CN106243012A - New indole analog derivative and preparation method thereof - Google Patents

New indole analog derivative and preparation method thereof Download PDF

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CN106243012A
CN106243012A CN201610624882.8A CN201610624882A CN106243012A CN 106243012 A CN106243012 A CN 106243012A CN 201610624882 A CN201610624882 A CN 201610624882A CN 106243012 A CN106243012 A CN 106243012A
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indole
compound
analog derivative
new indole
methoxyl group
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洪伟
王昊
常喆
谭晓丽
杨浩
欧阳溢凡
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North Minzu 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The new indole analog derivative that the present invention provides, chemical structure of general formula such as following formula (I, II):Wherein, R1Selected from OCH3WithR2Selected from the alkyl of 14 carbochains, such as methyl, ethyl, n-pro-pyl, isopropyl, cyclopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, R3Alkyl or tolyl, ethylbenzene, phenyl, R selected from 14 carbochains4Selected from COOCH3、‑COOC2H5、

Description

New indole analog derivative and preparation method thereof
Technical field
The invention belongs to organic chemistry filed, particularly a kind of indole derivatives and synthetic method, this compounds The Large-scale Screening research of follow-up medicinal activity purposes can be carried out as the compound in medicinal activity micromolecular compound storehouse.
Background technology
Indole and derivant thereof have very important biology and pharmacologically active, as anticancer, antibacterial, resisting hypertension etc., extensively General it is applied in agricultural, medicine and other fields.Transforming growth factor β (transforming growth factor-β, TGF-β) is Cytokine important in organism, can control polytype cell proliferation, stick, move, break up and apoptosis etc..? In the evolution of cancer, TGF-β plays dual effect, and the initial stage can be thin by suppression growth of tumour cell and promotion tumor The apoptosis of born of the same parents and suppress the generation of tumor；And at the middle and advanced stage of cancer, TGF-β is often process LAN, its cancer suppressing action weakens, Tumor promotion progressively manifests.Therefore TGF-β is as a kind of multifunctional protein that can regulate cell proliferation, differentiation, apoptosis, in cancer Disease played an important role in developing.
Summary of the invention
The invention provides the indole derivatives of a kind of structure brand-new (novel), this compounds can be lived as medicine Property micromolecular compound storehouse compound carry out follow-up medicinal activity purposes Large-scale Screening research.Particularly through computer Aided drug design is analyzed, and this compounds demonstrates definitely to transforming growth factor β during computer simulation The inhibitory action of (transforming growth factor-β, TGF-β) activity.And suppress TGF-β can suppress tumor The propagation of cell, therefore this compounds can be used for carrying out antitumor guideization as the compound in micromolecular compound storehouse The screening of compound.
The new indole analog derivative that the present invention provides, chemical structure of general formula such as following formula (I, II):
Wherein,
R1Selected from-OCH3With
R2Selected from the alkyl of 1-4 carbochain, including methyl, ethyl, n-pro-pyl, isopropyl, cyclopropyl, normal-butyl, secondary Butyl, isobutyl group, the tert-butyl group,
R3Selected from alkyl or tolyl, ethylbenzene, the phenyl of 1-4 carbochain,
R4Selected from-COOCH3、-COOC2H5、
N is the integer of 0-4.
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that: wherein, R1 The position of substitution of group is 5 or 6.
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that: wherein, R1 In group
For
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that: wherein, R2 Selected from methyl.
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that: wherein, R3 Selected from methyl, phenyl.
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that: wherein, R4 Selected from-COOCH3、
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that: wherein, n is 0、1、2。
The new indole analog derivative that the present invention provides, it is also possible to have the feature that, it is characterised in that selected from following The compound of structural formula:
The present invention also provides for a kind of method synthesizing above-mentioned new indole analog derivative, it is characterised in that synthetic route is such as Under:
The process of operation a comprises the following steps: by raw material I-0 and NH2R2Stirring reaction a period of time in organic solvent A After solvent is evaporated, add stirring reaction after organic solvent B and reducing agent；
The process of operation b comprises the following steps: raw material II-0 and Ka Te condensing agent BOP, amine are dissolved in organic solvent C instead Should add after a period of timeRear stirring reaction,
Wherein, organic solvent A is selected from THF, dioxane,
Organic solvent B is selected from methanol, ethanol, isopropanol,
Organic solvent C is selected from DMF, DMSO,
Reducing agent is selected from NaBH4、KBH4, sodium triacetoxy borohydride, sodium cyanoborohydride,
Amine is selected from triethylamine, diethylamine, trimethylamine, dimethylamine, N, N-diisopropylethylamine.
