CN108484610B - Preparation method of peroxy-substituted pyrrole/furoindoline - Google Patents
Preparation method of peroxy-substituted pyrrole/furoindoline Download PDFInfo
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- CN108484610B CN108484610B CN201810330635.6A CN201810330635A CN108484610B CN 108484610 B CN108484610 B CN 108484610B CN 201810330635 A CN201810330635 A CN 201810330635A CN 108484610 B CN108484610 B CN 108484610B
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- HXPKLPDOGLCOST-UHFFFAOYSA-N 2,3-dihydro-1h-furo[2,3-g]indole Chemical compound C1=C2OC=CC2=C2NCCC2=C1 HXPKLPDOGLCOST-UHFFFAOYSA-N 0.000 title claims abstract description 25
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 150000003233 pyrroles Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000000758 substrate Substances 0.000 claims abstract description 52
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 19
- 239000007800 oxidant agent Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 claims abstract description 14
- MBBOMCVGYCRMEA-UHFFFAOYSA-N tryptophol Chemical compound C1=CC=C2C(CCO)=CNC2=C1 MBBOMCVGYCRMEA-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 13
- 239000011630 iodine Substances 0.000 claims abstract description 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 11
- 239000013067 intermediate product Substances 0.000 claims abstract description 10
- KCUNTYMNJVXYKZ-JTQLQIEISA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical class C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 KCUNTYMNJVXYKZ-JTQLQIEISA-N 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims abstract description 5
- 230000003213 activating effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 96
- 239000000047 product Substances 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 47
- 235000019439 ethyl acetate Nutrition 0.000 claims description 39
- 239000012074 organic phase Substances 0.000 claims description 39
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 239000012043 crude product Substances 0.000 claims description 24
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical group [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- 239000000741 silica gel Substances 0.000 claims description 15
- 229910002027 silica gel Inorganic materials 0.000 claims description 15
- 239000012279 sodium borohydride Substances 0.000 claims description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract description 2
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 17
- -1 artemisinin) Chemical class 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- 241000894007 species Species 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- ACIADIFDPPYYRZ-UHFFFAOYSA-N 1,2,3,6-tetrahydropyrrolo[2,3-e]indole Chemical compound C1=C2NC=CC2=C2NCCC2=C1 ACIADIFDPPYYRZ-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002978 peroxides Chemical group 0.000 description 3
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- VPIUVBLEDIDJQZ-UHFFFAOYSA-N n-[2-(1h-indol-3-yl)ethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCCC1=CNC2=CC=CC=C12 VPIUVBLEDIDJQZ-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UDQCRUSSQAXPJY-VIFPVBQESA-N (2s)-2-amino-3-(1h-indol-3-yl)propan-1-ol Chemical compound C1=CC=C2C(C[C@@H](CO)N)=CNC2=C1 UDQCRUSSQAXPJY-VIFPVBQESA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 241000006808 Sessiliflorae Species 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- HBAVNBDJHFGWKR-UHFFFAOYSA-N n-[2-(1h-indol-3-yl)ethyl]-4-nitrobenzenesulfonamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NCCC1=CNC2=CC=CC=C12 HBAVNBDJHFGWKR-UHFFFAOYSA-N 0.000 description 1
- SQBNLWFCKKNLCH-UHFFFAOYSA-N n-[2-(1h-indol-3-yl)ethyl]methanesulfonamide Chemical compound C1=CC=C2C(CCNS(=O)(=O)C)=CNC2=C1 SQBNLWFCKKNLCH-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of peroxy-substituted pyrrole/furoindoline, belonging to the technical field of fine chemical catalytic synthesis. The method comprises the steps of performing a one-pot two-step method by using tryptamine derivatives, tryptophan methyl ester derivatives or tryptophol as a substrate and organic iodide salt as a catalyst, wherein the catalyst and the oxidant react to generate high-valence iodine species in the presence of the oxidant; and activating the substrate by the high-valence iodine species, constructing an intermediate product containing a peroxide bond and a double bond, and reducing the double bond of the intermediate product under the action of a reducing agent to obtain the peroxide-substituted pyrrole/furoindoline. The method has the characteristics of environmental protection, high yield, mild condition, simple and convenient operation and the like.
