great significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a simple and efficient method for synthesizing the chiral spiro indolone compound, and has the characteristics of simple and convenient operation, mild conditions, easy enlargement of reaction scale, cheap and easy preparation of a catalyst, high yield, high stereoselectivity and the like.
In order to realize the technical purpose, the technical scheme of the invention is as follows:
a preparation method of chiral spiro indolone compounds comprises the steps of taking compounds containing active hydrogen functional groups derived from indolone as raw materials, taking quaternary ammonium iodide salt derived from cinchona alkaloid as a catalyst, taking peroxide as an oxidant, and carrying out intramolecular carbonyl alpha-asymmetric oxidative coupling reaction in an organic solvent to obtain the chiral spiro indolone compounds.
The indolone derivative compound containing active hydrogen functional groups has the following structure:
Figure SMS_1
wherein R is 1 Is hydrogen, halogen, alkyl, alkoxyA radical, benzyl, ester or aryl;
R 2 is hydrogen, alkyl or benzyl;
R 3 hydrogen, halogen, alkyl, alkoxy;
XH is functional group containing active hydrogen, and is amino, phenolic hydroxyl or carboxyl protected with sulfonyl.
The cinchona alkaloid derived quaternary ammonium iodide salt has a structure shown in a formula (I) or a formula (II):
Figure SMS_2
wherein R is 4 Is hydrogen or alkoxy;
R 5 is saturated branched or straight-chain alkane.
The peroxide is one of hydrogen peroxide, cumene hydroperoxide or tert-butyl alcohol peroxide, and the preferred peroxide is the cumene hydroperoxide.
The organic solvent is one of n-propyl acetate, ethyl acetate, dimethyl carbonate or toluene, and is preferably n-propyl acetate.
The amount of the catalyst is 3-10% of the molar amount of the raw materials, and the preferable amount is 3%.
The peroxide is used in an amount of 3 equivalents based on the molar amount of the raw material.
The reaction temperature was 20 ℃.
The reaction time is 12-24h, preferably 12h.
Furthermore, the preparation method is added with an additive, and the additive adopts a molecular sieve.
The amount of the additive is 0.4g/mol compared with the base material.
The technical scheme is that a compound which is derived from indolone and contains active hydrogen functional groups is used as a substrate, quaternary ammonium iodide salt which is derived from cinchona alkaloid is used as a catalyst, peroxide is used as an oxidant, a molecular sieve is used as an additive, an organic solvent is used as a reaction medium, and the spiro indolone compound with optical activity can be obtained through intramolecular carbonyl alpha-oxidative coupling reaction.
The reaction mechanism of the reaction process is as follows:
Figure SMS_3
the quinine derived quaternary ammonium iodide salt catalyst generates hypoiodate or hypoiodate species in situ under the oxidation of peroxide, and is used as an actual reaction active species to oxidize a substrate to form an N-I intermediate, and the N-I intermediate passes through intramolecular S N 2 reacting to obtain a chiral product; in the case of steric induction, on the one hand, there may be a tight ion pairing between the rigid quaternary ammonium unit and the indolone enol anion, and even an induction of hydrogen bonding between the catalyst secondary alcohol and the substrate sulfonyl group. Further, a water molecule is one of the reaction products, and as the water molecule is increased, the reaction is gradually slowed down until equilibrium is formed. The molecular sieve has good water absorption, and simultaneously, the molecular sieve is settled to the bottom as solid particles, and the molecular sieve does not influence a liquid-phase reaction system, along with the addition of the molecular sieve, water molecules are continuously absorbed by the molecular sieve, so that the whole reaction is carried out towards the direction of producing the water molecules, the reaction efficiency is improved, and the product yield is improved.
From the above description, it can be seen that the present invention has the following advantages:
1. the method provided by the invention has the characteristics of simple and convenient operation, mild conditions, easy enlargement of reaction scale, cheap and easy preparation of the catalyst, high yield, high stereoselectivity and the like.
2. The synthesis method has high enantioselectivity and yield, and provides a widely applicable method for constructing chiral spiro indolone compounds.
3. The starting materials related to the synthetic method are all industrial commodities, are simple and easy to obtain, and have wide sources.
Detailed Description
The present invention is described in detail with reference to examples, but the present invention is not limited to the claims.