Invention effect and effect
The indole derivatives of a kind of structure brand-new (novel), this compounds can be as medicinal activity little molecule chemical combination The compound in thing storehouse carries out the Large-scale Screening research of follow-up medicinal activity purposes.Particularly through Computer-Aided Drug Design Analyzing, this compounds demonstrates definitely to transforming growth factor β (transforming during computer simulation Growth factor-β, TGF-β) inhibitory action of activity.And suppress TGF-β i.e. can suppress the propagation of tumor cell, because of And this compounds can carry out the screening of antitumor lead compound as the compound in follow-up micromolecular compound storehouse.
It addition, this compounds does not has chirality, synthesis and purification are all convenient than the compound with chirality, especially for For pharmaceutical developments, there is no the advantage that the compound of chirality will be the biggest in terms of synthesis, purification, pharmacologically active test.
Present invention also offers the synthetic method of above-mentioned indole derivatives, the method obtains target through single step reaction Product, yield about 50%, the operating condition comparative maturity of simultaneous reactions, it is easy to repeat realize.
Detailed description of the invention
For the technological means making the present invention realize, creation characteristic, reach purpose and be easy to understand with effect, real below Execute example and the compound of the present invention, the preparation method of compound are done detailed introduction.
Embodiment
(1) preparation of compound 4a and 4b
Compound 2a, 1-benzenesulfonyl-3-formoxyl-5-bromo indole
Under nitrogen protection, 3-formoxyl-5-bromo indole 2.00g (8.8807mmol) is added to super dry dimethyl sulfoxide In DMSO 15ml, it is subsequently adding sodium hydride 0.392g (9.7706mmol), in room temperature reaction 1h.By benzene sulfonyl chloride 1.883g (10.664mmol) add to reactant liquor, and in room temperature reaction 18h.After reaction terminates, saturated ammonium chloride solution 100ml is added To reactant liquor, and extracting (200ml × 3) with dichloromethane DCM, organic layer washs with saturated sodium-chloride water solution and water respectively, Anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains crude product, after acetone/normal hexane recrystallization, obtains white solid 2.675g, yield It is 83%.m.p.235.2-239.3℃；1H-NMR(400MHz,DMSO):δ10.06(s,1H,CHO),8.96(s,1H,Ar- H), 8.22 (d, J=2.0,1H, Ar-H), 8.14-8.12 (m, 2H, Ar-H), 7.95 (d, J=8.8,1H, Ar-H), 7.81- 7.77(m,1H,Ar-H),7.69-7.65(m,2H,Ar-H),7.62(dd,J1=8.8, J2=2.0,1H, Ar-H)；ES- MS365.2(M+H)+。
Compound 2b, 1-mesyl-3-formoxyl-5-bromo indole
Preparation 2b be use 3-formoxyl-5-bromo indole be raw material, method is with the preparation of compound 2a.Obtain white solid Body, yield 69%, m.p.180.0-184.1 DEG C；1H NMR(400MHz,DMSO)δ10.08(s,1H,CHO),8.68(s,1H, Ar-H), 8.31 (s, 1H, Ar-H), 7.88 (d, J=8.9,1H, Ar-H), 7.67 (dd, J=8.9,2.0,1H, Ar-H), 3.71 (s,3H,CH3).ES-MS 301.9(M+H)+。