Description
Technical Field
The invention belongs to the technical field of catalytic synthesis in fine chemical engineering, and particularly relates to a preparation method of peroxy-substituted pyrrole/furoindoline.
Background
Pyrroloindoline and furoindoline are important structural motifs and widely exist in natural products with biological activity, dyes, chemical industry and various medical intermediates. For example: physostigmine can be extracted from herba Crotalariae sessiliflorae, is an alkaloid chemical containing pyrroline, and can be used for treating glaucoma, myasthenia gravis, Alzheimer disease, etc.
Also, since the bond energy of the peroxy bond is low, it is rather unstable and very sensitive to the reaction conditions. A number of documents have already demonstrated: the peroxy bond plays a crucial role in most medicines. Therefore, in the field of medicinal chemistry, introduction of a peroxy bond to an organic compound is also a very important and difficult direction. Therefore, the development of a method for introducing a peroxy group into the pyrroloindoline and furoindoline skeleton is of great significance.
Disclosure of Invention
In view of the above drawbacks or needs for improvement in the prior art, the present invention provides a method for preparing peroxy-substituted pyrrole/furoindoline, which aims to construct a stable target product peroxy-substituted pyrrole/furoindoline by a "one-pot two-step method", first oxidizing a tryptamine derivative, a tryptophan methyl ester derivative or a tryptol into a first product having a structure of formula (ii) in the presence of a small organic molecular catalyst, and then reducing the double bond of the first product with a suitable reducing agent.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a method for preparing peroxy-substituted pyrrole/furoindoline, comprising the steps of using a tryptamine derivative, a tryptophan methyl ester derivative or tryptophol as a substrate, using an organic iodide salt as a catalyst, and reacting the catalyst with the oxidant in the presence of the oxidant to generate a high-valence iodine species; and activating the substrate by the high-valence iodine species, constructing an intermediate product containing a peroxide bond and a double bond, and reducing the double bond of the intermediate product under the action of a reducing agent to obtain the peroxide-substituted pyrrole/furoindoline.
Preferably, the preparation method comprises the following steps:
(1) taking a substrate I and a substrate II as initial raw materials, and reacting in a solvent under the catalytic action of an organic iodide salt catalyst to generate a first product; wherein the substrate I has a structural formula shown as a formula (I), the substrate II simultaneously acts as an oxidizing agent, and the first product has a structural formula shown as a formula (II):
(2) adding a reducing agent into the first product obtained in the step (1), and separating after reaction to obtain peroxy-substituted pyrrole/furoindoline shown in a structural formula (III);
wherein R is an electron-withdrawing group or an electron-donating group(ii) a X is O or NR1；R1Is an electron withdrawing group, R2Is methyl or phenyl; r3Is H or COOMe.
Preferably, R is hydrogen, alkyl, alkoxy or halogen; r1Is a sulfonyl group Ts, Ns or Ms, R2Is methyl or phenyl.
Further preferably, R1Is Ts.
Preferably, the catalyst is TBAI (tetraethylammonium iodide) and the amount of the catalyst is 10-30% of the amount of the substrate I.
Preferably, the amount of the catalyst is 20% of the amount of the substrate I.
Preferably, the substrate II is TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide).
Preferably, the molar ratio of substrate I to substrate II is 1 (3-4), preferably 1: 4.
Preferably, the reaction temperature in the step (1) is 80-120 ℃; the reaction time is 2-3 hours.
Preferably, the reaction temperature in step (1) is 90 ℃.
Preferably, the solvent is ethyl acetate, tetrahydrofuran, acetonitrile, toluene or 1, 4-dioxane.
Preferably, the solvent is 1, 4-dioxane.
Preferably, the reducing agent in the step (2) is sodium borohydride, and the molar ratio of the reducing agent to the substrate I is (3-4): 1.
Preferably, the reaction temperature in the step (2) is 25-30 ℃, and the reaction time is 0.5-1 hour.
