CN105906544A - S-type 3-hydroxy-3-alkynyloxoindole compound and synthetic method and application thereof - Google Patents

S-type 3-hydroxy-3-alkynyloxoindole compound and synthetic method and application thereof Download PDF

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CN105906544A
CN105906544A CN201610237008.9A CN201610237008A CN105906544A CN 105906544 A CN105906544 A CN 105906544A CN 201610237008 A CN201610237008 A CN 201610237008A CN 105906544 A CN105906544 A CN 105906544A
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compound
hydroxyl
alkynyl
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copper
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CN105906544B (en
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郭勋祥
许宁
顾大伟
訾晶
伍新燕
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East China University of Science and Technology
Shanghai Jiaotong University
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East China University of Science and Technology
Shanghai Jiaotong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses an S-type 3-hydroxy-3-alkynyloxoindole compound, the structural general formula of which is as shown in the formula (I). In the formula (I), R1 is electrondrawing group; R2 is hydrogen atom, C1-4 alkyl group, phenyl group, benzyl group and its derivative or naphthyl group; and R3 is phenyl group or its derivative, naphthyl group, cyclohexenyl group, thiophene, pyridine or furan. The invention also discloses a synthetic method of the compound and an application of the compound used as a raw material for organic synthesis. The S-type 3-hydroxy-3-alkynyloxoindole compound with its structural general formula as shown in the formula (I) has a novel structure. The synthetic method has advantages as follows: raw materials are cheap and easily available; reaction conditions are mild; operation is simple; atom economy is good; and enantioselectivity is high. Therefore, the compound of the invention has a great application prospect and social and economic benefits.

Description

A kind of S type 3-hydroxyl-3-alkynyl oxidized indole compounds and synthetic method thereof and application
Technical field
The present invention relates to chipal compounds, be specifically related to a kind of S type 3-hydroxyl-3-alkynyl oxidized indole compounds and synthetic method thereof, and described S type 3-hydroxyl-3-alkynyl oxidized indole compounds is as raw material application in organic synthesis.
Background technology
Chiral 3-hydroxy-Oxoindole construction unit is widely present in a series of natural products with physiologically active and drug molecule.Research finds, the compound with this construction unit has anti-cell toxicity, antibacterial activity, and can be as growth hormone drug or proteasome inhibitor.In view of it has biologically active widely, the synthesis of this compounds is by the extensive concern of scientific research personnel.
As 3-hydroxyl-oxidized indole compounds that a class is important, 3-hydroxyl-3-alkynyl oxidized indole compounds has shown that good biologically active, as suppressed the duplication of HIV-1 and not having the pharmacological properties such as obvious cytotoxicity, suppression Echinococcus multilocularis.But, synthesis for 3-hydroxyl-3-alkynyl oxidized indole compounds, what document was reported at present is only limitted to synthesize achiral 3-hydroxyl-3-alkynyl oxidized indole compounds, as Hao et al. uses zincon to be applied to terminal alkyne addition (Chen, G. to isatin compounds as accelerator；Wang,Y.；Gao,S.；He,H.-P.；Li,S.-L.；Zhang,J.-X.；Ding,J.；Hao,X.-J.J.Heterocyclic Chem.2009,46,217.)；Chen and Li et al. uses NHC-Ag catalyst achieve the alkynylation reaction of isatin and obtain 3-hydroxyl-3-alkynyl oxidized indole compounds (Fu, X.-P. efficiently；Liu,L.；Wang D.；Chen,Y.-J.；Li,C.-J.Green Chem.2011,13,549.)；Recently, Nair et al. uses CuI/DBU catalyst to obtain 3-hydroxyl-3-alkynyl oxidized indole compounds (Chouhan, M. with high yield under mild conditions；Senwar,K.R.；Kumar,K.；Sharma,R.；Nair,V.A.Synthesis 2014,46,195.).Therefore, the method finding the synthesis hand-type 3-hydroxyl-3-alkynyl oxidized indole compounds that a kind of cheaper starting materials is easy to get, reaction condition is gentle, simple to operate, enantioselectivity is high has great importance.
Summary of the invention
In order to solve the problems referred to above of the prior art, the invention provides a kind of S 3-hydroxyl-3-alkynyl oxidized indole compounds and synthetic method thereof and application, described S 3-hydroxyl-3-alkynyl oxidized indole compounds can be as raw material in organic synthesis.The method of this synthesis S 3-hydroxyl-3-alkynyl oxidized indole compounds has that cheaper starting materials is easy to get, reaction condition is gentle, simple to operate, enantioselectivity advantages of higher.
Technical scheme is as follows:
A kind of S type 3-hydroxyl-3-alkynyl oxidized indole compounds, its general structure (I) is:
In general structure (I), R1Selected from electron withdraw group, for Br, NO2、CO2Me、CF3, Cl or CF3；R2For hydrogen atom, C1-4Alkyl, phenyl, benzyl and derivative thereof or naphthyl；R3For phenyl and derivative, naphthyl, cyclohexenyl group, thiophene, pyridine or furans.
Present invention also offers the synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds shown in a kind of general structure (I), described synthetic method comprises the steps:
(1) under inert gas shielding, the addition copper salt of difference, chiral ligand, organic solvent in reaction unit, stir 0.5～2h；
(2) after, then addition isatin compounds, terminal alkyne compound, organic base and described organic solvent respectively, add thermal response；
(3), after reaction completely, post-treated the described compound as shown in general structure (I) is obtained.
In the step (1) of the present invention, preferably described copper salt is cuprous iodide (CuI), cuprous bromide (CuBr), TFMS cuprous (CuOTf), cuprous oxide (Cu2O), Salicylaldoxime (Cu (OAc)2), copper acetate monohydrate (Cu (OAc)2.H2O), copper trifluoromethanesulfcomposite (Cu (OTf)2), copper chloride (CuCl2), copper bromide (CuBr2), cupric oxide (CuO), trifluoroacetic acid copper (Cu (OOCCF3)2), copper chloride dihydrate (CuCl2.2H2O), two water copper bromide (CuBr2.2H2O), copper carbonate (CuCO3), nitrate trihydrate copper (Cu (NO3)2.3H2O), cuprous cyanide (CuCN), acetylacetone copper (Cu (acac)2), copper fluoride (CuF2), Kocide SD (Cu (OH)2) or cupric sulfate pentahydrate (CuSO4.5H2O) one or more.
nullIn the step (1) of the present invention，Preferably described chiral ligand be R-(+)-1,1'-dinaphthalene-2,2'-diphenyl phosphine、(R,R)-2,2 '-isopropylidene is double (4-phenyl-2-oxazoline)、(R,R)-2,2’-(2,6-pyridine diyl)-bis-(4-isopropyl-2-oxazolines)、N-((1R,2R)-2-(diphenylphosphino) hexamethylene) benzamide、((S)-1-(((1R,2R)-2-(diphenylphosphino) cyclohexyl) amine)-1-oxygen-3-phenyl propyl-2-base) carbamate、(S)-N-((1R,2R)-2-(diphenylphosphino)-cyclohexyl)-2-(benzene sulfonamido)-3-Phenylpropionamide、(S)-N-((1R,2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-2-Phenylpropionamide or (S)-N-((1R,2R)-2-(diphenylphosphino)-cyclohexyl) one or more of-2-phenyl-2-((4-aminomethyl phenyl) sulfoamido)-acetamide.
In the step (2) of the present invention, preferably described isatin compounds be the substituent on phenyl ring be the isatin compounds of electron withdraw group.nullCan be specifically，1-benzyl-7-trifluoromethyl isatin、1-(4-methyl-benzyl)-7-trifluoromethyl isatin、1-(4-t-butylbenzyl)-7-trifluoromethyl isatin、1-(4-luorobenzyl)-7-trifluoromethyl isatin、1-(4-chlorobenzyl)-7-trifluoromethyl isatin、1-(4-bromobenzyl)-7-trifluoromethyl isatin、1-(4-cyanobenzyls)-7-trifluoromethyl isatin、1-(1-menaphthyl)-7-trifluoromethyl isatin、1-methyl-7-trifluoromethyl isatin、1-ethyl-7-trifluoromethyl isatin、1-butyl-7-trifluoromethyl isatin、1-benzyl-6-trifluoromethyl isatin、1-benzyl-5-trifluoromethyl isatin、1-benzyl-5-methyl formate isatin、1-benzyl-5-Nitroisatoic、1-benzyl-6-chlorisatide or the one of 1-benzyl-4-bromo-isatin.
