CN113200905B - Chiral indolone derivative and synthesis method thereof - Google Patents
Chiral indolone derivative and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses a synthesis method of chiral indolone derivatives and the synthesized chiral indolone derivatives. The synthesis method provided by the invention comprises the steps of taking diazoamide, aldehyde and enamine as raw materials, adding a water absorbent, forming a catalytic system by substituted aniline, palladium (II) dimer and chiral phosphoric acid, and reacting by a one-pot method to obtain the chiral indolone derivative. The synthesis method has the advantages of simple operation, fast reaction, wide substrate adaptability and the like. The indolone structure prepared by the invention is widely existed in natural products, medicines and bioactive molecules, and has great application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals. More particularly, relates to a chiral indolone derivative and a synthesis method thereof.
Background
The 2-indolone structure widely exists in natural products, medicines and bioactive molecules, and has pharmacological effects of resisting tumor, resisting inflammation, promoting growth, resisting Parkinson, etc. For example, L-Oxindolylalanine is a metabolite of L-tryptophan and has good bacteriostatic activity; FR900452 and Maremycins B are alkaloid compounds generated from Streptomyces sp.B9173, and have certain inhibitory activity on lymphoma cells; scala et al (Bioorg Med chem.,2014,22 (3): 1063-9) report a class of 3-substituted-2-indolone compounds having antiproliferative effects on Leishmania protozoans; prioline separated from Salvia officinalis root can be used for treating tonsillitis, pharyngitis, pulmonary tuberculosis and bacillary dysentery; alkaloid compounds amosamide B and pimperumbellactam A have similar oxoindole structure, and have antitumor activity and alpha-glucosidase inhibitory effect. Therefore, the 2-indolone compound with structural diversity has potential application value.
The existing methods for synthesizing chiral indolone mainly focus on asymmetric addition reaction of prochiral indole, for example Yuan et al report that under the chiral catalyst of diphenylethylenediamine, the asymmetric Michael addition reaction of indolone and ketene constructs chiral 3-substituted 2-indolone derivatives, but the reaction can only effectively catalyze the reaction under the combined action of primary amine and D-Boc protected amino acid, and the reaction route is too long (Organic Letters,2015.17,11, 2732-2735); paolo Melchiorre et al reported that 1,4Michael addition reaction of unsaturated olefin and indolone was achieved by using a novel bifunctional primary amine thiourea catalyst, but this reaction only acted simultaneously with synergistic activation of primary amine and thiourea catalyst, and the C-C bond formation could be promoted stereoselectively, and the substrate application range was not wide, and the reaction route was too long (Chemistry A European Journal,2010,15 (32), 7846-7849). In conclusion, the existing synthetic method has the defects of overlong synthetic route, limited substrate application range and the like. Therefore, the development of a simple and high-efficiency method for synthesizing the chiral indolone derivatives has important significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects and shortcomings of the existing synthesis method of chiral indolone derivatives and provide a synthesis method of chiral indolone derivatives. The synthesis method is simple, fast in reaction and wide in substrate applicability, provides a new method for preparing the chiral 3-substituted-2-indolone derivatives, and has a wide application prospect.
The invention also aims to provide a chiral indolone derivative.
The above purpose of the invention is realized by the following technical scheme:
a synthesis method of chiral indolone derivatives comprises the steps of taking diazo amide, aldehyde and enamine as raw materials, adding a water absorbent, taking substituted aniline, palladium (II) dimer and chiral phosphoric acid as catalysts, reacting in an organic solvent to obtain the chiral indolone derivatives shown in the formula (I),
the structural formula of the diazo amide is
The aldehyde has the formula R 4 -CHO；
The enamine has the structural formula
The structural formula of the chiral phosphoric acid is
The configuration is S configuration;
wherein R is 1 Selected from C6-C10 aryl or C1-C6 alkyl;
R 2 selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 3 selected from hydrogen, C1-C3 alkyl;
R 4 selected from C6-C10 aryl, C4-C8 heterocyclic aryl or C2-C8 alkynyl;
ar is selected from C6-C10 aryl or C4-C8 heterocyclic aryl;
wherein the hydrogen atom on the C2-C8 alkynyl group is optionally substituted with a substituent of the group: halogen, C1-C3 alkoxy, C1-C3 haloalkyl, cyano, nitro, ester group, C6-C10 aryl or C4-C8 heterocycloaryl;
the hydrogen atom on the C1-C6 alkyl group is optionally substituted with a substituent of the group: halogen, C1-C3 haloalkyl, cyano, nitro, ester group or C1-C6 alkoxy;
the hydrogen atom on the C6-C10 aryl group is optionally substituted with a substituent of the group: halogen, C1-C3 haloalkyl, cyano, nitro, ester group, C1-C6 alkoxy or C1-C6 alkyl.