Preferably, the preparation method further comprises a step (3) of separation and purification, wherein the step (3) is specifically as follows:
(3-1) adding saturated NH to the reaction System4Stirring the Cl solution for a few minutes, and extracting the Cl solution with EtOAc (ethyl acetate) for 2-3 times in a separating funnel;
(3-2) washing the loaded organic phase obtained in the step (3-1) with a saturated sodium thiosulfate solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to remove the solvent to obtain a crude product;
(3-3) filling columns with 100-200 meshes of silica gel and petroleum ether, filling the columns by a dry method, and dissolving the crude product with a small amount of dichloromethane to fill the upper end parts of the silica gel columns;
and (3-4) eluting by using a mixed solvent of petroleum ether and ethyl acetate, collecting a target product, concentrating the organic phase under reduced pressure to remove the solvent, and drying in vacuum to obtain the target product with the structure shown as the formula (III).
In general, compared with the prior art, the above technical solution contemplated by the present invention can achieve the following beneficial effects:
(1) the invention adopts a 'one-pot two-step method', tryptamine derivatives, tryptophan methyl ester derivatives or tryptophanol are taken as substrates, organic iodides are taken as catalysts, the catalysts and the oxidants react to generate high-valence iodine species under the condition of the existence of the oxidants, the high-valence iodine species activate the substrates to construct intermediate products containing peroxide bonds and double bonds, and then the double bonds of the intermediate products are reduced under the action of a reducing agent to obtain the peroxide substituted pyrrole/furoindoline.
(2) The invention uses easy-to-obtain tryptamine substrate and cheap and easy-to-obtain peroxide TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide) as starting materials. And (3) taking TBAI as a catalyst, fully stirring at 80-120 ℃, cooling to room temperature (no need of post-treatment), and adding a cheap reducing agent sodium borohydride to obtain the target product peroxy-substituted pyrrole/indoline. Replacing tryptamine substrates with tryptophol under the same conditions, and obtaining the target product peroxy-substituted furoindoline according to the same method. The starting materials in the preparation method are all industrial commodities, are simple and easy to obtain, and have wide sources. The catalyst and the reducing agent are cheap and easily obtained industrial products.
(3) The target product (formula (III)) of the present invention is more stable than other peroxides (e.g., artemisinin), does not require special storage conditions, and is not sensitive to light and air.
(4) The preparation method disclosed by the invention is relatively mild in reaction conditions, strong in operability, low in cost, high in safety and environment-friendly.
(5) The preparation method has the advantages of high reaction conversion rate and yield, short process flow, easy enlargement of reaction scale, simple product separation and suitability for industrial production.
Drawings
FIG. 1 shows the NMR spectrum of the objective product obtained in example 1.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the objective product obtained in example 1.
FIG. 3 is the NMR spectrum of the objective product obtained in example 2.
FIG. 4 shows the NMR spectrum of the objective product obtained in example 4.
FIG. 5 shows the NMR spectrum of the objective product obtained in example 6.
FIG. 6 shows the NMR spectrum of the objective product obtained in example 9.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The invention provides a preparation method of peroxy-substituted pyrrole/furoindoline, which takes tryptamine derivatives, tryptophan methyl ester derivatives or tryptol as raw materials, TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide) as a substrate and also serves as an oxidizing agent, under the catalysis of small organic molecule TBAI, the tryptamine derivatives, the tryptophan methyl ester derivatives or the tryptol and the like are oxidized into unsaturated peroxy-substituted pyrrole/furoindoline, and then the unsaturated peroxy-substituted pyrrole/furoindoline is reduced under the action of a reducing agent to obtain the peroxy-substituted pyrrole/furoindoline.
Using tryptamine derivative, tryptophan methyl ester derivative or tryptophol as a substrate, using organic iodide salt as a catalyst, and reacting the catalyst and the oxidant in the presence of the oxidant to generate high-valence iodine species IO-Or IO2-(ii) a High-valence iodineActivating a substrate by species, constructing an intermediate product containing a peroxide bond and a double bond, and reducing the double bond of the intermediate product under the action of a reducing agent to obtain the peroxide-substituted pyrrole/furoindoline.