A preparation method of chiral spiro indolone compounds takes compounds containing active hydrogen functional groups derived from indolone as substrates, quaternary ammonium iodide salts derived from quinine as catalysts, peroxides as oxidants, molecular sieves as additives, organic solvents as reaction media, and the chiral spiro indolone compounds with optical activity can be obtained through intramolecular carbonyl alpha-oxidation coupling reaction, wherein the reaction general formula is as follows:
Figure SMS_4
wherein:
R 1 is hydrogen, halogen, alkyl, alkoxy or benzyl, ester group or aryl;
R 2 is hydrogen, alkyl or benzyl;
R 3 hydrogen, halogen, alkyl, alkoxy;
XH is functional group containing active hydrogen, and is amino, phenolic hydroxyl or carboxyl protected with sulfonyl.
The organic solvent adopts n-propyl acetate.
The quinine-derived quaternary ammonium iodide salt catalyst is N-dodecyl quinine iodide.
The peroxide is cumene hydroperoxide.
The per-additive is
Figure SMS_5
And (3) a molecular sieve.
The amount of the catalyst used was 3% of the molar amount of the substrate. The peroxide was used in an amount of 3 equivalents based on the molar amount of the substrate. The described
Figure SMS_6
The amount of molecular sieve used was 0.4g/mol.
The reaction temperature was 20 ℃.
The reaction time was 12 hours.
Example 1
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_7
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 20.3mg), catalyst (1.5 x 10 mg) -3 mmol)，
Figure SMS_8
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 99% isolated yield with e.r. value of 88.5.
Nuclear magnetic analysis: 1 H NMR(600MHz,CDCl 3 )δ7.80(d,J＝8.3Hz,2H),7.33(td,J＝ 7.7,1.0Hz,1H),7.24–7.19(m,3H),7.19–7.13(m,2H),7.00–6.95(m,2H),6.91(d,J＝7.8Hz,1H),6.89(t,J＝7.5Hz,1H),3.72(d,J＝15.7Hz,1H),3.34(s,3H), 3.17(d,J＝15.7Hz,1H),2.37(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ176.0(s), 144.2(s),142.6(s),141.7(s),136.6(s),130.7(s),129.9(s),129.6(s),128.2(s),128.1(s),127.4(s),125.2(s),123.1(s),123.0(s),122.6(s),112.5(s),108.9(s),71.7 (s),42.0(s),27.0(s),21.7(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝16.6min,t minor ＝13.5min)；e.r.＝88.5:11.5。
Example 2
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_9
to a 25 mL round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 21.7mg), catalyst (1).5*10 -3 mmol)，
Figure SMS_10
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 91% isolated yield with an e.r. value of 92.
Nuclear magnetic analysis: 1 H NMR(400MHz,CDCl 3 )δ7.84(d,J＝8.2Hz,2H),7.31(t,J＝ 7.7Hz,1H),7.24–7.12(m,5H),7.01–6.95(m,2H),6.92(d,J＝7.9Hz,1H),6.88 (t,J＝7.5Hz,1H),3.80–3.80(m,1H),3.77–3.66(m,2H),3.16(d,J＝15.6Hz, 1H),2.37(s,3H),1.88–1.76(m,2H),1.04(t,J＝7.4Hz,3H)； 13 C NMR(101MHz, CDCl 3 )δ175.9(s),144.2(s),142.1(s),141.8(s),136.7(s),131.1(s),129.8(s),129.6 (s),128.3(s),128.1(s),127.4(s),125.2(s),123.0(s),122.9(s),122.6(s),112.5(s),109.1(s),71.8(s),42.4(s),42.3(s),21.7(s),20.7(s),11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝40.0min,t minor ＝11.7min)；e.r.＝92:8。
Example 3
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_11
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 24.1mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_12
Molecular sieves (20 mg), 5ml n-propyl acetate, most preferablyThen, cumene hydroperoxide (0.15mmol, 26.5. Mu.L) was added thereto. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quench and extract three times with ethyl acetate (5 ml x 3), combine the organic phases and use anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 94% isolated yield with an e.r. value of 86.