Compound 3a, 1-benzenesulfonyl-3-formoxyl-5-is to trifluoromethoxy benzaldehyde base indole
1-benzenesulfonyl-3-formoxyl-5-bromo indole 0.5g (1.37mmol) is added 10ml tetrahydrofuran THF and 10ml In water, then it is sequentially added into potassium carbonate 0.28g (2.055mmol), to trifluoromethoxy benzaldehyde ylboronic acid 0.34g (1.64mmol), 1, Double (di-t-butyl phosphine) ferrocene two chloro palladium 8.9mg (0.0137mmol) of 1'-, heat up 60 DEG C of stirring reaction 8h.Reaction terminates After, it being extracted with ethyl acetate (100ml × 3), anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains crude product, and through column chromatography, eluant is second Acetoacetic ester/petroleum ether, yield is 89%.m.p.180.4-181.3℃；1HNMR(400MHz,DMSO):δ10.12(s,1H, CHO), 8.98 (s, 1H, Ar-H), 8.34 (d, J=1.6,1H, Ar-H), 8.18-8.16 (m, 2H, Ar-H), 8.07 (d, J= 8.8,1H,Ar-H),7.80-7.75(m,2H,Ar-H),7.69-7.65(m,3H,Ar-H),7.61-7.57(m,2H,Ar-H), 7.37 (d, J=8.4,1H, Ar-H)；ES-MS 446.4(M+H)+。
Compound 3b, 1-mesyl-3-formoxyl-5-is to trifluoromethoxy benzaldehyde base indole
Preparation 3b be use 1-mesyl-3-formoxyl-5-bromo indole be raw material, method is with the preparation of compound 3a. White solid, yield is 66%, m.p.200.0-204.8 DEG C；1H NMR(400MHz,DMSO)δ10.14(s,1H,CHO), 8.68 (s, 1H, Ar-H), 8.41 (d, J=1.6,1H, Ar-H), 8.01 (d, J=8.7,1H, Ar-H), 7.83-7.78 (m, 3H, Ar-H),7.49(s,1H,Ar-H),7.47(s,1H,Ar-H),3.72(s,3H,CH3).ES-MS 384.0(M+H)+。
Compound 4a, 1-benzenesulfonyl-3-Methyaminomethyl-5-is to trifluoro phenyl indole
Preparation 4a be use 1-benzenesulfonyl-3-formoxyl-5-be raw material to trifluoromethoxy benzaldehyde base indole, the same chemical combination of method The preparation of thing 4b.Colorless oil, yield is 76%；1H NMR(400MHz,DMSO)δ8.03-7.96(m,4H,Ar-H), 7.84-7.78 (m, 3H, Ar-H), 7.68 (m, 2H, Ar-H), 7.60 (t, J=7.7,2H, Ar-H), 7.45 (d, J=8.1,2H, Ar-H),3.92(s,2H,CH2),2.34(s,3H,CH3).ES-MS 461.1(M+H)+。
Compound 4b, 1-mesyl-3-Methyaminomethyl-5-is to trifluoro phenyl indole
Trifluoro oxygen Phenylindole (200mg, 0521mmol) is added by compound 1-mesyl-3-formoxyl-5- In 15ml THF, it is subsequently adding the THF solution (0.4ml, 2.605mmol) of methylamine, reaction is stirred at room temperature overnight.Reactant liquor is revolved Add ethanol 15ml after Gan, be subsequently adding NaBH4(18mg, 0.521mmol), is stirred at room temperature reaction.After reaction terminates, it is spin-dried for second Alcohol, ethyl acetate extracts, and saturated NaCl wash water is washed, and anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains crude product.Through column chromatography, eluant For methylene chloride/methanol (30/1), obtaining colorless oil 102mg, yield is 53%；1H NMR(400MHz,DMSO)δ8.04 (d, J=1.5,1H, Ar-H), 7.90 (d, J=8.6,1H, Ar-H), 7.87-7.82 (m, 2H, Ar-H), 7.69 (dd, J= 8.6,1.8,1H,Ar-H),7.54-7.44(m,4H,Ar-H),3.89(s,2H,CH2),3.41(s,6H,CH3)；ES-MS 399.0(M+H)+。
Substituting as one, the THF in above-mentioned synthesis compound 4b can also replace with dioxane, and ethanol can make Replace with methanol, isopropanol, reducing agent NaBH4KBH can be used4, sodium triacetoxy borohydride, sodium cyanoborohydride replace.