Specifically, the preparation method comprises the following steps:
(1) taking a substrate I and a substrate II as initial raw materials, and reacting in a solvent to generate a first product under the catalytic action of an organic small molecular catalyst; wherein, the substrate I has a structural formula shown in a formula (I), the substrate II simultaneously acts as an oxidant, and the first product has a structural formula shown in a formula (II):
the catalyst is organic iodine salt such as NaI, KI and TBAI (tetraethylammonium iodide), etc., preferably organic small molecule TBAI (tetraethylammonium iodide), and the molar amount of the catalyst is 10-30%, preferably 20% of the substrate I. The substrate II, i.e.the oxidizing agent, is TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide). The substrate II of the invention simultaneously acts as an oxidizing agent to react with the catalyst. The molar ratio of the substrate I to the substrate II is 1 (3-4), preferably 1: 4. The reaction temperature in the step (1) is 80-120 ℃, and preferably 90 ℃; the reaction time is 2-3 hours. The solvent is ethyl acetate, tetrahydrofuran, acetonitrile, toluene or 1, 4-dioxane, preferably 1, 4-dioxane.
(2) Adding a reducing agent into the first product obtained in the step (1) to obtain peroxy-substituted pyrrole/furoindoline shown in the structural formula (III);
wherein R is an electron withdrawing group or an electron donating group, preferably hydrogen, alkyl, alkoxy or halogen; x is O or NR1；R1As an electron-withdrawing group, a sulfonyl group Ts, Ns, Ms, etc. are preferable, and Ts is more preferable; r2Is methyl or phenyl; r3Is H or COOMe. The reducing agent is preferably sodium borohydride in a molar ratio to the substrate I1 is calculated as (3-4). The reaction temperature in the step (2) is 25-30 ℃, and the reaction time is 0.5-1 hour.
The preparation method also comprises a step (3) of separation and purification, wherein the step (3) is specifically as follows:
(3-1) adding saturated NH to the reaction System4Stirring the Cl solution for a few minutes, and extracting the Cl solution with EtOAc (ethyl acetate) for 2-3 times in a separating funnel;
(3-2) washing the obtained loaded organic phase with a saturated sodium thiosulfate solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to remove the solvent to obtain a crude product;
(3-3) filling columns with 100-200 meshes of silica gel and petroleum ether, filling the columns by a dry method, and dissolving the crude product with a small amount of dichloromethane to fill the upper end parts of the silica gel columns;
and (3-4) eluting by using a mixed solvent of petroleum ether and ethyl acetate, collecting a target product, concentrating the organic phase under reduced pressure to remove the solvent, and drying in vacuum to obtain the target product with the structure shown as the formula (III).
Specifically, when the substrate I is a substituted tryptamine derivative and a methyl tryptophate derivative represented by the formula (I), TBAI accounting for 20 mol% of the amount of the substrate I is used as a catalyst, TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide) accounting for 4.0 equivalents is used as an oxidant and simultaneously used as a substrate, 1, 4-dioxane is used as a reaction solvent, and the reaction is carried out at the temperature of 90 ℃ for 2-3 hours. And cooling to room temperature, adding sodium borohydride which is 4 times of the amount of the substrate I as a reducing agent, stirring at room temperature for 0.5-1 hour, and then performing simple post-treatment and purification to obtain the target product, namely the peroxy-substituted pyrroloindoline.
When the substrate I is tryptophol represented by the structure of formula (I), TBAI of 20 mol% of the amount of the substrate I is used as a catalyst, TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide) of 4.0 equivalents is used as an oxidizing agent and simultaneously serves as a substrate, 1, 4-dioxane is used as a reaction solvent, the reaction temperature is 90 ℃, and the reaction time is slightly prolonged to 3 hours. And cooling to room temperature, adding sodium borohydride which is 4 times of the amount of the substrate I as a reducing agent, stirring at room temperature for 0.5-1 hour, and then performing simple post-treatment and purification to obtain the target product, namely the peroxy-substituted furoindoline.