In the step (2) of the present invention, preferably described terminal alkyne compound is the substituted acetylene compound of 1-, and the described substituted substituent of 1-is unsaturated hydro carbons or unsaturated heterocyclic compound.Can be specifically, phenylacetylene, 2-methylbenzene acetylene, 2-Methoxy-phenylacetylene, 3-methylbenzene acetylene, 4-methylbenzene acetylene, 4-Methoxy-phenylacetylene, 4-Liquid Crystal Compounds Intermediate p-Ethyl-phenylacetylene, 4-tert-butyl benzene acetylene, 4-fluorobenzene acetylene, 1-acetenyl naphthalene, 2-thiophene acetylene or the one of 1-acetenyl cyclohexene.
In the step (2) of the present invention, preferably described organic base is organic amine compound.Can be specifically, benzyl lauryl amine, triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, 1,8-diazacyclo [4,3,0]-5-nonene, 4-(N, N-dimethyl)-pyridine or 1, one or more of 4-diazacyclo [2,2,2] octane.
In the step (1) of the present invention and (2), described organic solvent be ethyl acetate, n-hexane, hexamethylene, oxolane, dichloromethane, 1,2-dichloroethanes, acetonitrile, toluene, benzene, dimethylbenzene, 1, one or more of 4-dioxane, methyl alcohol, DMF, dimethyl sulfoxide (DMSO) or methyl tertiary butyl ether(MTBE).It is more highly preferred to methyl tertiary butyl ether(MTBE).
In the step (2) of the present invention, preferably described reaction temperature is 0-100 DEG C, more preferably 20-80 DEG C, particularly preferably 40 DEG C.
In the method for the S type 3-hydroxyl-3-alkynyl oxidized indole compounds described in the synthesis of the present invention, described copper salt, described chiral ligand, described isatin compounds, mol ratio between described terminal alkyne compound and described organic base are 1:(1-100): (1-100): (1-100): (1-100), more preferably 1:(1-50): (1-50): (1-50): (1-50), particularly preferably 1:(1-1.2): (1-20): (1-21): (1-40).
The invention also discloses and the hydroxyl-3-alkynyl oxidized indole compounds of S type 3-shown in general structure (I) is used in organic synthesis as raw material.
Compared with prior art, beneficial effects of the present invention is as follows:
The oneth, present invention synthesizes a series of S 3-hydroxyl-3-alkynyl oxidized indole compounds first, provides important basis for research to this compounds from now on；
The 2nd, present invention is first with copper salt and hand-type part as catalyst, synthesizing S 3-hydroxyl-3-alkynyl oxidized indole compounds with isatin compounds and terminal alkyne compound for initiation material, the method has that cheaper starting materials is easy to get, reaction condition is gentle, simple to operate, enantioselectivity advantages of higher.
Certainly, the arbitrary product implementing the present invention it is not absolutely required to reach all the above advantage simultaneously.
Accompanying drawing explanation
Fig. 1 is the general structure of a kind of S type 3-hydroxyl-3-alkynyl oxidized indole compounds of the present invention；
Fig. 2 is the reaction scheme figure of the synthesis S type 3-hydroxyl-3-alkynyl oxidized indole compounds of the present invention；
Fig. 3 (a) and Fig. 3 (b) is respectively hydrogen spectrum and the carbon spectrum nuclear magnetic spectrogram of S type 1-benzyl-3-hydroxyl-3-(the phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound of embodiments of the invention 1；
Fig. 4 is the high-efficient liquid phase chromatogram of raceme 1-benzyl-3-hydroxyl-3-(the phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound of embodiments of the invention 1；
Fig. 5 is the high-efficient liquid phase chromatogram of S type 1-benzyl-3-hydroxyl-3-(the phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound of embodiments of the invention 1；
Fig. 6 is the single crystal diffraction figure of S type 1-benzyl-3-hydroxyl-3-(the phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound of embodiments of the invention 1；
Fig. 7 (a) and Fig. 7 (b) is respectively hydrogen spectrum and the carbon spectrum nuclear magnetic spectrogram of the compound 1-1 of embodiments of the invention 29；
Fig. 8 (a) and Fig. 8 (b) is respectively hydrogen spectrum and the carbon spectrum nuclear magnetic spectrogram of the compound 1-2 of embodiments of the invention 29.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention, rather than limit protection scope of the present invention.Those skilled in the art make according to the present invention in actual applications improvement and adjustment, still fall within protection scope of the present invention.
A kind of S type 3-hydroxyl-3-alkynyl oxidized indole compounds, its general structure (I) is:
In general structure (I), R1Selected from electron withdraw group, it is specifically as follows Br, NO2、CO2Me、CF3, Cl or CF3Deng electron withdraw group；R2For hydrogen atom, C1-4Alkyl, phenyl, benzyl and derivative or naphthyl etc.；R3For phenyl and derivative, naphthyl, cyclohexenyl group, thiophene, pyridine or furans etc..
Present invention also offers the synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds shown in a kind of general structure (I), described synthetic method comprises the steps:
(1) at N2Under protection, the addition copper salt of difference, chiral ligand, organic solvent in reaction unit, stir 0.5～2h so that described mantoquita and described chiral ligand are fully complexed；
(2) after being fully complexed, then addition isatin compounds, terminal alkyne compound, organic base and described organic solvent respectively, then reaction unit being placed in heater and add thermal response, reaction temperature is 0-100 DEG C, reacts some hours；
(3) to after reaction completely, post-treated the described compound as shown in general structure (I) is obtained.
Described post processing is: filtering through diatomite, remove solvent, mixture obtains the compound as shown in general structure (I) through column chromatography for separation again.
Below with specific embodiment, the present invention will be further described.
Embodiment 1
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 1), its structural formula is:
Preparation method one: under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 30 minutes, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 76.6mg compound 1 through routine post processing, productivity 94%, enantioselectivity is 92%ee (S).
Preparation method two: under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 6.8mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-2-phenyl-acetamides, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 30 minutes, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 66.0mg compound 1 through routine post processing, productivity 81%, enantioselectivity is 79%ee (S).
Preparation method three: under nitrogen protection, addition 1.2mg cuprous acetate successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 30 minutes, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 63.5mg compound 1 through routine post processing, productivity 78%, enantioselectivity is 83%ee (S).
The fusing point of compound 1 is 88-89 DEG C.
The nuclear-magnetism characterization result of compound 1 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=6.6Hz, 1H), 7.60 (d, J=7.4Hz, 1H), 7.45-7.35 (m, 2H), 7.35-7.08 (m, 9H), 5.22 (s, 2H), 4.40 (brs, 1H)；13C NMR(100MHz,CDCl3): δ 45.8 (q, J=5.2Hz), 68.0,85.0, (q, J=33.3Hz), 87.3,113.8 121.3,123.2 (q, J=272.7Hz), 125.6,127.1, (128.4,128.5 q, J=6.1Hz), 128.6,128.9,129.3,131.9,132.2,135.6,140.38,140.39,175.7.
Hydrogen spectrum nuclear magnetic spectrogram such as Fig. 3 (a) of compound 1 is described, carbon spectrum nuclear magnetic spectrogram such as Fig. 3 (b).
The high resolution mass spectrum HRMS (ESI) of compound 1 is calculated as: C24H17NO2F3(M+H)+, 408.1211, find: 408.1218.
The enantiomeric excess of compound 1 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=14.12min (R), t2=22.13min (S), enantioselectivity is 92%ee (S), and spectrogram asks for an interview Fig. 4 and Fig. 5.
The specific rotatory power of compound 1 is [α]D 20-64.6(c 0.55,CH2Cl2)。
Embodiment 2
(S) synthesis of-1-(4-methyl-benzyl)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 2), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 63.9mg1-(4-methyl-benzyl)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 75.9mg compound 2 through routine post processing, productivity 90%, enantioselectivity is 91%ee (S).
The fusing point of compound 2 is 147-148 DEG C.
The nuclear-magnetism characterization result of compound 2 is:1H NMR(400MHz,CDCl3): δ 7.84 (d, J=7.3Hz, 1H), 7.61 (d, J=7.7Hz, 1H), 7.45-7.37 (m, 2H), 7.35-7.19 (m, 4H), 7.09-7.00 (m, 4H), 5.17 (s, 2H), 4.40 (brs, 1H), 2.27 (s, 3H)；13C NMR(100MHz,CDCl3): δ 21.1,45.6 (q, J=5.0Hz), 67.9,85.0, (q, J=33.3Hz), 87.2,113.8 121.4,123.2 (q, J=272.7Hz), 123.5,125.6, (128.4,128.6 q, J=6.1Hz), 128.9,129.3,129.4,131.9,132.2,132.6,136.7,140.5,175.7.