The chiral indolone derivative is efficiently constructed by the one-pot reaction, and the synthesis method has the advantages of simple operation, quick reaction, wide substrate adaptability and the like. The invention takes diazoamide, aldehyde and enamine as raw materials, substituted aniline, palladium (II) dimer and chiral phosphoric acid form a catalytic system, in an organic solvent, the aldehyde forms imine under the action of the substituted aniline, then the imine and enamine generate an imine salt intermediate with high electrophilicity under the action of the chiral phosphoric acid, the diazoamide forms metal carbene under the action of the palladium (II) dimer, then intramolecular C-H activation reaction is carried out to form a zwitterion pair intermediate with a five-membered ring structure, the intermediate is captured by the imine salt intermediate to form enamine products, and the enamine products are hydrolyzed to form chiral indolone derivatives. The reaction mechanism of the invention is as follows:
in a catalytic system consisting of substituted aniline, palladium (II) dimer and chiral phosphoric acid, the chiral phosphoric acid is an organic molecular catalyst and has the functions of promoting the formation of an imine salt intermediate and controlling the stereoselectivity of the reaction, so that the chiral indolone derivative is synthesized more efficiently; the palladium (II) dimer is a metal catalyst and has the function of decomposing diazoamide to form a five-membered ring structured zwitterion pair intermediate; the substituted aniline is an organic molecular catalyst and has the function of activating aldehyde.
Preferably, the palladium (II) dimer is an allylpalladium chloride dimer, a 2-methallylpalladium chloride dimer, a butenylpalladium chloride dimer, or a cinnamylpalladium chloride dimer.
More preferably, the palladium (II) dimer is an allylpalladium chloride dimer.
Preferably, the substituted aniline is p-chloroaniline, m-chloroaniline, o-chloroaniline, p-toluidine, o-toluidine, m-toluidine, p-methoxyaniline, m-methoxyaniline, o-methoxyaniline, p-bromoaniline, o-bromoaniline, m-bromoaniline, p-nitroaniline, o-nitroaniline or m-nitroaniline.
Preferably, in the catalyst, the molar ratio of substituted aniline, palladium (II) dimer and chiral phosphoric acid is 1 to 10.
More preferably, the molar ratio of substituted aniline, palladium (II) dimer and chiral phosphoric acid in the catalyst is 6.
Preferably, the molar ratio of aldehyde, diazoamide and enamine in the starting material is 1.0: 1.2-1.8: 1.2.
more preferably, the molar ratio of aldehyde, diazoamide and enamine in the starting material is 1.0:1.5:1.2.
preferably, the water-absorbing agent is a molecular sieve. The molecular sieve usually used is
Molecular sieve,
Molecular sieves or
And (3) a molecular sieve.
More preferably, the water absorbing agent is
A molecular sieve.
Preferably, the dosage of the water absorbing agent is 50-200 mg/mmol based on the molar weight of aldehyde.
Preferably, the temperature of the reaction is-30 ℃ to 0 ℃.
More preferably, the temperature of the reaction is 0 ℃.
Preferably, the reaction time is 1 to 2 hours.
More preferably, the reaction time is 1h.
Preferably, the organic solvent is one or more of dichloromethane, dichloroethane, toluene or methyl tert-butyl ether.
Preferably, the molar volume ratio of the organic solvent to the aldehyde is 0.5 to 1.0mL:0.1mmol.
More preferably, the molar volume ratio of the organic solvent to the aldehyde is 1.0mL:0.1mmol.
In a specific embodiment, the method for synthesizing chiral indolone derivatives of the invention comprises the following steps: based on the molar weight of aldehyde, the mol ratio of diazoamide: aldehyde: enamine: substituted aniline: palladium (II) dimer: chiral phosphoric acid =1.5:1.0:1.2:0.6:0.05:0.1, weighing the raw materials. Dissolving aldehyde, substituted aniline, palladium (II) dimer, chiral phosphoric acid and a water absorbent in an organic solvent to prepare a mixed solution A; dissolving diazoamide and enamine in an organic solvent to prepare a mixed solution B; adding the mixed solution B into the mixed solution A at 0 ℃ within 3h through a peristaltic pump; stirring vigorously; after the mixed solution B is added, continuously stirring for 1h at the temperature of 0 ℃ until the diazo compound is completely consumed; and (3) carrying out column chromatography on the crude product to obtain a pure product chiral indolone derivative shown in the formula (I).
The invention also provides a chiral indolone derivative which has a structure shown in the formula (I):
wherein R is 1 Selected from C6-C10 aryl or C1-C6 alkyl;
R 2 selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 3 selected from hydrogen or C1-C3 alkyl;
R 4 selected from C6-C10 aryl, C4-C8 heterocyclic aryl or C2-C8 alkynyl;
ar is selected from C6-C10 aryl or C4-C8 heterocyclic aryl;
wherein a hydrogen atom on the C2-C8 alkynyl group is optionally substituted with a substituent of the group: halogen, C1-C6 alkoxy, C1-C3 haloalkyl, cyano, nitro, ester group, C6-C10 aryl or C4-C8 heterocycloaryl;
the hydrogen atom on the C1-C6 alkyl group is optionally substituted with the following group of substituents: halogen, C1-C3 haloalkyl, cyano, nitro, ester group or C1-C3 alkoxy;
the hydrogen atom on the C6-C10 aryl group is optionally substituted with a substituent of the group: halogen, C1-C3 haloalkyl, cyano, nitro, ester group, C1-C3 alkoxy or C1-C6 alkyl.