The reaction mechanism for preparing the peroxy-substituted pyrrole/furoindoline is as follows: TBAI (tetrabutylammonium iodide) can react with TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide) to form tBuOO and (Me), respectively2PhCOO simultaneously produces higher iodine species (e.g., IO-, IO 2-). The higher iodine species can further activate the substrate, while tBuOO.and (Me)2PhCOO is involved in the reaction to construct a peroxide bond, firstly a slightly unstable unsaturated compound formula (II) is generated, and then NaBH is used4The double bond is reduced to form a stable product. The construction of t-butyl peroxy-substituted pyrroloindolines using TBAI as catalytic tryptamine derivative is illustrated by the following examples: TBAI (tetrabutylammonium iodide) can react with TBHP (tert-butyl hydroperoxide) or CHP (cumene hydroperoxide) to generate tBuOO and higher iodine species (e.g., IO-, IO2-), respectively. High-valence iodine species can further activate a substrate, simultaneously tBuOO is involved in the reaction to construct a peroxy bond, firstly a slightly unstable unsaturated compound formula (II) is generated, and then NaBH is used4The double bond is reduced to form a stable product.
The following are examples:
example 1
Tetrabutylammonium iodide (0.04mmol,14.8mg), N- (2- (1H-indol-3-yl) ethyl) -4-methylbenzenesulfonamide (0.2mmol,62.9mg), 8 ml of 1, 4-dioxane and finally tert-butanol peroxide (0.8mmol) were added in a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 30 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 30: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 79% yield from the two-step separation. The structural formula of the obtained product is shown as a formula (III), wherein: r ═ H, X ═ NTs, R2＝Me，R3＝H。
FIG. 1 shows the NMR spectrum of the objective product obtained in example 1. FIG. 2 is a nuclear magnetic resonance carbon spectrum of the objective product obtained in example 1.
1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.1Hz,1H),7.33(d,J＝7.9Hz,1H),7.12–7.22(m,1H),6.87–6.59(m,1H),5.43(d,J＝1.8Hz,1H),4.91(s,1H),3.42–3.34(m,1H),3.32–3.21(m,1H),2.49–2.60(m,1H),2.43(s,3H),2.21–2.09(m,1H),1.06(s,9H).
13C NMR(101MHz,CDCl3)δ150.2,143.8,135.1,130.9,129.8,127.7,126.0,124.8,119.1,110.3,97.9,80.1,79.4,47.4,33.9,26.5,21.6.
Example 2
Tetrabutylammonium iodide (0.04mmol,14.8mg), N- (2- (1H-indol-3-yl) ethyl) methanesulfonamide (0.2mmol,47.7mg), 8 ml of 1, 4-dioxane, and finally tert-butanol peroxide (0.8mmol) were added in a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 30 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 30: 1. The desired product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 78% yield over the two step separation. The structural formula of the obtained product is shown as the formula (III): r is H, X is NMs, R2＝Me，R3＝H。
FIG. 3 is the NMR spectrum of the objective product obtained in example 2.
1H NMR(400MHz,CDCl3)δ7.29–7.12(m,2H),6.84(td,J＝7.5,1.0Hz,1H),6.69(d,J＝7.9Hz,1H),5.64(d,J＝3.2Hz,1H),4.74(d,J＝3.3Hz,1H),3.64(ddd,J＝9.7,8.0,2.9Hz,1H),3.19(td,J＝9.7,6.2Hz,1H),2.95(s,3H),2.80(ddd,J＝12.5,9.9,8.0Hz,1H),2.27(ddd,J＝12.5,6.2,2.9Hz,1H),1.19(s,9H).
13C NMR(101MHz,CDCl3)δ150.4,130.9,126.6,125.0,119.8,110.8,98.0,80.4,79.5,46.8,38.4,34.2,26.7.