(2) preparation of compound 9
Compound 6,3-formoxyl-5-carboxyl indole
Under nitrogen protection, 5-methoxycarbonyl indole 0.5g (2.85mmol) is added to super dry dimethylformamide DMF (4ml) in, and it is cooled to 0 DEG C, is then slowly added dropwise phosphorus oxychloride 0.36ml (3.876mol).After 0 DEG C of reaction 10min, turn Room temperature reaction 3h.After reactant liquor is cooled to 0 DEG C, add water (2ml) quencher reaction, then with 30%NaOH aqueous solution 7ml, return Stream reaction 5h.Reactant liquor is cooled to room temperature, and 30%HCl adjusts pH to 2-3, and reduce pressure sucking filtration, obtains filter cake, dried pink solid 0.538g, yield is 99%.M.p.304.8 DEG C (decomposition)；1H NMR(400MHz,DMSO)δ12.51(s,1H,COOH),9.97 (s, 1H, CHO), 8.74 (d, J=1.1,1H, Ar-H), 8.41 (d, J=15.0,1H, Ar-H), 7.86 (dd, J=8.5,1.7, 1H, Ar-H), 7.55 (d, J=8.5,1H, Ar-H) .ES-MS 190.0 (M+H)+。
Compound 7,3-formoxyl-5-(morpholine-4-carbonyl) indole
Under nitrogen protection, 3-formoxyl-5-carboxyl indole 100mg (0.53mmol) is added in 10ml dichloromethane, It is subsequently adding morpholine 92 μ L (1.06mmol), DIPEA0.18ml (1.06mmol) and DMAP129mg (1.06mmol).It is cooled to 0 DEG C, after being then slowly added into EDCI202mg (1.06mol), turn room temperature reaction 16h.Reaction is spin-dried for after terminating, and ethyl acetate extracts Taking, use 5% citric acid, saturated NaHCO3, saturated NaCl and water washing respectively, anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains product, Yellow solid 46mg, yield is 34%；m.p.221.8-224.3℃；1HNMR(400MHz,DMSO)δ10.52(s,1H,NH), 9.94 (s, 1H, CHO), 8.34 (s, 1H, Ar-H), 7.74 (d, J=3.1,1H, Ar-H), 7.24 (dd, J=8.4,1.5,1H, Ar-H), 7.16 (d, J=8.4,1H, Ar-H), 3.81 (s, 8H, CH2)；ES-MS 289.1(M+H)+。
Compound 8,1-mesyl-3-formoxyl-5-(morpholine-4-carbonyl) indole
Preparation 8 be use 3-formoxyl-5-(morpholine-4-carbonyl) indole be raw material, method is with the preparation of compound 2a.In vain Color solid, yield is 86%.m.p.217.8-218.0℃；1H NMR(400MHz,DMSO)δ10.11(s,1H,CHO),8.71 (s, 1H, Ar-H), 8.21 (s, 1H, Ar-H), 7.97 (d, J=8.6,1H, Ar-H), 7.55 (d, J=8.6,1H, Ar-H), 3.72(s,3H,CH3),3.60(s,8H,CH2)；ES-MS 337.1(M+H)+。
Compound 9,1-mesyl-3-Methyaminomethyl-5-(morpholine-4-carbonyl) indole
Preparation 9 be use 1-mesyl-3-formoxyl-5-(morpholine-4-carbonyl) indole be raw material, the same compound of method The preparation of 4b.Yellow oil yield is 51%；1HNMR(400MHz,DMSO)δ7.90-7.78(m,2H,Ar-H),7.55(s, 1H, Ar-H), 7.42 (d, J=8.5,1H, Ar-H), 3.84 (s, 2H, CH2),3.60(s,8H,CH2),3.42(s,3H,CH3), 2.34(s,3H,CH3).ES-MS 351.1(M+H)+。
(3) preparation of compound 10
Compound 10,3-Methyaminomethyl-5-(morpholine-4-carbonyl) indole
Preparation 10 be use 3-formoxyl-5-(morpholine-4-carbonyl) indole be raw material, method is with the preparation of compound 4b. Yellow oil, yield is 56%；m.p.256.3-256.5℃；1HNMR(400MHz,DMSO)δ11.09(s,1H,NH), 7.70 (s, 1H, Ar-H), 7.37 (d, J=8.4,1H, Ar-H), 7.29 (d, J=2.0,1H, Ar-H), 7.13 (dd, J=8.3, 1.5,1H,Ar-H),3.79(s,2H,CH2), 3.56 (d, J=28.4,8H, CH2),2.30(s,3H,CH3).ES-MS 274.1 (M+H)+。
(4) preparation of compound 12
Compound 11,1-mesyl-3-carboxyl-5-(morpholine-4-carbonyl) indole