Wherein the C4-C8 heterocyclic aryl group is a C4-C8 heterocyclic aryl group containing an oxygen, sulfur or nitrogen atom.
Preferably, R 1 Is methyl, ethyl or benzyl.
Preferably, R 2 Hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine or bromine.
More preferably, R 2 Is hydrogen, 5-methyl, 5-methoxy, 5-fluoro, 5-chloro, 5-bromo, 4-methyl or 6-methyl.
Preferably, R 3 Is hydrogen, methyl or ethyl.
Preferably, R 4 Is phenylethynyl, 2-methylphenylethynyl, 4-methoxyphenylethynyl, 2-fluorophenylethynyl, 3-chlorophenylethynyl, 4-trifluoromethylphenylethynyl, 4-methoxycarbonylphenylethynyl, 4-cyanophenylethynyl, 2-thienylethynyl, 3-thienylethynyl, heptynyl, 2-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 4-bromophenyl, 4-iodophenyl, 4-nitrophenyl, 2-thienyl, 2-naphthyl, 3-indolyl, 2-furyl, 3-benzothienyl or 2- (N-methylpyrrole) yl.
More preferably, R 4 Is phenylethynyl, 4-methylphenylethynyl, 4-methoxyphenylethynyl, 4-chlorophenylethynyl or 4-methoxycarbonylphenylethynyl.
Preferably, ar is selected from phenyl, halophenyl, C1-C6 alkylphenyl, or heterocycloaryl.
More preferably, ar is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 2-furyl.
The invention also provides an optically active indolone derivative obtained by further derivation according to the synthesis method, the structure of the optically active indolone derivative is shown as the formula (II) and the formula (III),
the synthesis method can simply and efficiently prepare the chiral indolone derivatives, and can also construct the optically active indolone derivatives shown in the formulas (II) and (III) through further chemical conversion. In addition, the condensed indolone structural unit of the compound has pharmacological effects of resisting tumors, resisting inflammation, promoting growth and the like, and has high application value.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a synthesis method of chiral indolone derivatives and the synthesized chiral indolone derivatives. The synthesis method provided by the invention takes diazoamide, aldehyde and enamine as raw materials, adds a water absorbent to replace aniline, palladium (II) dimer and chiral phosphoric acid to form a catalytic system, and efficiently constructs the chiral indolone derivatives in one step in an organic solvent. The synthesis method can simply and efficiently synthesize the chiral indolone derivatives with two quaternary carbon centers, and can also construct the indolone derivatives with optical activity through further chemical conversion. Therefore, the invention has good application prospect in the field of pharmaceutical chemicals.
Drawings
FIG. 1 is a single crystal diffractogram of product k of the present invention;
FIG. 2 is a single crystal diffractogram of product l of the present invention;
FIG. 3 shows the product obtained in example 1 1 H NMR chart;
FIG. 4 shows the product obtained in example 1 13 C NMR chart;
FIG. 5 shows the product obtained in example 2 1 H NMR chart;
FIG. 6 shows the product obtained in example 2 13 C NMR chart;
FIG. 7 shows the product obtained in example 3 1 H NMR chart;
FIG. 8 shows the product obtained in example 3 13 C NMR chart;
FIG. 9 shows the product obtained in example 4 1 H NMR chart;
FIG. 10 shows the product obtained in example 4 13 C NMR chart;
FIG. 11 shows the product obtained in example 4 19 F NMR chart;
FIG. 12 shows the product obtained in example 5 1 H NMR chart;
FIG. 13 shows the product obtained in example 5 13 C NMR chart;
FIG. 14 shows the product obtained in example 6 1 H NMR chart;
FIG. 15 shows the product obtained in example 6 13 C NMR chart;
FIG. 16 shows the product obtained in example 7 1 H NMR chart;
FIG. 17 shows the product obtained in example 7 13 C NMR chart;
FIG. 18 shows the results of example 8 1 H NMR chart;
FIG. 19 shows the product obtained in example 8 13 C NMR chart;
FIG. 20 shows the results of example 9 1 H NMR chart;
FIG. 21 shows the product obtained in example 9 13 C NMR chart;
FIG. 22 shows the results of example 10 1 H NMR chart;
FIG. 23 shows the results of example 10 13 C NMR chart;
FIG. 24 shows the results of example 11 1 H NMR chart;
FIG. 25 shows the results of example 11 13 C NMR chart;
FIG. 26 shows the product obtained in example 12 1 H NMR chart;
FIG. 27 shows the product obtained in example 12 13 C NMR chart.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The synthesis method of the raw material compound diazoamide comprises the following steps: taking N-methyldiazoacetoacet-p-toluidine as an example, N-methylaniline (0.4 g,3.8 mmol) and diisopropylethylamine (0.66mL, 3.8 mmol) were dissolved in dichloromethane (20.0 mL), and a solution of bromoacetyl bromide (0.34mL, 3.8 mmol) in dichloromethane (5.0 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the temperature was raised to room temperature and stirred for 2h. After the reaction was completed, 1N hydrochloric acid (about 20 mL) was added to quench the reaction, the solution was separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was directly dissolved with bis-p-toluenesulfonylhydrazide (3.2g, 9.5 mmol) in tetrahydrofuran (20.0 mL) without purification, and DBU (2.7mL, 18.0 mmol) was added dropwise over an ice-water bath. Stirring in ice water bath for 10min, adding 20mL saturated sodium bicarbonate water solution to quench reaction, adding 20mL ethyl acetate to dilute, separating, drying with anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain crude product. And (3) performing column chromatography separation and purification on the crude product (ethyl acetate: petroleum ether =1 = 10-1) to obtain 0.4g of orange oily product, namely N-methyl diazo-p-toluidine, wherein the two-step reaction yield is 60%.