Example 3
Tetrabutylammonium iodide (0.04mmol,14.8mg), N- (2- (1H-indol-3-yl) ethyl) -4-nitrobenzenesulfonamide (0.2mmol,69.1mg), 8 ml of 1, 4-dioxane and finally tert-butanol peroxide (0.8mmol) were added in a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2.5 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 30 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 35: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 56% yield from the two-step separation. The structural formula of the obtained product is shown as the formula (III): r is H, X is NNs, R2＝Me，R3＝H。
1H NMR(400MHz,CDCl3)δ8.36(d,J＝8.5Hz,2H),8.10(d,J＝8.5Hz,2H),7.20(dt,J＝7.3,3.7Hz,2H),6.80(t,J＝7.4Hz,1H),6.65(d,J＝8.2Hz,1H),5.62(d,J＝2.6Hz,1H),4.89–4.77(m,1H),3.52(ddd,J＝10.5,8.2,3.8Hz,1H),3.24(td,J＝9.5,6.5Hz,1H),2.62(dt,J＝12.7,8.6Hz,1H),2.21(ddd,J＝12.7,6.5,3.9Hz,1H),1.09(s,9H).
13C NMR(101MHz,CDCl3)δ150.2,150.0,144.8,131.1,128.8,125.9,124.9,124.4,119.8,110.6,97.8,80.4,79.7,47.3,33.9,26.5.
Example 4
Tetrabutylammonium iodide (0.04mmol,14.8mg), 4-methyl-N- (2- (4-methyl-1H-indol-3-yl) ethyl) benzenesulfonamide (0.2mmol,65.7mg), 8 ml of 1, 4-dioxane, and finally tert-butanol peroxide (0.8mmol) were added in a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added portionwiseAnd stirred for 30 minutes. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 35: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 75% yield from the two step separation. The structural formula of the obtained product is shown as the formula (III): r is 4-Me, X is NTs, R2＝Me，R3H. FIG. 4 shows the NMR spectrum of the objective product obtained in example 4.
1H NMR(600MHz,CDCl3)δ7.84–7.74(m,2H),7.34(d,J＝8.0Hz,2H),7.06(t,J＝7.7Hz,1H),6.53(d,J＝7.5Hz,1H),6.47(d,J＝7.9Hz,1H),5.32(d,J＝2.1Hz,1H),4.95(d,J＝2.1Hz,1H),3.40(ddd,J＝9.1,7.6,4.7Hz,1H),3.23(dt,J＝9.1,7.6Hz,1H),2.66–2.57(m,1H),2.43(s,3H),2.30–2.23(m,4H),1.01(s,9H).
Example 5
Tetrabutylammonium iodide (0.04mmol,14.8mg), N- (2- (6-methoxy-1H-indol-3-yl) ethyl) -4-methylbenzenesulfonamide (0.2mmol,68.9mg),8 ml of 1, 4-dioxane and finally tert-butanol peroxide (0.8mmol) were added in a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 30 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 30: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 72% yield from the two-step separation. The structural formula of the obtained product is shown as the formula (III): r ═ 6-OMe, X ═ NTs, R2＝Me，R3＝H。
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.1Hz,2H),7.32(d,J＝7.9Hz,2H),7.06(d,J＝8.3Hz,1H),6.31(dd,J＝8.3,2.3Hz,1H),6.20(d,J＝2.2Hz,1H),5.41(d,J＝1.6Hz,1H),4.91(s,1H),3.76(s,3H),3.38(ddd,J＝10.0,8.3,4.4Hz,1H),3.26(ddd,J＝10.0,8.3,6.6Hz,1H),2.53(dt,J＝12.6,8.3Hz,1H),2.42(s,3H),2.11(ddd,J＝12.6,6.6,4.4Hz,1H),1.06(s,9H).
Example 6
Tetrabutylammonium iodide (0.04mmol,14.8mg), N- (2- (6-bromo-1H-indol-3-yl) ethyl) -4-methylbenzenesulfonamide (0.2mmol,78.7mg), 8 ml of 1, 4-dioxane were placed in a 25 ml single-neck flask and tert-butanol peroxide (0.8mmol) was added last. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 30 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 35: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 77% yield from the two step separation. The structural formula of the obtained product is shown as the formula (III): r is 6-Br, X is NTs, R2＝Me，R3H. FIG. 5 shows the NMR spectrum of the objective product obtained in example 6.