The high resolution mass spectrum HRMS (ESI) of compound 2 is calculated as: C25H19NO2F3(M+H)+, 422.1368, find: 422.1357.
The enantiomeric excess of compound 2 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=12.20min (R), t2=19.85min (S), enantioselectivity is 91%ee (S)；
The specific rotatory power of compound 2 is [α]D 20-76.8(c 0.59,CH2Cl2)。
Embodiment 3
(S) synthesis of-1-(4-t-butylbenzyl)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 3), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 30 minutes, addition 72.3mg1-(4-t-butylbenzyl)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 85.3mg compound 3 through routine post processing, productivity 92%, enantioselectivity is 92%ee (S).
The fusing point of compound 3 is 155-157 DEG C.
The nuclear-magnetism characterization result of compound 3 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=7.4Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 7.48-7.41 (m, 2H), 7.37-7.22 (m, 6H), 7.08 (d, J=8.3Hz, 2H), 5.19 (s, 2H), 3.98 (brs, 1H), 1.26 (s, 9H).13C NMR(100MHz,CDCl3): δ 31.4,34.5,45.6 (q, J=5.1Hz), 67.9, (85.0,87.2,113.9 q, J=33.3Hz), 121.4, (123.5,123.6 q, J=272.7Hz), 125.4,125.5, (128.4,128.6 q, J=6.1Hz), 128.9,129.4,131.3,131.8,132.2,132.59,140.63,140.7,150.0,175.6.
The high resolution mass spectrum HRMS (ESI) of compound 3 is calculated as: C28H25NO2F3(M+H)+, 464.1837, find: 464.1836.
The enantiomeric excess of compound 3 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=8.55min (R), t2=10.91min (S), enantioselectivity is 92%ee (S).
The specific rotatory power of compound 3 is [α]D 20-67.7(c 0.57,CH2Cl2)。
Embodiment 4
(S) synthesis of-1-(4-luorobenzyl)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound 4, its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 64.6mg1-(4-luorobenzyl)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 82.5mg compound 4 through routine post processing, productivity 97%, enantioselectivity is 92%ee (S).
The fusing point of compound 4 is 131-132 DEG C.
The nuclear-magnetism characterization result of compound 4 is:1H NMR(400MHz,CDCl3): δ 7.86 (d, J=7.3Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.47-7.38 (m, 2H), 7.37-7.22 (m, 4H), 7.12 (dd, J=8.5,5.2Hz, 2H), 6.97-6.89 (m, 2H), 5.17 (d, J=2.2Hz, 2H), 4.19 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.3 (q, J=5.1Hz), 67.9,84.8,87.4,113.8 (q, J=33.3Hz), 115.6 (d, J=22.2Hz), 121.2,123.2 (q, J=272.7Hz), 123.8,127.4 (d, J=8.0Hz), (128.5,128.6 q, J=6.1Hz), 129.0,129.5,131.4,131.8,132.2,140.2, (140.3,162.1 d, J=246.4Hz), 175.6.
The high resolution mass spectrum HRMS (ESI) of compound 4 is calculated as: C24H16NO2F4(M+H)+, 426.1117, find: 426.1123.
The enantiomeric excess of compound 4 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=12.69min (R), t2=18.69min (S), enantioselectivity is 92%ee (S).
The specific rotatory power of compound 4 is [α]D 20-60.7(c 0.61,CH2Cl2)。
Embodiment 5
(S) synthesis of-1-(4-chlorobenzyl)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 5), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 30 minutes, addition 67.9mg1-(4-chlorobenzyl)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 84.8mg compound 5 through routine post processing, productivity 96%, enantioselectivity is 92%ee (S).
The fusing point of compound 5 is 187-188 DEG C.
The nuclear-magnetism characterization result of compound 5 is:1H NMR(400MHz,CDCl3): δ 7.87 (d, J=7.3Hz, 1H), 7.62 (d, J=8.1Hz, 1H), 7.40 (d, J=7.1Hz, 2H), 7.33 (t, J=7.3Hz, 1H), 7.26 (d, J=6.9Hz, 3H), 7.19 (d, J=8.4Hz, 2H), 7.07 (d, J=8.3Hz, 2H), 5.17 (q, J=3.7Hz, 2H), 4.55 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.3 (q, J=5.2Hz), 67.9,84.7, (q, J=33.3Hz), 87.4,113.8 121.2,123.1 (q, J=272.7Hz), 123.8,127.1, (128.5,128.6 q, J=6.1Hz), 128.8,129.0,129.5,131.9,132.2,133.0,134.2,140.1,175.9.
The high resolution mass spectrum HRMS (ESI) of compound 5 is calculated as: C24H16NO2ClF3(M+H)+, 442.0822, find: 442.0815.
The enantiomeric excess of compound 5 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=14.10min (R), t2=20.82min (S), enantioselectivity is 92%ee (S).
The specific rotatory power of compound 5 is [α]D 20-28.8(c 0.45,CH2Cl2)。
Embodiment 6
(S) synthesis of-1-(4-bromobenzyl)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 6), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 76.8mg1-(4-bromobenzyl)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 85.6mg compound 6 through routine post processing, productivity 88%, enantioselectivity is 90%ee (S).
The fusing point of compound 6 is 189-190 DEG C.
The nuclear-magnetism characterization result of compound 6 is:1H NMR(400MHz,CDCl3): δ 7.86 (d, J=7.2Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.46-7.24 (m, 8H), 7.02 (d, J=8.4Hz, 2H), 5.15 (d, J=6.2Hz, 2H), 4.07 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.4 (q, J=5.1Hz), 67.9,84.7,87.5,113.8 (q, J=33.3Hz), 121.1,121.2,123.1 (q, J=272.7Hz), 123.8,127.5, (128.5,128.6 q, J=6.1Hz), 129.1,129.5,131.77,131.84,132.2,134.8,140.10,140.11,175.8.
The high resolution mass spectrum HRMS (ESI) of compound 6 is calculated as: C24H16NO2F3Br(M+H)+, 486.0317, find: 486.0316.
The enantiomeric excess of compound 6 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=15.03min (R), t2=21.89min (S), enantioselectivity is 90%ee (S).
The specific rotatory power of compound 6 is [α]D 20-65.6(c 0.38,CH2Cl2)。
Embodiment 7
(S) synthesis of-1-(4-cyanobenzyls)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 7), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 66.1mg1-(4-cyanobenzyls)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 79.6mg compound 7 through routine post processing, productivity 92%, enantioselectivity is 90%ee (S).
The fusing point of compound 7 is 150-151 DEG C.
The nuclear-magnetism characterization result of compound 7 is:1H NMR(400MHz,CDCl3): δ 7.88 (d, J=7.2Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.54 (d, J=8.3Hz, 2H), 7.43-7.21 (m, 8H), 5.24 (d, J=2.3Hz, 2H), 4.46 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.6 (q, J=5.0Hz), 67.8,84.5,87.6, (111.2,113.7 q, J=33.3Hz), 118.7, (121.1,123.1 q, J=272.7Hz), 124.0, (126.4,128.5,128.7 q, J=6.1Hz), 129.1,129.6,131.8,132.1,132.5,139.7,141.4,175.6.
The high resolution mass spectrum HRMS (ESI) of compound 7 is calculated as: C25H16N2O2F3,433.1164(M+H)+, find: 433.1176.
The enantiomeric excess of compound 7 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=37.02min (R), t2=52.19min (S), enantioselectivity is 90%ee (S).
The specific rotatory power of compound 7 is [α]D 20-69.8(c 0.58,CH2Cl2)。
Embodiment 8
(S) synthesis of-1-(1-menaphthyl)-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 8), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 71.1mg1-(naphthyl-1-ylmethyl)-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 83.3mg compound 8 through routine post processing, productivity 91%, enantioselectivity is 90%ee (S).
The fusing point of compound 8 is 175-176 DEG C.