Nuclear magnetic analysis: 1 H NMR(600MHz,CDCl 3 )δ7.87(d,J＝8.2Hz,2H),7.45(d,J＝ 7.6Hz,2H),7.35(t,J＝7.6Hz,2H),7.31–7.25(m,2H),7.22(d,J＝8.2Hz,2H),7.21–7.16(m,3H),7.00(t,J＝7.3Hz,2H),6.86(td,J＝7.6,0.7Hz,1H),6.73(d,J ＝7.9Hz,1H),5.11(d,J＝15.8Hz,1H),5.02(d,J＝15.8Hz,1H),3.80(d,J＝15.5Hz,1H),3.23(d,J＝15.6Hz,1H),2.38(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ 176.1(s),144.2(s),141.8(s),141.5(s),136.6(s),135.6(s),130.8(s),129.7(s),129.6(s),128.9(s),128.3(s),128.2(s),127.7(s),127.4(s),127.3(s),125.2(s), 123.2(s),123.0(s),122.4(s),112.5(s),110.0(s),71.9(s),44.7(s),42.7(s),21.7(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝27.5min,t minor ＝18.4min)；e.r.＝86:14。
Example 4
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_13
to a 25 ml round bottom flask equipped with magnetons were added successively the substrate (0.05mmol, 19.6 mg), the catalyst (1.5 x 10) -3 mmol)，
Figure SMS_14
Molecular sieves (20 mg), 5mL n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L). The reaction mixture was stirred at 20 ℃ for 12 hours. Reaction junctionAfter completion of the reaction, saturated Na was used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 94% isolated yield with an e.r. value of 88.
Nuclear magnetic analysis: 1 H NMR(400MHz,DMSO)δ10.77(s,1H),7.69(d,J＝8.3Hz, 2H),7.33(d,J＝8.2Hz,2H),7.30–7.23(m,2H),7.23–7.14(m,2H),7.01(td,J＝7.3,1.2Hz,1H),6.93(d,J＝7.7Hz,1H),6.82(t,J＝7.5Hz,1H),6.75(d,J＝7.1Hz, 1H),3.52(d,J＝16.2Hz,1H),3.22(d,J＝16.3Hz,1H),2.35(s,3H)； 13 C NMR(101 MHz,DMSO)δ176.7(s),144.3(s),141.1(s),141.0(s),136.0(s),130.5(s),129.7(s),129.6(s),127.9(s),127.5(s),127.4(s),125.4(s),122.9(s),122.5(s),122.0(s), 111.8(s),110.4(s),71.4(s),41.6(s),21.0(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝41.3min,t minor ＝19.3min)；e.r.＝88:12。
Example 5
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_15
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 22.4 mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_16
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The crude product obtained is passed through a columnPurification by chromatography gave the product as a white solid in isolated yield of 94%, e.r. value 90.
Nuclear magnetic analysis: 1 H NMR(400MHz,CDCl 3 )δ7.75(d,J＝8.3Hz,2H),7.30(d,J＝ 8.1Hz,1H),7.23–7.13(m,4H),7.08(d,J＝7.7Hz,1H),6.99(t,J＝7.4Hz,1H),6.81(d,J＝8.0Hz,1H),6.66(s,1H),3.88–3.77(m,1H),3.75–3.64(m,2H),3.14 (d,J＝15.7Hz,1H),2.36(s,3H),2.11(s,3H),1.86–1.76(m,2H),1.03(t,J＝7.4 Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ175.7(s),144.0(s),141.9(s),139.7(s), 136.8(s),132.4(s),130.5(s),130.0(s),129.5(s),128.1(s),127.5(s),125.2(s),123.5(s),122.9(s),112.6(s),108.9(s),77.5(s),77.2(s),76.8(s),71.6(s),42.4(s), 42.3(s),21.6(s),20.9(s),20.7(s),11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝46.5min,t minor ＝9.5min)；e.r.＝90:10。
Example 6
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_17
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 23.2mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_18
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 91% isolated yield with an e.r. value of 92.