EXAMPLE 1 Synthesis of Compound a
0.3mmol of phenylpropargylaldehyde, 0.18mmol of parachloroaniline, 0.015mmol of allyl palladium chloride dimer, (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazoacetyl p-toluidine (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours.After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, removing the solvent by rotary evaporation of filtrate, and then purifying the crude product by column chromatography to obtain a pure product a which is a yellow oily liquid, wherein the yield is 75%, the dr value is more than 20, and the ee value is 93%. Of the product 1 The H NMR is shown in FIG. 3, which shows 13 The C NMR chart is shown in FIG. 4.
1 H NMR(400MHz,CDCl 3 )δ8.02(d,J＝7.4Hz,2H),7.59(t,J＝7.3Hz,1H),7.49(t,J＝7.6Hz,2H),7.34(s,1H),7.21(dd,J＝6.3,3.6Hz,5H),7.12(d,J＝7.8Hz,1H),6.74(d,J＝7.9Hz,1H),3.92(dd,J＝13.8,6.3Hz,1H),3.72–3.68(m,1H),3.66–3.57(m,2H),3.19(s,3H),2.34(s,3H). 13 C NMR(126MHz,CDCl 3 )δ197.3,175.6,142.5,136.9,133.3,131.7,131.6,128.7,128.7,128.3,128.1,127.9,126.8,126.1,123.1,107.7,88.9,83.2,47.9,41.0,30.6,26.3,21.3.HRMS(ESI)[M+H] + calcd for C 27 H 24 NO 2 + ,394.1802,found 394.1801.
EXAMPLE 2 Synthesis of Compound b
Phenylpropargylaldehyde (0.3 mmol), p-chloroaniline (0.18 mmol), allyl palladium chloride dimer (0.015 mmol), (S) -6,6' -bis (triphenylsilyl) spirodiphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazo acetyl p-methoxyaniline (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, removing the solvent by rotary evaporation of filtrate, and then purifying the crude product by column chromatography to obtain a pure product b which is a yellow oily liquid, the yield is 73%, the dr value is more than 20, and the ee value is 90%. Of the product 1 The H NMR is shown in FIG. 5, which 13 The C NMR chart is shown in FIG. 6.
1 H NMR(400MHz,CDCl3)δ8.01(d,J＝7.4Hz,2H),7.56(t,J＝7.3Hz,1H),7.46(t,J＝7.6Hz,2H),7.23–7.13(m,1h),6.85(dd,J＝8.4,2.4Hz,1H),6.74(d,J＝8.5Hz,1H),4.10(td,J＝7.0,3.6Hz,1H),3.80(s,3H),3.78–3.70(m,2H),3.36(dd,J＝17.2,6.9Hz,1H),3.18(s,3H). 13 C NMR(101MHz,CDCl 3 )δ197.8,175.3,156.1,138.2,136.8,133.3,131.6,128.6,128.5,128.3,128.1,127.9,123.0,113.1,111.5,108.2,88.3,88.1,82.9,55.8,48.2,39.7,30.2,26.2.HRMS(ESI)[M+H] + calcd for C 27 H 24 NO 3 + ,410.1751,found 410.1751.
EXAMPLE 3 Synthesis of Compound c
0.3mmol of phenylpropargylaldehyde, 0.18mmol of parachloroaniline, 0.015mmol of allyl palladium chloride dimer, (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazo acetanilide (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product c which is a yellow oily liquid, wherein the yield is 67%, the dr value is more than 20, and the ee value is 86%. Of the product 1 The H NMR is shown in FIG. 7, which 13 The C NMR chart is shown in FIG. 8.