The nuclear-magnetism characterization result of compound 8 is:1H NMR(400MHz,CDCl3): δ 7.97 (d, J=8.3Hz, 1H), 7.89 (t, J=8.1Hz, 2H), 7.71 (d, J=8.2Hz, 1H), 7.63-7.50 (m, 3H), 7.49-7.40 (m, 2H), 7.33-7.23 (m, 5H), 7.04 (d, J=7.2Hz, 1H), 5.68 (s, 2H), 4.22 (brs, 1H).13C NMR(100MHz,CDCl3): δ 43.8 (q, J=5.0Hz), 68.0,85.0,87.4,113.9 (q, J=33.3Hz), 120.8,121.3,122.2,123.1 (q, J=272.7Hz), 123.7,125.5,126.0, (126.4,127.6,128.5,128.7 q, J=6.1Hz), 128.99,129.03,129.4,130.5,130.6,131.8,132.2,133.8,140.6,175.5.
The high resolution mass spectrum HRMS (ESI) of compound 8 is calculated as: C28H19NO2F3(M+H)+, 458.1368, find: 458.1357.
The enantiomeric excess of compound 8 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=22.54min (R), t2=31.19min (S), enantioselectivity is 90%ee (S).
The specific rotatory power of compound 8 is [α]D 20-56.4(c 0.62,CH2Cl2)。
Embodiment 9
(S) synthesis of-1-methyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 9), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 45.8mg1-methyl-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 63.6mg compound 9 through routine post processing, productivity 96%, enantioselectivity is 92%ee (S).
The fusing point of compound 9 is 143-145 DEG C.
The nuclear-magnetism characterization result of compound 9 is:1H NMR(400MHz,CDCl3): δ 7.80 (d, J=7.2Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.45-7.39 (m, 2H), 7.34-7.21 (m, 4H), 4.12 (brs, 1H), 3.44 (q, J=2.2Hz, 3H).13C NMR(100MHz,CDCl3): δ 29.5 (q, J=6.5Hz), 67.9,84.9, (q, J=33.3Hz), 87.0,113.5 121.4,123.0 (q, J=272.7Hz), 123.4,128.33 (q, J=6.1Hz), 128.35,128.5,129.3,131.7,140.0,140.1,175.0.
The high resolution mass spectrum HRMS (ESI) of compound 9 is calculated as: C18H13NO2F3(M+H)+, 332.0898, find: 332.0905.
The enantiomeric excess of compound 9 passes through high-performance liquid chromatogram determination, and chiral column uses chirality OD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=7.64min (R), t2=18.73min (S), enantioselectivity is 92%ee (S).
The specific rotatory power of compound 9 is [α]D 20-47.6(c 0.53,CH2Cl2)。
Embodiment 10
(S) synthesis of-1-ethyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 10), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), stirring complexing, addition 48.6mg 1-ethyl-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 67.7mg compound 10 through routine post processing, productivity 98%, enantioselectivity is 93%ee (S).
The fusing point of compound 10 is 115-116 DEG C.
The nuclear-magnetism characterization result of compound 10 is:1H NMR(400MHz,CDCl3): δ 7.81 (d, J=6.8Hz, 1H), 7.64 (d, J=8.1Hz, 1H), 7.44-7.37 (m, 2H), 7.33-7.18 (m, 4H), 4.61 (brs, 1H), 4.07-3.89 (m, 2H), 1.26 (t, J=7.0Hz, 3H).13C NMR(100MHz,CDCl3): δ 12.9 (q, J=2.0Hz), 38.1 (q, J=5.0Hz), 67.9,85.0,86.9,113.3 (q, J=33.3Hz), 121.5,123.2,123.4 (q, J=272.7Hz), 128.3,128.4 (q, J=6.1Hz), 128.8,129.2,132.2,140.37,140.39,175.3.
The high resolution mass spectrum HRMS (ESI) of compound 10 is calculated as: C19H15NO2F3(M+H)+, 346.1055, find: 346.1067.
The enantiomeric excess of compound 10 passes through high-performance liquid chromatogram determination, and chiral column uses chirality OD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=6.68min (R), t2=15.96min (S), enantioselectivity is 93%ee (S).
The specific rotatory power of compound 10 is [α]D 20-50.1(c 0.56,CH2Cl2)。
Embodiment 11
(S) synthesis of-1-butyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 11), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 54.2mg 1-butyl-7-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 72.4mg compound 11 through routine post processing, productivity 97%, enantioselectivity is 93%ee (S).
The fusing point of compound 11 is 81-83 DEG C.
The nuclear-magnetism characterization result of compound 11 is:1H NMR(400MHz,CDCl3): δ 7.80 (d, J=7.2Hz, 1H), 7.65 (d, J=7.6Hz, 1H), 7.41-7.39 (m, 2H), 7.32-7.19 (m, 4H), 4.40 (brs, 1H), 3.97-3.82 (m, 2H), 1.69-1.59 (m, 2H), 1.43-1.33 (m, 2H), 0.93 (t, J=7.4Hz, 3H).13C NMR(100MHz,CDCl3): δ 13.8,20.1,29.7 (d, J=2.1Hz), 42.9 (q, J=4.4Hz), 67.9,85.1,86.9,113.4 (q, J=33.3Hz), 121.5,123.2,123.5 (q, J=272.7Hz), 128.3,128.5 (q, J=6.1Hz), 128.8,129.2,132.1,132.2,140.59,140.60,175.4.
The high resolution mass spectrum HRMS (ESI) of compound 11 is calculated as: C21H19NO2F3(M+H)+, 374.1368, find: 374.1368.
The enantiomeric excess of compound 11 passes through high-performance liquid chromatogram determination, and chiral column uses chirality OD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=6.04min (R), t2=16.76min (S), enantioselectivity is 93%ee (S).
The specific rotatory power of compound 11 is [α]D 20-60.6(c 0.60,CH2Cl2)。
Embodiment 12
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-6-chlorooxindole (compound 12), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), stirring complexing, addition 54.3mg 1-benzyl-6-chlorisatide the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 63.5mg compound 12 through routine post processing, productivity 85%, enantioselectivity is 82%ee (S).
The fusing point of compound 12 is 135-137 DEG C.
The nuclear-magnetism characterization result of compound 12 is:1H NMR(400MHz,CDCl3): δ 7.53 (d, J=8.0Hz, 1H), 7.42 (d, J=7.1Hz, 2H), 7.37-7.21 (m, 8H), 7.08 (dd, J=8.0,1.5Hz, 1H), 6.71 (d, J=1.4Hz, 1H), 4.88 (d, J=5.5Hz, 2H), 4.28 (s, 1H).13C NMR(100MHz,CDCl3):δ44.3,69.3,85.0,87.0,110.7,121.5,123.9,125.9,127.2,127.5,128.1,128.4,129.1,129.3,132.2,134.6,136.3,143.4,174.3。
The high resolution mass spectrum HRMS (ESI) of compound 12 is calculated as: C23H17NO2Cl(M+H)+, 374.0948, find: 374.0953.
The enantiomeric excess of compound 12 passes through high-performance liquid chromatogram determination, and chiral column uses chirality OD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=70:30, flow velocity: 0.9mL/min, t1=9.01min (S), t2=20.98min (R), enantioselectivity is 82%ee (S).
The specific rotatory power of compound 12 is [α]D 20-46.5(c 0.50,CH2Cl2)。
Embodiment 13
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-6-trifluoromethyl Oxoindole (compound 13), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-6-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 74.1mg compound 13 through routine post processing, productivity 91%, enantioselectivity is 89%ee (S).
The fusing point of compound 13 is 148-149 DEG C.
The nuclear-magnetism characterization result of compound 13 is:1H NMR(400MHz,CDCl3): δ 7.72 (d, J=7.7Hz, 1H), 7.46-7.23 (m, 11H), 6.93 (s, 1H), 4.94 (q, J=15.8Hz, 2H), 4.27 (brs, 1H).13C NMR(100MHz,CDCl3): δ 44.4,69.4,84.7,87.4,106.7 (q, J=3.7Hz), 121.1 (q, J=4.0Hz), (121.3,123.6 q, J=272.7Hz), 125.3,127.3,128.3,128.4,129.2, (129.4,132.2,132.75 q, J=33.3Hz), 132.77,134.4,142.9,174.1.
The high resolution mass spectrum HRMS (ESI) of compound 13 is calculated as: C24H17NO2F3(M+H)+, 408.1211, find: 408.1216.
The enantiomeric excess of compound 13 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=20.68min (R), t2=22.78min (S), enantioselectivity is 89%ee (S).
The specific rotatory power of compound 13 is [α]D 20+24.5(c 0.53,CH2Cl2)。
Embodiment 14
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-5-trifluoromethyl Oxoindole (compound 14), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-5-trifluoromethyl isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 73.3mg compound 14 through routine post processing, productivity 90%, enantioselectivity is 93%ee (S).