1H NMR(400MHz,CDCl3)δ7.82–7.72(m,2H),7.39–7.29(m,2H),7.02(d,J＝7.9Hz,1H),6.87(dd,J＝7.9,1.6Hz,1H),6.78(d,J＝1.7Hz,1H),5.43(d,J＝1.8Hz,1H),4.97(d,J＝1.8Hz,1H),3.37(ddd,J＝9.9,7.9,5.1Hz,1H),3.28(ddd,J＝9.9,7.9,6.8Hz,1H),2.49(dt,J＝12.8,7.9Hz,1H),2.43(s,3H),2.12(ddd,J＝12.4,6.8,5.1Hz,1H),1.05(s,9H).
Example 7
Tetrabutylammonium iodide (0.04mmol,14.8mg), p-toluenesulfonyl-L-tryptophan methyl ester (0.2mmol,74.5mg), 8 ml of 1, 4-dioxane, and finally t-butanol peroxide (0.8mmol) were added in a 25 ml single-neck flask. The reaction is heated to 90 ℃ and the reaction time is 2 hoursThen (c) is performed. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 40 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 35: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 58% yield from the two-step separation. The structural formula of the obtained product is shown as the formula (III): r ═ H, X ═ NTs, R2＝Me，R3＝COOMe。
1H NMR(400MHz,CDCl3)δ7.84–7.73(m,4H),7.38–7.33(m,2H),7.30–7.23(m,2H),7.22–7.15(m,2H),7.12(ddd,J＝7.3,6.0,1.2Hz,2H),6.75(dtd,J＝13.0,7.5,0.9Hz,2H),6.68(d,J＝8.0Hz,1H),6.56(d,J＝7.9Hz,1H),5.85(d,J＝2.9Hz,1H),5.43(d,J＝0.9Hz,1H),5.06(d,J＝2.9Hz,1H),4.95(s,1H),4.39(dd,J＝9.1,2.9Hz,1H),4.26(dd,J＝8.2,5.5Hz,1H),3.70(s,3H),3.70(s,3H),3.31(s,3H),2.95–2.76(m,2H),2.57–2.47(m,2H),2.44(s,3H),2.39(s,3H),1.14(s,9H),1.04(s,9H).
Example 8
Tetrabutylammonium iodide (0.04mmol,14.8mg), N- (2- (1H-indol-3-yl) ethyl) -4-methylbenzenesulfonamide (0.2mmol,62.9mg), 8 ml of 1, 4-dioxane, and finally cumene hydroperoxide (0.8mmol) were added to a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 40 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 40: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid with a yield of 40% over the two steps. To obtainThe structural formula of the obtained product is shown as a formula (III): r ═ H, X ═ NTs, R2＝Ph，R3＝H。
1H NMR(600MHz,CDCl3)δ7.80–7.74(m,2H),7.52–7.48(m,1H),7.38–7.32(m,1H),7.30–7.22(m,5H),7.20–7.15(m,1H),7.14–7.11(m,1H),6.75(td,J＝7.4,0.9Hz,1H),6.64(d,J＝7.9Hz,1H),5.52(d,J＝2.1Hz,1H),4.91(d,J＝2.5Hz,1H),3.35(ddd,J＝9.9,7.8,5.1Hz,1H),3.26(ddd,J＝9.9,7.8,6.7Hz,1H),2.47–2.41(m,1H),2.41(s,3H),2.12(ddd,J＝12.4,6.7,5.1Hz,1H),1.42(s,3H),1.39(s,3H).
Example 9
Tetrabutylammonium iodide (0.04mmol,14.8mg), tryptophol (0.2mmol,32.2mg),8 ml of 1, 4-dioxane, and finally t-butanol peroxide (0.8mmol) were added to a 25 ml single-neck flask. The reaction was heated to 90 ℃ and reacted for 2 hours. The reaction was cooled to room temperature and sodium borohydride (0.6mmol,22.7mg) was added in portions and stirred for 40 min. Adding saturated NH into the reaction system4The Cl solution was stirred for 3 minutes and extracted three times with EtOAc in a separatory funnel. The EtOAc solution was washed three times with saturated sodium thiosulfate solution, the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to remove the solvent to give the crude product. The crude product was separated by silica gel column, and the eluent petroleum ether \ ethyl acetate was 40: 1. The target product was collected and the organic phase was concentrated under reduced pressure to remove the solvent to give a white solid in 33% yield from the two-step separation. The structural formula of the obtained product is shown as the formula (III): r ═ H, X ═ O, R2＝Me，R3H. FIG. 6 shows the NMR spectrum of the objective product obtained in example 9.