Nuclear magnetismAnd (3) analysis: 1 H NMR(400MHz,CDCl 3 )δ7.84(d,J＝8.3Hz,2H),7.24–7.17 (m,3H),7.17–7.11(m,2H),6.97(t,J＝7.3Hz,1H),6.87(d,J＝8.2Hz,1H),6.49(d,J＝2.1Hz,1H),6.34(dd,J＝8.2,2.1Hz,1H),3.86–3.77(m,4H),3.73–3.63 (m,2H),3.13(d,J＝15.6Hz,1H),2.37(s,3H),1.86–1.76(m,2H),1.03(t,J＝7.4 Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ176.4(s),161.4(s),144.1(s),143.6(s), 141.7(s),136.7(s),129.6(s),128.2(s),128.0(s),127.4(s),125.2(s),123.4(s), 123.2(s),122.9(s),112.5(s),106.2(s),97.3(s),77.5(s),77.2(s),76.8(s),71.6(s),55.7(s),42.4(s),42.4(s),21.7(s),20.7(s),11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝69.1min,t minor ＝16.9min)；e.r.＝92:8。
Example 7
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_19
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 25.6 mg), catalyst (1.5X 10) -3 mmol)，
Figure SMS_20
Molecular sieves (20 mg), 5mL n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L). The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 88% isolated yield with an e.r. value of 72.
Nuclear magnetic analysis: 1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝8.3Hz,2H),7.24(d,J＝ 8.1Hz,2H),7.20–7.12(m,3H),7.06(d,J＝1.5Hz,1H),7.03–6.95(m,2H),6.86 (d,J＝7.9Hz,1H),3.86–3.77(m,1H),3.74–3.62(m,2H),3.13(d,J＝15.7Hz,1H),2.38(s,3H),1.86–1.75(m,2H),1.04(t,J＝7.4Hz,3H)； 13 C NMR(101MHz, CDCl 3 )δ175.8(s),144.4(s),143.4(s),141.6(s),136.5(s),130.0(s),129.7(s),128.3 (s),128.2(s),127.1(s),125.7(s),125.3(s),123.8(s),123.5(s),123.1(s),112.6(s),112.5(s),71.4(s),42.6(s),42.2(s),21.7(s),20.6(s),11.5(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝34.7min,t minor ＝11.8min)；e.r.＝72:28。
Example 8
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_21
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 22.4 mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_22
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quenching was performed, followed by three extractions with ethyl acetate (5 ml x 3), the organic phases were combined and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 97% isolated yield with an e.r. value of 90.
Nuclear magnetic analysis: 1 H NMR(600MHz,CDCl 3 )δ7.84(d,J＝8.3Hz,2H),7.30(td,J＝ 7.8,1.1Hz,1H),7.22(d,J＝8.2Hz,2H),7.04(s,1H),7.02(d,J＝7.5Hz,1H),6.98(d,J＝6.8Hz,1H),6.91(d,J＝7.8Hz,1H),6.87(t,J＝7.5Hz,1H),6.79(d,J＝7.5 Hz,1H),3.87–3.80(m,1H),3.74–3.69(m,1H),3.67(d,J＝15.4Hz,1H),3.10(d, J＝15.4Hz,1H),2.38(s,3H),2.31(s,3H),1.86–1.78(m,2H),1.04(t,J＝7.4Hz, 3H)； 13 C NMR(151MHz,CDCl 3 )δ175.8(s),144.1(s),142.0(s),142.0(s),138.2 (s),136.8(s),131.1(s),129.7(s),129.6(s),128.2(s),124.8(s),124.5(s),123.7(s),122.9(s),122.6(s),113.4(s),109.1(s),72.1(s),42.4(s),42.0(s),21.9(s),21.7(s), 20.7(s),11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝46.5min,t minor ＝9.5min)；e.r.＝90:10。
Example 9
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_23
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 23.2mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_24
Molecular sieves (20 mg), 5mL n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L). The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quench and extract three times with ethyl acetate (5 ml x 3), combine the organic phases and use anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product obtained was purified and isolated by column chromatography to give the product as a white solid in an isolated yield of 95% with an e.r. value of 90.
Nuclear magnetic analysis: 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J＝8.3Hz,2H),7.30(td,J＝ 7.8,0.9Hz,1H),7.22(d,J＝8.2Hz,2H),7.04–6.98(m,2H),6.91(d,J＝7.8Hz, 1H),6.88(t,J＝7.5Hz,1H),6.82(d,J＝2.0Hz,1H),6.50(dd,J＝8.2,2.2Hz,1H),3.87–3.80(m,1H),3.75(s,3H),3.74–3.68(m,1H),3.64(d,J＝15.3Hz,1H),3.08 (d,J＝15.2Hz,1H),2.37(s,3H),1.85–1.78(m,2H),1.04(t,J＝7.4Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ175.7(s),160.1(s),144.2(s),142.9(s),142.0(s),136.7 (s),131.1(s),129.7(s),129.6(s),128.3(s),125.4(s),122.9(s),122.6(s),119.3(s),109.1(s),107.9(s),100.0(s),72.6(s),55.7(s),42.4(s),41.6(s),21.7(s),20.7(s), 11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝14.9min,t minor ＝16.4min)；e.r.＝90:10。
Example 10
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_25
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 22.6 mg), catalyst (1.5X 10) -3 mmol)，
Figure SMS_26
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quench and extract three times with ethyl acetate (5 ml x 3), combine the organic phases and use anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 96% isolated yield with e.r. value of 89.