The fusing point of compound 14 is 128-130 DEG C.
The nuclear-magnetism characterization result of compound 14 is:1H NMR(400MHz,CDCl3): δ 7.87 (s, 1H), 7.51 (d, J=8.2Hz, 1H), 7.44 (d, J=6.9Hz, 2H), 7.35-7.23 (m, 8H), 6.78 (d, J=8.3Hz, 1H), 4.94 (d, J=4.0Hz, 2H), 4.35 (brs, 1H).13C NMR(100MHz,CDCl3): δ 44.4,69.4,84.7,87.5, (110.0,121.3,122.2 q, J=3.7Hz), (124.1 q, J=272.7Hz), 126.3 (q, J=33.3Hz), (127.3,128.1 q, J=4.0Hz), 128.2,128.4,129.2,129.4,129.7,132.3,134.5,145.2,174.4.
The high resolution mass spectrum HRMS (ESI) of compound 14 is calculated as: C24H17NO2F3(M+H)+, 408.1211, find: 408.1222.
The enantiomeric excess of compound 14 passes through high-performance liquid chromatogram determination, and chiral column uses chirality OD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=11.67min (R), t2=16.40min (S), enantioselectivity is 93%ee (S).
The specific rotatory power of compound 14 is [α]D 20+31.2(c 0.56,CH2Cl2)。
Embodiment 15
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-5-methyl formate Oxoindole (compound 15), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 59.1mg 1-benzyl-5-methyl formate isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertbutyl, and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 62.0mg compound 15 through routine post processing, productivity 78%, enantioselectivity is 80%ee (S).
The fusing point of compound 15 is 148-150 DEG C.
The nuclear-magnetism characterization result of compound 15 is:1H NMR(400MHz,CDCl3): δ 8.30 (d, J=1.4Hz, 1H), 7.98 (dd, J=8.3,1.7Hz, 1H), 7.45 (d, J=7.0Hz, 2H), 7.34-7.25 (m, 8H), (6.76 d, J=8.3Hz, 1H), 4.95 (s, 2H), 4.10 (s, 1H), 3.89 (s, 3H).13C NMR(100MHz,CDCl3):δ44.4,52.3,69.3,84.9,87.1,109.7,121.4,125.8,126.3,127.2,128.1,128.3,129.1,129.3,132.2,132.9,134.6,146.2,166.5,174.5。
The high resolution mass spectrum HRMS (ESI) of compound 15 is calculated as: C25H20NO4(M+H)+, 398.1392, find: 398.1383.
The enantiomeric excess of compound 15 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=80:20, flow velocity: 0.9mL/min, t1=38.61min (R), t2=41.30min (S), enantioselectivity is 80%ee (S).
The specific rotatory power of compound 15 is [α]D 20+249.3(c 0.48,CH2Cl2)。
Embodiment 16
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-5-nitro Oxoindole (compound 16), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, 56.5mg 1-benzyl-5-Nitroisatoic the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 71.5mg compound 16 through routine post processing, productivity 93%, enantioselectivity is 84%ee (S).
The fusing point of compound 16 is 144-146 DEG C.
The nuclear-magnetism characterization result of compound 16 is:1H NMR(400MHz,CDCl3): δ 8.50 (d, J=2.3Hz, 1H), 8.20 (dd, J=8.7,2.3Hz, 1H), 7.47-7.43 (m, 2H), (7.37-7.26 m, 8H), 6.80 (d, J=8.7Hz, 1H), 4.98 (s, 2H), 4.41 (brs, 1H).13C NMR(100MHz,CDCl3):δ44.7,69.1,84.0,88.0,109.9,121.0,127.3,128.4,128.5,129.3,129.6,130.0,132.3,134.0,134.4,147.6,174.5。
The high resolution mass spectrum HRMS (ESI) of compound 16 is calculated as: C23H17N2O4(M+H)+, 385.1188, find: 385.1183.
The enantiomer excess quantity of compound 16 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=70:30, flow velocity: 0.9mL/min, t1=15.80min (S), t2=28.91min (R), enantioselectivity is 84%ee (S).
The specific rotatory power of compound 16 is [α] D20+142.7(c 0.99,CH2Cl2)。
Embodiment 17
(S) synthesis of-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-4-bromine Oxoindole (compound 17), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 63.2mg 1-benzyl-4-bromo-isatin the most successively, 21.4mg phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 60.2mg compound 17 through routine post processing, productivity 72%, enantioselectivity is 80%ee (S).
The fusing point of compound 17 is 171-173 DEG C.
The nuclear-magnetism characterization result of compound 17 is:1H NMR(400MHz,CDCl3): δ 7.50 (dd, J=8.0,1.5Hz, 2H), 7.38-7.18 (m, 9H), 7.09 (t, J=8.0Hz, 1H), 6.66 (d, J=7.9Hz, 1H), 4.92 (s, 2H), 3.70 (s, 1H).13C NMR(100MHz,CDCl3):δ44.4,70.6,83.6,87.2,109.1,120.1,121.7,127.2,127.5,127.6,128.1,128.4,129.1,129.3,131.6,132.4,134.7,144.0,172.8。
The high resolution mass spectrum HRMS (ESI) of compound 17 is calculated as: C23H17NO2Br(M+H)+, 418.0443, find: 418.0430.
The enantiomeric excess of compound 17 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=70:30, flow velocity: 0.9mL/min, t1=15.27min (R), t2=18.66min (S), enantioselectivity is 80%ee (S).
The specific rotatory power of compound 17 is [α]D 20+117.3(c 0.54,CH2Cl2)。
Embodiment 18
(S) synthesis of-1-benzyl-3-hydroxyl-3-(2-methoxyphenylethynyl)-7-trifluoromethyl Oxoindole (compound 18), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 27.8mg 2-Methoxy-phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 86.6mg compound 18 through routine post processing, productivity 99%, enantioselectivity is 93%ee (S).
The fusing point of compound 18 is 115-117 DEG C.
The nuclear-magnetism characterization result of compound 18 is:1H NMR(400MHz,CDCl3): δ 7.88 (d, J=7.1Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.37 (dd, J=7.6,1.6Hz, 1H), 7.33-7.14 (m, 7H), 6.91-6.82 (m, 2H), 5.22 (s, 2H), 4.29 (brs, 1H), 3.84 (s, 3H).13C NMR(100MHz,CDCl3): δ 45.7 (q, J=5.2Hz), 56.0,68.0,84.0, (88.9,110.6,110.9,113.7 q, J=32.3Hz), (120.6,123.2 q, J=272.7Hz) 123.5,125.6,127.1, (128.5 q, J=6.1Hz), 128.6,129.1,131.0,131.9,134.0,135.77,135.78,140.5,160.7,175.6.
The high resolution mass spectrum HRMS (ESI) of compound 18 is calculated as: C25H19NO3F3(M+H)+, 438.1317, find: 438.1317.
The enantiomeric excess of compound 18 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=28.30min (R), t2=32.61min (S), enantioselectivity is 93%ee (S).
The specific rotatory power of compound 18 is [α]D 20-48.8(c 0.62,CH2Cl2)。
Embodiment 19
(S) synthesis of-1-benzyl-3-hydroxyl-3-(2-methylphenylethynyl)-7-trifluoromethyl Oxoindole (compound 19), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 24.4mg 2-methylbenzene acetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 69.1mg compound 19 through routine post processing, productivity 82%, enantioselectivity is 85%ee (S).
The fusing point of compound 19 is 85-87 DEG C.
The nuclear-magnetism characterization result of compound 19 is:1H NMR(400MHz,CDCl3): δ 7.86 (d, J=7.3Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 7.40 (d, J=7.5Hz, 1H), 7.29-7.09 (m, 9H), 5.22 (s, 2H), 3.98 (brs, 1H), (2.37 s, 3H).13C NMR(100MHz,CDCl3): δ 20.7,45.8 (q, J=5.2Hz), 68.0,86.3, (q, J=33.3Hz), 88.8,113.9 121.1,123.2 (q, J=273.7Hz), 123.6,125.6,125.7,127.2,128.5 (q, J=6.1Hz), 128.6,128.8,129.5,129.7,131.9,132.5,135.7,140.5,141.2,175.6.
The high resolution mass spectrum HRMS (ESI) of compound 19 is calculated as: C25H19NO2F3(M+H)+, 422.1368, find: 422.1371.
The enantiomeric excess of compound 19 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=17.76min (R), t2=24.67min (S), enantioselectivity is 85%ee (S).