1 H NMR(500MHz,CDCl 3 )δ8.01(d,J＝7.4Hz,2H),7.56(t,J＝7.0Hz,2H),7.46(t,J＝7.4Hz,2H),7.32(t,J＝7.7Hz,1H),7.23–7.17(m,3H),7.13(dd,J＝14.8,7.2Hz,3H),6.84(d,J＝7.7Hz,1H),4.11(d,J＝6.7Hz,1H),3.83–3.66(m,2H),3.37(dd,J＝17.2,6.7Hz,1H),3.20(s,3H). 13 C NMR(126MHz,CDCl 3 )δ197.8,175.7,144.7,136.8,133.3,131.6,128.7,128.5,128.3,128.1,127.9,127.3,124.3,123.0,122.8,107.9,88.3,82.8,47.9,39.7,30.2,26.1.HRMS(ESI)[M+H] + calcd for C 21h22 NO 2 + ,380.1645,found 380.1643.
EXAMPLE 4 Synthesis of Compound d
0.3mmol of phenylpropargylaldehyde, 0.18mmol of parachloroaniline, 0.015mmol of allyl palladium chloride dimer, (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazoacetyl para-fluoroaniline (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, rotatably evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product d which is yellow oily liquid, wherein the yield is 66%, the dr value is more than 20, and the ee value is 90%. Of the product 1 The H NMR is shown in FIG. 9, which 13 The C NMR is shown in FIG. 10, which 19 The F NMR chart is shown in FIG. 11.
1 H NMR(500MHz,CDCl 3 )δ8.01(d,J＝7.5Hz,2H),7.57(t,J＝7.3Hz,1H),7.47(t,J＝7.4Hz,2H),7.32(d,J＝7.8Hz,1H),7.22(q,J＝6.8Hz,3H),7.16(d,J＝6.9Hz,2H),7.03(t,J＝8.8Hz,1H),6.76(d,J＝8.0Hz,1H),4.09(s,1H),3.80(dd,J＝16.8,7.4Hz,2H),3.38(d,J＝6.4Hz,1H),3.19(s,3H). 13 C NMR(126MHz,CDCl 3 )δ197.7,175.3,159.3(d,J＝240.5Hz),140.7,136.7,133.4,131.6,129.0(d,J＝8.4Hz),128.7,128.3,128.2,128.1,122.8,114.6(d,J＝23.5Hz),112.5(d,J＝25.0Hz),108.3(d,J＝8.2Hz),87.8,83.0,48.0,39.6,30.1,26.3. 19 F NMR(376MHz,CDCl 3 )δ-120.32.HRMS(ESI)[M+H] + calcd for C 21h21 NO 2 F + ,398.1551,found 398.1552.
EXAMPLE 5 Synthesis of Compound e
0.3mmol of phenylpropargylaldehyde, 0.18mmol of parachloroaniline, 0.015mmol of allyl palladium chloride dimer, (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-ethyl diazo acetanilide (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, rotatably evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product e which is a yellow oily liquid, wherein the yield is 63%, the dr value is more than 20, and the ee value is 90%. Of the product 1 The H NMR is shown in FIG. 12, which 13 A C NMR chart is shown in FIG. 13.
1 H NMR(400MHz,CDCl 3 )δ8.05–8.00(m,2H),7.60–7.51(m,2H),7.49–7.43(m,2H),7.31(t,J＝7.7Hz,1H),7.18(tdd,J＝4.7,4.0,1.3Hz,3H),7.15–7.07(m,3H),6.85(d,J＝7.9Hz,1H),4.11(tt,J＝6.9,3.3Hz,1H),3.84(ddd,J＝9.4,7.3,3.7Hz,2H),3.76–3.73(m,1H),3.67(dd,J＝14.1,7.1Hz,1H),3.44–3.36(m,1H),1.20(t,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ197.9,175.4,143.7,136.8,133.3,131.6,129.1,128.7,128.4,128.3,128.1,127.9,127.7,124.4,122.5,108.0,88.2,83.3,82.7,47.6,39.7,34.6,30.2,12.8.HRMS(ESI)[M+H] + calcd for C 27 H 24 NO 2 + ,394.1802,found 394.1799.
EXAMPLE 6 Synthesis of Compound f
0.3mmol of phenylpropargylaldehyde, 0.18mmol of parachloroaniline, 0.015mmol of allyl palladium chloride dimer, (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving alpha-methyl-N-methyl diazoacetanilide (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, rotatably evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product f which is a yellow oily liquid, wherein the yield is 70%, the dr value is more than 20, and the ee value is 90%. Of the product 1 The H NMR is shown in FIG. 14, which 13 The C NMR chart is shown in FIG. 15.