Nuclear magnetic analysis: 1 H NMR(600MHz,CDCl 3 )δ7.81(d,J＝8.3Hz,2H),7.31(t,J＝ 7.7Hz,1H),7.23(d,J＝8.2Hz,2H),7.06(dd,J＝7.8,5.8Hz,1H),7.00–6.94(m, 2H),6.92(d,J＝7.8Hz,1H),6.88(t,J＝7.5Hz,1H),6.66(td,J＝8.7,2.2Hz,1H), 3.87–3.80(m,1H),3.74–3.68(m,1H),3.65(d,J＝15.4Hz,1H),3.11(d,J＝15.5 Hz,1H),2.38(s,3H),1.85–1.78(m,2H),1.04(t,J＝7.4Hz,3H)； 13 C NMR(151 MHz,CDCl 3 )δ175.4(s),163.0(d,J＝243.8Hz),144.5(s),143.1(d,J＝11.9Hz), 142.1(s),136.3(s),130.6(s),129.9(s),129.7(s),128.2(s),125.7(d,J＝9.9Hz),123.0(s),122.7(d,J＝2.5Hz),122.6(s),109.4(d,J＝22.8Hz),109.2(s),101.2(d, J＝29.2Hz),72.7(s),42.4(s),41.6(s),21.7(s),20.6(s),11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝10.5min,t minor ＝7.8min)；e.r.＝89:11。
Example 11
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_27
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 17.9mg), catalyst (1.5X 10) -3 mmol)，
Figure SMS_28
Molecular sieves (20 mg), 5mL n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L). The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quench and extract three times with ethyl acetate (5 ml x 3), combine the organic phases and use anhydrous Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 92% isolated yield with e.r. value 89.
Nuclear magnetic analysis: 1 H NMR(400MHz,CDCl 3 )δ7.41(d,J＝8.1Hz,1H),7.34–7.26 (m,2H),7.22(d,J＝7.4Hz,2H),7.07(t,J＝7.5Hz,1H),7.02(t,J＝7.5Hz,1H),6.89(d,J＝7.9Hz,1H),3.82–3.71(m,2H),3.71–3.62(m,1H),3.26(d,J＝16.0 Hz,1H),3.10(s,3H),1.83–1.71(m,2H),1.01(t,J＝7.4Hz,3H)； 13 C NMR(101 MHz,CDCl 3 )δ175.4(s),142.0(s),132.2(s),129.8(s),128.6(s),127.5(s),125.5(s), 123.4(s),123.3(s),122.6(s),112.5(s),109.3(s),71.4(s),42.5(s),42.3(s),40.0(s),20.7(s),11.6(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝40.0min,t minor ＝34.6min)；e.r.＝89:11。
Example 12
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_29
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 14.2mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_30
Molecular sieves (20 mg), 5ml of n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L) were added. The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quench and extract three times with ethyl acetate (5 ml x 3), combine the organic phases and use anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 95% isolated yield with an e.r. value of 78.5.