The specific rotatory power of compound 19 is [α]D 20-44.3(c 0.54,CH2Cl2)。
Embodiment 20
(S) synthesis of-1-benzyl-3-hydroxyl-3-(3-methylphenylethynyl)-7-trifluoromethyl Oxoindole (compound 20), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 24.4mg 3-methylbenzene acetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 80.1mg compound 20 through routine post processing, productivity 95%, enantioselectivity is 94%ee (S).
The fusing point of compound 20 is 87-88 DEG C.
The nuclear-magnetism characterization result of compound 20 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=7.3Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.29-7.09 (m, 10H), 5.21 (s, 2H), 4.56 (brs, 1H), 2.25 (s, 3H).13C NMR(100MHz,CDCl3): δ 21.2,45.7 (q, J=5.2Hz), 67.9,84.6, (q, J=33.3Hz), 87.4,113.8 121.1,123.1 (q, J=273.7Hz), 123.6,125.6,127.1,128.3,128.5 (q, J=6.1Hz), 128.6,128.9,129.2,130.2,132.0,132.7,135.7,138.1,140.32,140.34,175.8.
The high resolution mass spectrum HRMS (ESI) of compound 20 is calculated as: C25H19NO2F3(M+H)+, 422.1368, find: 422.1380.
The enantiomeric excess of compound 20 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=13.04min (R), t2=16.50min (S), enantioselectivity is 94%ee (S).
The specific rotatory power of compound 20 is [α]D 20-48.3(c 0.61,CH2Cl2)。
Embodiment 21
(S) synthesis of-1-benzyl-3-hydroxyl-3-(4-methylphenylethynyl)-7-trifluoromethyl Oxoindole (compound 21), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 24.4mg 4-methylbenzene acetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), it is placed in 40 DEG C of oil baths reaction 72 hours, finally obtain 78.4mg compound 21 through routine post processing, productivity 93%, enantioselectivity is 93%ee (S).
The fusing point of compound 21 is 147-148 DEG C.
The nuclear-magnetism characterization result of compound 21 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=7.3Hz, 1H), 7.59 (dd, J=8.1Hz, 1H), 7.30 (d, J=7.9Hz, 2H), 7.28-7.16 (m, 4H), 7.14 (d, J=7.4Hz, 2H), 7.05 (d, J=7.9Hz, 2H), 5.21 (s, 2H), 4.29 (brs, 1H), 2.31 (s, 3H).13C NMR(100MHz,CDCl3): δ 21.6,45.7 (q, J=5.2Hz), 68.0,84.3, (q, J=33.3Hz), 87.5,113.8 118.2,123.1 (q, J=273.7Hz), 123.6,125.6,128.4 (q, J=6.1Hz), 128.6,128.9,129.1,132.0,132.1,135.7,139.6,140.36,140.37,175.7.
The high resolution mass spectrum HRMS (ESI) of compound 21 is calculated as: C25H19NO2F3(M+H)+, 422.1368, find: 422.1369.
The enantiomeric excess of compound 21 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=13.55min (R), t2=22.44min (S), enantioselectivity is 93%ee (S).
The specific rotatory power of compound 21 is [α]D 20-63.1(c 0.65,CH2Cl2)。
Embodiment 22
(S) synthesis of-1-benzyl-3-hydroxyl-3-(4-methoxyphenylethynyl)-7-trifluoromethyl Oxoindole (compound 22), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 27.8mg 4-Methoxy-phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 68.2mg compound 22 through routine post processing, productivity 78%, enantioselectivity is 89%ee (S).
The fusing point of compound 22 is 128-130 DEG C.
The nuclear-magnetism characterization result of compound 22 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=7.3Hz, 1H), 7.59 (d, J=8.1Hz, 1H), 7.33 (d, J=8.6Hz, 2H), 7.27-7.12 (m, 6H), 6.76 (d, J=8.6Hz, 2H), 5.21 (s, 2H), 4.54 (brs, 1H), 3.76 (s, 1H).13C NMR(100MHz,CDCl3): δ 45.7 (q, J=5.0Hz), 55.4,68.0,83.8, (q, J=33.3Hz), 87.4,113.3,113.7 114.0,123.2 (q, J=273.7Hz), 123.6,125.6, (127.1,128.4 q, J=6.1Hz), 128.6,128.8,132.1,133.8,135.7,140.29,140.30,160.4,175.9.
The high resolution mass spectrum HRMS (ESI) of compound 22 is calculated as: C25H19NO3F3(M+H)+, 438.1317, find: 438.1302.
The enantiomeric excess of compound 22 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=18.68min (R), t2=30.93min (S), enantioselectivity is 89%ee (S).
The specific rotatory power of compound 22 is [α]D 20-50.9(c 0.55,CH2Cl2)。
Embodiment 23
(S) synthesis of-1-benzyl-3-hydroxyl-3-(4-ethylphenyl acetenyl)-7-trifluoromethyl Oxoindole (compound 23), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 27.3mg 4-Liquid Crystal Compounds Intermediate p-Ethyl-phenylacetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 83.6mg compound 23 through routine post processing, productivity 96%, enantioselectivity is 92%ee (S).
The fusing point of compound 23 is 124-125 DEG C.
The nuclear-magnetism characterization result of compound 23 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=7.1Hz, 1H), 7.61 (d, J=7.8Hz, 1H), 7.35 (d, J=8.1Hz, 2H), 7.28-7.18 (m, 4H), 7.14 (d, J=7.3Hz, 2H), 7.11 (d, J=8.2Hz, 2H), 5.22 (s, 2H), 4.01 (brs, 1H), 2.62 (q, J=7.6Hz, 2H), 2.31 (t, J=7.6Hz, 3H).13C NMR(100MHz,CDCl3): δ 15.4,29.0,45.7 (q, J=5.2Hz), 67.9, (84.3,87.6,113.8 q, J=33.3Hz), 118.5, (123.2 q, J=273.7Hz), 123.6,125.6,127.2, (128.0,128.5 q, J=6.1Hz), 128.6,128.9,131.9,132.2,135.7,140.45,140.46,146.0,175.6.
The high resolution mass spectrum HRMS (ESI) of compound 23 is calculated as: C26H21NO2F3(M+H)+, 436.1524, find: 436.1530.
The enantiomeric excess of compound 23 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=14.00min (R), t2=20.53min (S), enantioselectivity is 92%ee (S).
The specific rotatory power of compound 23 is [α]D 20-49.2(c 0.59,CH2Cl2)。
Embodiment 24
(S) synthesis of-1-benzyl-3-hydroxyl-3-(4-tert-butyl-phenyl acetenyl)-7-trifluoromethyl Oxoindole (compound 24), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 33.2mg 4-tert-butyl benzene acetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 76.0mg compound 24 through routine post processing, productivity 82%, enantioselectivity is 91%ee (S).
The fusing point of compound 24 is 153-154 DEG C.
The nuclear-magnetism characterization result of compound 24 is:1H NMR(400MHz,CDCl3): δ 7.85 (d, J=7.1Hz, 1H), (7.59 d, J=8.0Hz, 1H), (7.35 d, J=8.4Hz, 2H), 7.30-7.12 (m, 8H), 5.22 (s, 2H), 4.59 (brs, 1H), (1.28 s, 9H).13C NMR(100MHz,CDCl3): δ 31.2,35.0,45.7 (q, J=5.2Hz), 68.0, (84.4,87.5,113.8 q, J=33.3Hz), 118.3, (123.2 q, J=273.7Hz), 123.6,125.4, (125.6,127.1,128.4 q, J=6.1Hz), 128.6,128.9,132.0,132.1,135.7,140.4,152.8,175.9.
The high resolution mass spectrum HRMS (ESI) of compound 24 is calculated as: C28H25NO2F3(M+H)+, 464.1837, find: 464.1843.
The enantiomeric excess of compound 24 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=6.96min (R), t2=17.39min (S), enantioselectivity is 91%ee (S).
The specific rotatory power of compound 24 is [α]D 20-54.4(c 0.61,CH2Cl2)。
Embodiment 25
(S) synthesis of-1-benzyl-3-hydroxyl-3-(4-fluorophenylethynyl)-7-trifluoromethyl Oxoindole (compound 25), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 25.2mg 4-fluorobenzene acetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 68.9mg compound 25 through routine post processing, productivity 81%, enantioselectivity is 88%ee (S).
The fusing point of compound 25 is 169-171 DEG C.