1 H NMR(500MHz,CDCl 3 )δ7.85(d,J＝7.3Hz,2H),7.64(d,J＝7.2Hz,1H),7.52(t,J＝7.2Hz,1H),7.42(t,J＝7.3Hz,2H),7.35(t,J＝7.5Hz,1H),7.31–7.22(m,5H),7.12(t,J＝7.3Hz,1H),6.90(d,J＝7.6Hz,1H),3.88(d,J＝9.9Hz,1H),3.23(s,3H),2.93–2.76(m,2H),1.62(s,3H). 13 C NMR(126MHz,CDCl 3 )δ197.2,178.9,143.3,136.8,133.1,131.8,131.6,128.6,128.5,128.3,128.2,128.0,123.9,123.1,123.0,108.1,88.3,84.4,50.3,39.5,36.1,26.3,22.7.HRMS(ESI)[M+H] + calcd for C 27 H 24 NO 2 + ,394.1802,found 394.1803.
EXAMPLE 7 Synthesis of Compound g
4-methyl phenylpropargylaldehyde (0.3 mmol), parachloroaniline (0.18 mmol), allyl palladium chloride dimer (0.015 mmol), (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazoacetyl p-toluidine (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, removing the solvent by rotary evaporation of filtrate, and then purifying the crude product by column chromatography to obtain a pure product g which is a yellow oily liquid, wherein the yield is 80%, the dr value is more than 20, and the ee value is 93 percent. Of the product 1 The H NMR is shown in FIG. 16, which 13 The C NMR chart is shown in FIG. 17.
1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝7.4Hz,2H),7.56(t,J＝7.3Hz,1H),7.46(t,J＝7.6Hz,2H),7.37(s,1H),7.10(d,J＝7.9Hz,1H),7.03(dd,J＝18.1,8.1Hz,4H),6.72(d,J＝7.9Hz,1H),4.07(td,J＝7.0,3.6Hz,1H),3.76(dd,J＝17.2,7.3Hz,1H),3.72(d,J＝3.2Hz,1H),3.35(dd,J＝17.2,6.7Hz,1H),3.17(s,3H),2.37(s,3H),2.29(s,3H). 13 C NMR(126MHz,CDCl 3 )δ198.0,175.7,142.3,137.9,136.8,133.3,132.2,131.4,128.9,128.6,128.6,128.3,127.4,125.2,120.0,107.5,87.6,82.8,48.0,39.9,30.3,26.1,21.4,21.2.HRMS(ESI)[M+H] + calcd for C 28 H 26 NO 2 + ,408.1958,found 408.1958.
EXAMPLE 8 Synthesis of Compound h
4-methoxybenzenePropiolic aldehyde (0.3 mmol), p-chloroaniline (0.18 mmol), allylpalladium chloride dimer (0.015 mmol), (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazoacetyl p-toluidine (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, rotatably evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product h which is yellow oily liquid, wherein the yield is 76%, the dr value is more than 20, and the ee value is 92%. Of the product 1 The H NMR is shown in FIG. 18, which 13 A schematic C NMR chart is shown in FIG. 19.
1 H NMR(500MHz,CDCl 3 )δ8.02(d,J＝7.6Hz,2H),7.56(t,J＝7.2Hz,1H),7.46(t,J＝7.4Hz,2H),7.38(s,1H),7.10(t,J＝8.8Hz,3H),6.73(t,J＝6.4Hz,3H),4.07(t,J＝6.7Hz,1H),3.76(s,3H),3.75–3.70(m,2H),3.35(dd,J＝17.2,6.7Hz,1H),3.18(s,3H),2.37(s,3H). 13 C NMR(101MHz,CDCl 3 )δ198.0,175.7,159.3,142.3,136.8,133.3,132.9,132.2,128.6,128.6,128.3,127.4,125.2,115.2,113.7,107.5,86.8,82.6,55.2,48.0,39.9,30.3,26.1,21.3.HRMS(ESI)[M+H] + calcd for C 28 H 26 NO 3 + ,424.1907,found 424.1906.
EXAMPLE 9 Synthesis of Compound i
4-chlorophenylpropynylaldehyde (0.3 mmol), p-chloroaniline (0.18 mmol), allyl palladium chloride dimer (0.015 mmol), (S) -6,6' -bis (triphenylsilyl) spirocyclic diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; dissolving N-methyl diazoacetyl p-toluidine (0.45 mmol) and beta-morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, rotatably evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product i which is a yellow oily liquid, wherein the yield is 73%, the dr value is more than 20, and the ee value is 90 percent. Of the product 1 The H NMR is shown in FIG. 20, which 13 A C NMR chart is shown in FIG. 21.