Nuclear magnetic analysis: 1 H NMR(400MHz,CDCl 3 )δ7.34(t,J＝7.8Hz,1H),7.29(d,J＝ 7.4Hz,1H),7.25(d,J＝8.4Hz,1H),7.19(t,J＝7.7Hz,1H),7.04(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.91–6.84(m,2H),3.76–3.62(m,3H),3.44(d,J＝15.8 Hz,1H),1.80–1.69(m,2H),0.99(t,J＝7.4Hz,3H)； 13 C NMR(101MHz,CDCl 3 ) δ175.1(s),159.2(s),143.2(s),130.6(s),130.0(s),128.6(s),125.7(s),125.0(s),124.0(s),123.3(s),121.4(s),110.1(s),109.0(s),85.3(s),41.9(s),39.4(s),20.8(s), 11.5(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝76.9min,t minor ＝74.4min)；e.r.＝78.5:21.5。
Example 13
A preparation method of chiral spiro indolone compounds comprises the following reaction steps:
Figure SMS_31
to a 25 ml round bottom flask equipped with magnetons were added sequentially the substrate (0.05mmol, 15.5 mg), catalyst (1.5 x 10) -3 mmol)，
Figure SMS_32
Molecular sieves (20 mg), 5mL n-propyl acetate, and finally cumene hydroperoxide (0.15mmol, 26.5. Mu.L). The reaction mixture was stirred at 20 ℃ for 12 hours. After the reaction is finished, saturated Na is used 2 S 2 O 3 Quench and extract three times with ethyl acetate (5 ml x 3), combine the organic phases and use anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure. The crude product was purified and isolated by column chromatography to give the product as a white solid in 92% isolated yield with an e.r. value of 68.
Nuclear magnetic analysis: 1 H NMR(600MHz,CDCl 3 )δ8.19(d,J＝7.7Hz,1H),7.59(td,J＝ 7.5,0.9Hz,1H),7.48(t,J＝7.6Hz,1H),7.33(td,J＝7.8,1.1Hz,1H),7.25(d,J＝ 7.5Hz,1H),6.92(t,J＝7.5Hz,1H),6.90–6.85(m,2H),3.67–3.62(m,2H),3.56(d,J＝16.6Hz,1H),3.26(d,J＝16.6Hz,1H),1.75–1.69(m,2H),0.96(t,J＝7.4 Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ172.4(s),163.9(s),142.9(s),136.1(s), 134.3(s),131.0(s),130.2(s),128.3(s),128.1(s),127.5(s),125.0(s),124.2(s), 123.1(s),109.3(s),80.5(s),42.0(s),34.3(s),20.7(s),11.4(s)。
high performance liquid chromatography analysis: chiralpak IA (n-Hexane/i-PrOH =70/30, flow rate =1.0 mL/min, λ =254nm, t major ＝58.1min,t minor ＝37.3min)；e.r.＝68:32。
It should be understood that the detailed description of the invention is merely illustrative of the invention and is not intended to limit the invention to the specific embodiments described. It will be appreciated by those skilled in the art that the present invention may be modified or substituted equally as well to achieve the same technical result; and are within the scope of the present invention as long as the requirements of use are met.

Claims (1)

1. A preparation method of chiral spiro indolone compounds is characterized in that: preparing a chiral spiro indolone compound by using a compound which is derived from indolone and contains active hydrogen functional groups as a raw material, using quaternary ammonium iodide salt derived from cinchona alkaloid as a catalyst and using peroxide as an oxidant through intramolecular carbonyl alpha-asymmetric oxidative coupling reaction in an organic solvent;
the indolone derivative compound containing active hydrogen functional groups has the following structure:
Figure 118978DEST_PATH_IMAGE001
；
the chiral spiro indolone compound has the following structure:
Figure 15652DEST_PATH_IMAGE002
；
wherein R is 1 Is hydrogen, halogen, alkyl, alkoxy, benzyl, ester group or aryl;
R 2 is hydrogen, alkyl or benzyl;
R 3 hydrogen, halogen, alkyl, alkoxy;
XH is functional group containing active hydrogen, and is amido, phenolic hydroxyl or carboxyl protected by sulfonyl;
the cinchona alkaloid derived quaternary ammonium iodide salt has a structure shown in a formula (I) or a formula (II):
Figure 319770DEST_PATH_IMAGE003
Figure 627386DEST_PATH_IMAGE004
formula (one) formula (two)
Wherein R is 4 Is hydrogen or alkoxy;
R 5 is saturated branched or straight chain alkane;
the peroxide is cumene hydroperoxide;
the organic solvent is one of n-propyl acetate and ethyl acetate;
the dosage of the catalyst is 3-10% of the molar weight of the raw materials; the using amount of the peroxide is 3 equivalents of the molar weight of the raw materials; the reaction temperature is 20 ℃; the reaction time is 12-24h; the preparation method is characterized in that an additive is added, the additive adopts a molecular sieve, and the molecular sieve adopts a 5A molecular sieve.
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