The nuclear-magnetism characterization result of compound 25 is:1H NMR(400MHz,CDCl3): δ 7.84 (d, J=6.6Hz, 1H), 7.62 (d, J=8.1Hz, 1H), 7.43-7.35 (m, 2H), 7.30-7.17 (m, 4H), 7.14 (d, J=7.1Hz, 2H), 7.01-6.90 (m, 2H), 5.22 (s, 2H), 4.26 (brs, 1H).13C NMR(100MHz CDCl3): δ 45.8 (q, J=5.0Hz), 67.9,84.8,86.2,113.9 (q, J=33.3Hz), 115.8 (d, J=22.2Hz), (117.4 d, J=3.3Hz), 123.1 (q, J=272.7Hz), 123.7,125.6, (127.2,128.64 q, J=6.1Hz), 128.65,128.9,131.7, (134.2 d, J=8.6Hz), 135.6,140.43,1140.44,163.2 (d, J=252.5Hz), 175.6.
The high resolution mass spectrum HRMS (ESI) of compound 25 is calculated as: C24H16NO2F4(M+H)+, 426.1117, find: 426.1113.
The enantiomeric excess of compound 25 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=13.97min (R), t2=25.87min (S), enantioselectivity is 88%ee (S).
The specific rotatory power of compound 25 is [α]D 20-51.7(c 0.55,CH2Cl2)。
Embodiment 26
(S) synthesis of-1-benzyl-3-hydroxyl-3-(1-naphthyl acetylene base)-7-trifluoromethyl Oxoindole (compound 26), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 32.0mg 1-acetenyl naphthalene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 86.9mg compound 26 through routine post processing, productivity 95%, enantioselectivity is 89%ee (S).
The fusing point of compound 26 is 206-207 DEG C.
The nuclear-magnetism characterization result of compound 26 is:1H NMR(400MHz,CDCl3): δ 8.23-8.13 (m, 1H), 7.95 (d, J=7.3Hz, 1H), 7.83 (dd, J=9.0,4.5Hz, 2H), 7.65 (t, J=8.1Hz, 2H), 7.50 (dd, J=9.2,5.2Hz, 2H), 7.37 (t, J=7.7Hz, 1H), 7.30-7.15 (m, 6H), 5.25 (d, J=2.9Hz, 2H), 4.17 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.8 (q, J=5.1Hz), 68.2,85.7,89.7,114.0 (q, J=32.3Hz), 118.9,123.2 (q, J=272.7Hz), 123.7,125.1,125.6,125.9,126.7,127.2, (127.4,128.5,128.7,128.8 q, J=6.1Hz), 129.0,130.0,131.6,131.8,133.2,133.5,135.7,140.5,140.6,175.7.
The high resolution mass spectrum HRMS (ESI) of compound 26 is calculated as: C28H19NO2F3(M+H)+, 458.1368, find: 458.1364.
The enantiomeric excess of compound 26 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=16.98min (R), t2=24.60min (S), enantioselectivity is 89%ee (S).
The specific rotatory power of compound 26 is [α]D 20-40.5(c 0.52,CH2Cl2)。
Embodiment 27
(S) synthesis of-1-benzyl-3-hydroxyl-3-(2-thienylethynyl)-7-trifluoromethyl Oxoindole (compound 27), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 22.7mg 2-thiophene acetylene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 76.9mg compound 27 through routine post processing, productivity 93%, enantioselectivity is 85%ee (S).
The fusing point of compound 27 is 83-84 DEG C.
The nuclear-magnetism characterization result of compound 27 is:1H NMR(400MHz,CDCl3): δ 7.84 (d, J=6.9Hz, 1H), 7.61 (d, J=7.7Hz, 1H), 7.37-7.08 (m, 8H), 6.93 (dd, J=5.1,3.7Hz, 1H), 5.21 (s, 2H), 4.21 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.8 (q, J=5.0Hz), 68.1,80.8, (q, J=33.3Hz), 88.7,113.9 121.1,123.2 (d, J=272.7Hz), 123.7,125.6, (127.2,128.64 d, J=6.1Hz), 128.65,128.7,129.0,131.5,133.9,135.6,140.41,140.42,175.4.
The high resolution mass spectrum HRMS (ESI) of compound 27 is calculated as: C22H15NO2F3S(M+H)+, 414.0776, find: 414.0777.
The enantiomeric excess of compound 27 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=16.98min (R), t2=25.66min (S), enantioselectivity is 85%ee (S).
The specific rotatory power of compound 27 is [α]D 20-53.3(c 0.54,CH2Cl2)。
Embodiment 28
(S) synthesis of-1-benzyl-3-hydroxyl-3-(1-cyclohexenyl group acetenyl)-7-trifluoromethyl Oxoindole (compound 28), its structural formula is:
Under nitrogen protection, addition 1.9mg cuprous iodide successively in reaction tube, 7.1mg (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-3-Phenylpropionamide, 0.5mL methyl tertiary butyl ether(MTBE), it is sufficiently stirred for being complexed 1 hour, addition 61.1mg 1-benzyl-7-trifluoromethyl isatin the most successively, 22.3mg 1-acetenyl cyclohexene, 40.5mg triethylamine and 0.5mL methyl tertiary butyl ether(MTBE), and it is positioned in 40 DEG C of oil baths reaction 72 hours, finally obtain 79.0mg compound 28 through routine post processing, productivity 96%, enantioselectivity is 91%ee (S).
The fusing point of compound 28 is 67-69 DEG C.
The nuclear-magnetism characterization result of compound 28 is:1H NMR(400MHz,CDCl3): δ 7.78 (d, J=6.7Hz, 1H), 7.59 (d, J=8.1Hz, 1H), 7.30-7.18 (m, 4H), (7.12 d, J=7.2Hz, 2H), 6.25-6.13 (m, 1H), 5.20 (s, 2H), 3.81 (brs, 1H), 2.12-2.03 (m, 4H), 1.63-1.52 (m, 4H).13C NMR(100MHz,CDCl3): δ 21.4,22.2,25.8,28.7,45.6 (q, J=5.0Hz), 67.8,82.4,89.2,113.7 (q, J=33.3Hz), 119.4,123.2 (q, J=272.7Hz), 123.5, (125.6,127.1,128.3 q, J=6.1Hz), 128.6,128.8,132.1,132.2,135.7,137.8,137.9,140.3,175.8.
The high resolution mass spectrum HRMS (ESI) of compound 28 is calculated as: C24H21NO2F3(M+H)+, 412.1524, find: 412.1522.
The enantiomeric excess of compound 28 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=12.51min (R), t2=14.17min (S), enantioselectivity is 91%ee (S).
The specific rotatory power of compound 28 is [α]D 20-56.1(c 0.58,CH2Cl2)。
Hydroxyl-3-alkynyl the oxidized indole compounds of S type 3-shown in described general structure (I) is also used in organic synthesis by the present invention as raw material, specifically have chosen (S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound (compound 1) described in embodiment 1 as raw material application in organic synthesis, described (S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound (compound 1): as alkynyl being reduced into saturated hydrocarbons through Pd/C hydrogenation, through Lindlar reagent, alkynyl is reduced into alkene etc..Those skilled in the art are according to actual needs, in application process, it is not limited only to the application to (S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole compound (compound 1), can arbitrarily select any one compound of S type 3-hydroxyl-3-alkynyl oxidized indole compounds shown in described general structure (I)；Those skilled in the art are according to the needs of actual scientific research simultaneously, are also not limited to the application to the alkynyl in S type 3-hydroxyl-3-alkynyl oxidized indole compounds shown in described general structure (I), as can be to the application of the group such as hydroxyl, carbonyl.
Embodiment 29
(S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 1) obtains compound 1-1 through Pd/C reduction, and its reaction equation is:
Under hydrogen (1atm) atmosphere, addition 5.3mg Pd/C, 1mL ethyl acetate successively and 40.7mg (S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (92%ee) in reaction tube, the most at room temperature reaction 1 hour, finally obtain 39.9mg compound 1-1 through routine post processing, productivity 97%, enantioselectivity is 90%ee (S).
The fusing point of compound 1-1 is 107-109 DEG C.
The nuclear-magnetism characterization result of compound 1-1 is:1H NMR(400MHz,CDCl3): δ 7.62 (d, J=7.4Hz, 1H), 7.59 (d, J=8.2Hz, 1H), 7.27-7.09 (m, 9H), 7.01 (d, J=6.9Hz, 2H), 5.11 (q, J=17.0Hz, 2H), 3.58 (brs, 1H), 2.56-2.44 (m, 2H), 2.41-2.24 (m, 2H).13C NMR(100MHz,CDCl3): δ 29.6,40.7,45.7 (q, J=4.8Hz), (q, J=33.3Hz), 74.5,113.5 123.1,123.7 (q, J=272.7Hz), 125.9,126.3, (127.87,127.91 q, J=6.1Hz), 128.4,128.6,132.9,136.0,140.4,141.0,178.0.