1H NMR(600MHz,CDCl3)δ7.36–7.22(m,1H),7.16(td,J＝7.7,1.4Hz,1H),6.79(td,J＝7.4,1.0Hz,1H),6.72–6.47(m,1H),5.73(d,J＝3.0Hz,1H),4.61(s,1H),4.05(ddd,J＝8.7,7.6,2.7Hz,1H),3.72(ddd,J＝10.2,8.8,5.4Hz,1H),2.68(ddd,J＝12.0,10.2,7.6Hz,1H),2.17(ddd,J＝12.0,5.4,2.6Hz,1H),1.20(s,9H).
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (6)
1. A preparation method of peroxy-substituted pyrrole/furoindoline is characterized in that tryptamine derivatives, tryptophan methyl ester derivatives or tryptophol are used as substrates, organic iodized salt is used as a catalyst, and the catalyst and the oxidant react to generate high-valence iodine species in the presence of the oxidant; activating the substrate by the high-valence iodine species, constructing an intermediate product containing a peroxide bond and a double bond, and reducing the double bond of the intermediate product under the action of a reducing agent to obtain peroxide-substituted pyrrole/furoindoline;
the preparation method comprises the following steps:
(1) taking a substrate I and a substrate II as initial raw materials, and reacting in a solvent under the catalytic action of an organic iodide salt catalyst to generate a first product; wherein the substrate I has a structural formula shown as a formula (I), the substrate II simultaneously acts as an oxidizing agent, and the first product has a structural formula shown as a formula (II):
(2) adding a reducing agent into the first product obtained in the step (1), and separating after reaction to obtain peroxy-substituted pyrrole/furoindoline shown in a structural formula (III);
wherein R is an electron-withdrawing group or an electron-donating group which is hydrogen, alkyl, alkoxy or halogen; x is O or NR1；R1Is an electron withdrawing group which is a sulfonyl group Ts, Ns or Ms; r2Is methyl or phenyl; r3Is H or COOMe;
the catalyst is TBAI, and the dosage of the catalyst is 10-30% of the dosage of the substrate I; the substrate II is TBHP or CHP; the molar ratio of the substrate I to the substrate II is 1 (3-4).
2. The preparation method according to claim 1, wherein the reaction temperature in the step (1) is 80-120 ℃; the reaction time is 2-3 hours.
3. The method of claim 1, wherein the solvent is ethyl acetate, tetrahydrofuran, acetonitrile, toluene, or 1, 4-dioxane.
4. The preparation method according to claim 1, wherein the reducing agent in the step (2) is sodium borohydride, and the molar ratio of the reducing agent to the substrate I is (3-4): 1.
5. The method according to claim 1, wherein the reaction temperature in the step (2) is 25 ℃ to 30 ℃ and the reaction time is 0.5 to 1 hour.
6. The preparation method according to claim 1, further comprising a step (3) of separation and purification, wherein the step (3) is specifically:
(3-1) adding saturated NH to the reaction System4Stirring the Cl solution for a few minutes, and extracting the Cl solution with EtOAc (ethyl acetate) for 2-3 times in a separating funnel;
(3-2) washing the loaded organic phase obtained in the step (3-1) with a saturated sodium thiosulfate solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to remove the solvent to obtain a crude product;
(3-3) filling columns with 100-200 meshes of silica gel and petroleum ether, filling the columns by a dry method, and dissolving the crude product with a small amount of dichloromethane to fill the upper end parts of the silica gel columns;
and (3-4) eluting by using a mixed solvent of petroleum ether and ethyl acetate, collecting a target product, concentrating the organic phase under reduced pressure to remove the solvent, and drying in vacuum to obtain the target product with the structure shown as the formula (III).
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