1 H NMR(400MHz,CDCl 3 )δ8.04–7.95(m,2H),7.57(t,J＝7.4Hz,1H),7.47(t,J＝7.6Hz,2H),7.35(s,1H),7.20–7.17(m,1H),7.17–7.15(m,1H),7.12(d,J＝7.9Hz,1H),7.08–7.06(m,1H),7.05(d,J＝1.8Hz,1H),6.73(d,J＝7.9Hz,1H),4.07(td,J＝7.0,3.6Hz,1H),3.78(dd,J＝17.3,7.2Hz,1H),3.72–3.68(m,1H),3.39(dd,J＝17.3,6.8Hz,1H),3.18(s,3H),2.37(s,3H). 13 C NMR(101MHz,CDCl 3 )δ197.8,175.6,142.3,136.7,133.9,133.4,132.8,132.3,128.7,128.7,128.4,128.3,127.2,125.1,121.5,107.6,89.5,81.7,47.9,39.8,30.2,26.1,21.3.HRMS(ESI)[M+H] + calcd for C 27 H 23 NO 2 Cl + ,428.1412,found 428.1412.
EXAMPLE 10 Synthesis of Compound j
4-methoxy formyl phenylpropargyl aldehyde (0.3 mmol), p-chloroaniline (0.18 mmol), allyl palladium chloride dimer (0.015 mmol), (S) -6,6' -bis (triphenyl silyl) spiro diphenol phosphate (0.03 mmol),
Dissolving a molecular sieve in 1.5mL of anhydrous dichloromethane to prepare a mixed solution A; N-Methyldiazoacetyl-p-toluidine (0.45 mmol) and betaDissolving morpholine styrene (0.36 mmol) in 1mL of anhydrous dichloromethane to prepare a mixed solution B; the mixed solution A was stirred at 0 ℃ and the mixed solution B was added by a syringe pump over 3 hours. After injection, the reaction was stirred at 0 ℃ for 1h. After the reaction is finished, filtering, evaporating the filtrate to remove the solvent, and then purifying the crude product by column chromatography to obtain a pure product j which is a yellow oily liquid, wherein the yield is 61%, the dr value is more than 20, and the ee value is 86%. Of the product 1 The H NMR is shown in FIG. 22, which 13 A schematic diagram of C NMR is shown in FIG. 23.
1 H NMR(500MHz,CDCl 3 )δ8.02(d,J＝7.4Hz,2H),7.88(d,J＝7.8Hz,2H),7.58(t,J＝7.2Hz,1H),7.48(t,J＝7.3Hz,2H),7.36(s,1H),7.19(d,J＝7.8Hz,2H),7.13(d,J＝7.8Hz,1H),6.74(d,J＝7.8Hz,1H),4.14–4.07(m,1H),3.89(s,3H),3.81(dd,J＝17.4,7.1Hz,1H),3.73(s,1H),3.42(dd,J＝17.3,6.6Hz,1H),3.19(s,3H),2.38(s,3H). 13 C NMR(126MHz,CDCl 3 )δ197.7,175.5,166.5,142.3,136.7,133.4,132.3,131.5,129.3,129.3,128.8,128.7,128.3,127.8,127.2,125.1,107.6,91.8,82.1,52.2,47.8,39.7,30.3,26.2,21.2.HRMS(ESI)[M+H] + calcd for C 29 H 26 NO 4 + ,452.1856,found 452.1857.
EXAMPLE 11 Synthesis of Compound k
To a dry 10mL ground reaction tube was added product a (117.9 mg, 0.30mmol), and trifluoroacetic acid (1.5 mL) was added with slow stirring, after which the reaction was continued at room temperature for 30 minutes. After the reaction is finished, adding a saturated sodium bicarbonate solution, adding ethyl acetate for extraction after bubbles are not generated, separating, combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic solution under reduced pressure, adding 2mL of dichloromethane, adding 0.5mL of triethylamine, stirring for 6 hours, separating and purifying the concentrated solution through column chromatography to obtain a pure product k, wherein the yield is 83% and the ee value is 90%. The single crystal diffractogram of this product is shown in figure 1, 1 the H NMR is shown in FIG. 24, which 13 A C NMR chart is shown in FIG. 25.
1 H NMR(500MHz,CDCl 3 )δ7.81–7.76(m,2H),7.53–7.49(m,1H),7.42–7.35(m,1h),7.23(dd,J＝16.2,8.5Hz,2H),6.82(dd,J＝10.4,7.8Hz,2H),6.29(d,J＝6.2Hz,1H),3.38(ddd,J＝11.4,6.2,3.4Hz,1H),3.28(s,3H),3.00(dd,J＝15.9,3.4Hz,1H),2.48(dd,J＝15.9,11.4Hz,1H),1.55(s,3H). 13 C NMR(101MHz,CDCl 3 )δ198.1,180.9,142.3,138.1,137.4,136.8,133.1,130.6,129.9,129.4,128.5,128.4,128.4,128.1,128.1,127.8,118.4,107.4,46.1,39.1,36.9,26.6,21.9.HRMS(ESI)[M+H] + calcd for C 27 H 24 NO 2 + ,384.1802,found 384.1806.