The high resolution mass spectrum HRMS (ESI) of compound 1-1 is calculated as: C24H21NO2F3(M+H)+, 412.1524, find: 412.1529.
The enantiomeric excess of compound 1-1 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=22.12min (R), t2=31.41min (S), enantioselectivity is 90%ee (S).
The specific rotatory power of compound 1-1 is [α]D 20-67.7(c 1.12,CH2Cl3)。
Embodiment 30
(S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (compound 1) obtains compound 1-2 through Lindlar catalyst reduction, and its reaction equation is:
Under hydrogen (1atm) atmosphere, addition 20.4mg (S)-1-benzyl-3-hydroxyl-3-(phenylene-ethynylene)-7-trifluoromethyl Oxoindole (92%ee) successively, 1mL ethyl acetate, 2.6 μ L quinoxaline and 2.0mg Pd/CaCO in reaction tube3, the most at room temperature reaction 24 hours, finally obtain 14.0mg compound 1-2, productivity 68% through routine post processing, enantioselectivity is 92%ee (S).
The fusing point of compound 1-2 is 162-164 DEG C.
The nuclear-magnetism characterization result of compound 1-2 is:1H NMR(400MHz,CDCl3): δ 7.57 (d, J=7.3Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.25-7.08 (m, 7H), 7.04 (d, J=7.2Hz, 2H), 7.01-6.93 (m, 2H), 6.82 (d, J=12.1Hz, 1H), 6.00 (d, J=12.1Hz, 1H), 4.94 (d, J=17.2Hz, 1H), 4.75 (d, J=17.2Hz, 1H), 3.32 (brs, 1H).13C NMR(100MHz,CDCl3): δ 45.4 (q, J=4.8Hz), 74.7,113.5 (q, J=33.3Hz), 123.1,123.2 (q, J=272.7Hz), 125.7,127.0,127.8, (127.9 q, J=6.1Hz), 128.0,128.5,131.0,133.8,133.9,135.9,177.9.
The high resolution mass spectrum HRMS (ESI) of compound 1-2 is calculated as: C24H21NO2F3(M+H)+, 410.1368, find: 410.1361.
The enantiomeric excess of compound 1-2 passes through high-performance liquid chromatogram determination, and chiral column uses chirality AD-H post, detects wavelength 254 nanometer, eluent: n-hexane: isopropanol=90:10, flow velocity: 0.9mL/min, t1=15.59min (R), t2=25.48min (S), enantioselectivity is 92%ee (S).
The specific rotatory power of compound 1-2 is [α]D 20+11.2(c 0.55,CHCl3)。
The present invention is with copper salt and hand-type part as catalyst, with isatin compounds and terminal alkyne compound as initiation material, there is nucleophilic addition in a heated condition, obtaining S 3-hydroxyl-3-alkynyl oxidized indole compounds, the method has that cheaper starting materials is easy to get, reaction condition is gentle, simple to operate, Atom economy good, enantioselectivity advantages of higher；A series of S 3-hydroxyl-3-alkynyl oxidized indole compounds of present invention synthesis, provide important basis for research to this compounds from now on.
Present invention disclosed above preferred embodiment is only intended to help to illustrate the present invention.Preferred embodiment does not has all of details of detailed descriptionthe, is not intended to the detailed description of the invention that this invention is only described yet.Obviously, according to the content of this specification, can make many modifications and variations.These embodiments are chosen and specifically described to this specification, is to preferably explain the principle of the present invention and actual application, so that skilled artisan can be best understood by and utilize the present invention.The present invention is only limited by claims and four corner thereof and equivalent.

Claims (14)

1. a S type 3-hydroxyl-3-alkynyl oxidized indole compounds, it is characterised in that its general structure (I) For:
In general structure (I), R1Selected from electron withdraw group, for Br, NO2、CO2Me、CF3、Cl Or CF3；R2For hydrogen atom, C1-4Alkyl, phenyl, benzyl and derivative thereof or naphthyl；R3For phenyl And derivative, naphthyl, cyclohexenyl group, thiophene, pyridine or furans.
2. S type 3-hydroxyl-3-alkynyl oxidized indole shown in a general structure as claimed in claim 1 (I) The synthetic method of compound, it is characterised in that described synthetic method comprises the steps:
(1) under inert gas shielding, in reaction unit addition copper salt, chiral ligand respectively, have Machine solvent, stirs 0.5～2h；
(2) after, more respectively add isatin compounds, terminal alkyne compound, organic base and described Organic solvent, adds thermal response；
(3), after reaction completely, post-treated the described compound as shown in general structure (I) is obtained.
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described copper salt is that cuprous iodide, cuprous bromide, TFMS be cuprous, oxygen Change cuprous, Salicylaldoxime, copper acetate monohydrate, copper trifluoromethanesulfcomposite, copper chloride, copper bromide, Cupric oxide, trifluoroacetic acid copper, copper chloride dihydrate, two water copper bromides, copper carbonate, nitrate trihydrate copper, cyanogen Change one or more of cuprous, acetylacetone copper, copper fluoride, Kocide SD or cupric sulfate pentahydrate.
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described chiral ligand be R-(+)-1,1'-dinaphthalene-2,2'-diphenyl phosphine, (R, R)-2,2 '-different Asia Propyl group double (4-phenyl-2-oxazoline), (R, R)-2,2 '-(2,6-pyridine diyl)-bis-(4-isopropyl-2-oxazoline), N-((1R, 2R)-2-(diphenylphosphino) hexamethylene) benzamide, ((S)-1-(((1R, 2R)-2-(diphenylphosphino) Cyclohexyl) amine)-1-oxygen-3-phenyl propyl-2-base) carbamate, (S)-N-((1R, 2R)-2-(two Phenyl phosphino-)-cyclohexyl)-2-(benzene sulfonamido)-3-Phenylpropionamide, (S)-N-((1R, 2R)-2-(diphenyl Phosphino-)-cyclohexyl)-2-((4-aminomethyl phenyl) sulfoamido)-2-Phenylpropionamide or (S)-N-((1R, 2R)-2-(diphenylphosphino)-cyclohexyl)-2-phenyl-2-((4-aminomethyl phenyl) sulfoamido)-second One or more of acid amides.
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described isatin compounds be the substituent on phenyl ring be the isatin class of electron withdraw group Compound.
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described terminal alkyne compound is the substituted acetylene compound of 1-, and described 1- Substituted substituent is unsaturated hydro carbons or unsaturated heterocyclic compound.
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described organic base is organic amine compound.
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described organic solvent be ethyl acetate, n-hexane, hexamethylene, oxolane, two Chloromethanes, 1,2-dichloroethanes, acetonitrile, toluene, benzene, dimethylbenzene, 1,4-dioxane, methyl alcohol, N, N- One or more of dimethylformamide, dimethyl sulfoxide (DMSO) or methyl tertiary butyl ether(MTBE).
9. according to the synthesis side of the S type 3-hydroxyl-3-alkynyl oxidized indole compounds described in claim 2 or 8 Method, it is characterised in that described organic solvent is methyl tertiary butyl ether(MTBE).
The synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds the most according to claim 2, It is characterized in that, described reaction temperature is 0-100 DEG C.
11. according to the synthesis of the S type 3-hydroxyl-3-alkynyl oxidized indole compounds described in claim 2 or 10 Method, it is characterised in that described reaction temperature is 40 DEG C.
12. the synthetic method of S type 3-hydroxyl-3-alkynyl oxidized indole compounds according to claim 2, It is characterized in that, described copper salt, described chiral ligand, described isatin compounds, institute Mol ratio between terminal alkyne compound and the described organic base stated is 1:(1-100): (1-100): (1-100):(1-100)。
13. according to the synthesis of the S type 3-hydroxyl-3-alkynyl oxidized indole compounds described in claim 2 or 12 Method, it is characterised in that described copper salt, described chiral ligand, described isatin class chemical combination Thing, mol ratio between described terminal alkyne compound and described organic base are 1:(1-1.2): (1-20): (1-21):(1-40)。
-3-alkynyl oxidized indole the chemical combination of S type 3-hydroxyl shown in general structure (I) described in 14. claims 1 Thing is as raw material application in organic synthesis.
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