EXAMPLE 12 Synthesis of Compound I
To a dry 10mL ground reaction tube was added product f (39.3 mg,0.10 mmol), and trifluoroacetic acid (0.5 mL) was added with slow stirring, and after the addition was completed, the reaction was continued at room temperature for 30 minutes. After the reaction is finished, adding a saturated sodium bicarbonate solution, adding ethyl acetate for extraction after bubbles are not blown out, separating, combining organic phases, drying with anhydrous sodium sulfate, concentrating the organic solution under reduced pressure, and separating and purifying by column chromatography (EA: PE =1 10-1) to obtain a pure product, wherein the yield is 88%, the dr value is more than 20, and the ee value is 90.
The above-mentioned product (39.3mg, 0.10mmol), pyridine (31.6mg, 0.4mmol), hydroxylamine hydrochloride (27.8mg, 0.4mmol) and ethanol (2 mL) were charged into a dry 10mL ground reaction tube, and reacted at ordinary temperature overnight. After the reaction, the reaction mixture was washed with brine and 3N hydrochloric acid, dried over anhydrous sodium sulfate, and then the organic solution was concentrated under reduced pressure and purified by column chromatography (EA: PE =1>20, 1,ee value is 90%. The single crystal diffraction pattern of the product is shown in figure 2, 1 the H NMR is shown in FIG. 26, which 13 A C NMR chart is shown in FIG. 27.
1 H NMR(500MHz,CDCl 3 )δ7.99(s,1H),7.50–7.46(m,2H),7.37–7.28(m,6H),7.23(t,J＝7.8Hz,1H),7.17–7.13(m,2H),6.80(dd,J＝14.8,7.8Hz,2H),5.80(d,J＝6.1Hz,1H),3.28(dd,J＝10.9,6.5Hz,1H),3.25(s,3H),2.82(dd,J＝12.4,4.9Hz,1H),2.42(t,J＝11.8Hz,1H),1.49(s,3H). 13 C NMR(126MHz,CDCl 3 )δ180.9,142.6,138.2,137.8,135.6,130.8,129.5,129.1,128.8,128.6,128.4,128.3,128.0,127.7,126.4,118.3,107.4,46.5,37.8,26.5,24.9,21.7.HRMS(ESI)[M+H] + calcd for C 27 H 25 N 2 O 2 + ,409.1911,found 409.1908.(Chiral IA3,λ＝254nm,n-hexane/2-propanol＝80/20,Flow rate＝1.0mL/min),t R ＝8.171min,15.581min(major).
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. A method for synthesizing chiral indolone derivatives is characterized in that diazo amide, aldehyde and enamine are used as raw materials, a water absorbent is added, substituted aniline, palladium (II) dimer and chiral phosphoric acid are used as catalysts, and the chiral indolone derivatives shown in formula (I) are obtained by reaction in an organic solvent,
the structural formula of the diazo amide is
The aldehyde has the formula R 4 -CHO；
The enamine has the structural formula
Structural formula of chiral phosphoric acidIs composed of
The configuration is S configuration;
wherein R is 1 Selected from C6-C10 aryl or C1-C6 alkyl;
R 2 selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 3 selected from hydrogen or C1-C3 alkyl;
R 4 selected from C6-C10 aryl, C4-C8 heterocyclic aryl or C2-C8 alkynyl;
ar is selected from C6-C10 aryl or C4-C8 heterocyclic aryl;
wherein a hydrogen atom on the C2-C8 alkynyl group is optionally substituted with a substituent of the group: halogen, C1-C3 alkoxy, C1-C3 haloalkyl, cyano, nitro, ester group, C6-C10 aryl or C4-C8 heterocycloaryl;
the hydrogen atom on the C1-C6 alkyl group is optionally substituted with the following group of substituents: halogen, C1-C3 haloalkyl, cyano, nitro, ester group or C1-C6 alkoxy;
the hydrogen atom on the C6-C10 aryl group is optionally substituted with the following group of substituents: halogen, C1-C3 haloalkyl, cyano, nitro, ester group, C1-C6 alkoxy or C1-C6 alkyl.
2. The method of claim 1, wherein the palladium (II) dimer is allyl palladium chloride dimer, 2-methallyl palladium chloride dimer, butene palladium chloride dimer, or cinnamyl palladium chloride dimer.
3. The synthesis method according to claim 1, wherein in the catalyst, the molar ratio of the substituted aniline to the palladium (II) dimer to the chiral phosphoric acid is 1-10.
4. The synthesis method according to claim 1, wherein the molar ratio of substituted aniline, palladium (II) dimer and chiral phosphoric acid in the catalyst is 6.
5. The synthesis method according to claim 1, wherein the organic solvent is one or more of dichloromethane, dichloroethane, toluene or methyl tert-butyl ether.
6. The method of claim 1, wherein the substituted aniline is p-chloroaniline, m-chloroaniline, o-chloroaniline, p-toluidine, m-toluidine, o-toluidine, p-methoxyaniline, m-methoxyaniline, o-methoxyaniline, p-bromoaniline, m-bromoaniline, o-bromoaniline, p-nitroaniline, m-nitroaniline or o-nitroaniline.
7. The synthesis method of claim 1, wherein the water absorbent is a molecular sieve.
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