By 1-mesyl-3-formoxyl-5-(morpholine-4-carbonyl) indole 300mg (0.89mmol) add 10mlTHF with In the 6ml tert-butyl alcohol, it is subsequently adding THF (10ml) solution containing 2-methyl 2-butylene (111 μ L).By NaClO2241.74mg (2.67mmol) and NaH2PO4480.87mg (4.01mmol) is dissolved in 5ml water in addition reaction bulb, after room temperature reaction 12h, then Add NaClO2161.16mg (1.78mmol) and NaH2PO4302.7mg (2.67mmol) continue stirring reaction 2h.Reaction terminates After, ethyl acetate extracts, and organic layer merges aqueous phase, 6N HCl Acidified aqueous layer after adding 2mol/LNaOH, then extracts by ethyl acetate Taking, anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains crude product.Through column chromatography, eluant is ethyl acetate, obtains white solid 220mg, Yield is 70%.m.p.256.1-260.5℃；1H NMR(400MHz,DMSO)δ12.98(s,1H,COOH),8.18(s,1H, Ar-H), 8.15 (d, J=1.1,1H, Ar-H), 7.95 (d, J=8.6,1H, Ar-H), 7.50 (dd, J=8.6,1.6,1H, Ar- H),3.68(s,3H,CH3),3.60(s,8H,CH2).ES-MS353.0(M+H)+。
Compound 12,1-mesyl-5-(morpholine-4-carbonyl)-3-[(2-ethoxy) carbamoyl] indole
1-mesyl-3-carboxyl-5-(morpholine-4-carbonyl) indole 50mg (0.14mmol) is added in 5mlDMF, so Rear addition BOP (special condensing agent i.e. BTA-1-base epoxide three (dimethylamino) the phosphorus hexafluorophosphate of card) 72.1mg (0.17mmol), NEt340 μ L (0.28mmol), 0 DEG C of stirring reaction 0.5h.Add ethanolamine 13.18 μ L (0.2134mmol) to turn Reaction 20h is stirred at room temperature.Ethyl acetate extracts, and anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains crude product, and through column chromatography, eluant is Ethyl acetate/methanol (30/1), obtains colorless oil object 36.7mg, and yield is 65%；1H NMR(400MHz,DMSO)δ 8.47-8.42 (m, 2H, Ar-H and NH), 8.30 (d, J=1.1,1H, Ar-H), 7.91-7.88 (m, 1H, Ar-H), 7.47 (dd, J=8.6,1.7,1H, Ar-H), 5.34-5.30 (m, 2H, CH2),4.73(s,1H,OH),3.58(s,3H,CH3),3.53 (s,8H,CH2), 2.18 (t, J=7.4,2H, CH2).ES-MS 396.1(M+H)+。
In the operation of above-mentioned synthesis compound 12, DMF can use DMSO to replace, amine NEt3Diethylamine, front three can also be used Amine, dimethylamine, N, N-diisopropylethylamine replaces.
(5) preparation of compound 15a and 15b
Compound 13a, 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-formyl indole
Preparation 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-formyl indole is to use 5-(morpholine 4-carbonyl)-3- Formyl indole is raw material, the same 2a of method, colorless oil 0.53g, and yield is 73%；1H NMR(400MHz,DMSO)δ9.96 (s, 1H, CHO), 8.56 (s, 1H, Ar-H), 8.15 (d, J=0.9,1H, Ar-H), 7.67 (d, J=8.5,1H, Ar-H), 7.33 (dd, J=8.5,1.5,1H, Ar-H), 7.26 (t, J=7.9,1H, Ar-H), 6.94 (s, 1H, Ar-H), 6.90-6.82 (m, 2H,Ar-H),5.53(s,2H,CH2),3.72(s,3H,CH3),3.58(s,8H,CH2).ES-MS 379.1(M+H)+。
Compound 13b, methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-formyl indole between 1-
Preparation 1-between methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-formyl indole be use 5-(morpholine 4-carbonyl)- 3-formyl indole is raw material, the same 2a of method, colorless oil 0.68g, and yield is 88%；1HNMR(400MHz,DMSO)δ 9.98 (s, 1H, CHO), 8.60 (s, 1H, Ar-H), 8.17 (d, J=1.0,1H, Ar-H), 7.97 (s, 1H, Ar-H), 7.88 (d, J=7.7,1H, Ar-H), 7.66 (d, J=8.5,1H, Ar-H), 7.59 (d, J=7.8,1H, Ar-H), 7.51 (t, J=7.7, 1H, Ar-H), 7.33 (dd, J=8.5,1.6,1H, Ar-H), 5.67 (s, 2H, CH2),3.83(s,3H,CH3),3.58(s,8H, CH2).ES-MS 407.1(M+H)+。
Compound 14a, 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-carboxyl indole
Preparation 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-carboxyl indole is to use 1-meta-methoxy benzyl-5- (morpholine 4-carbonyl)-3-formyl indole is raw material, the same 18c of method, colorless oil 0.23g, and yield is 55%；1H NMR (400MHz, DMSO) δ 12.08 (s, 1H, COOH), 8.26 (d, J=2.9,1H, Ar-H), 8.08 (s, 1H, Ar-H), 7.57 (d, J=8.5,1H, Ar-H), 7.24-7.18 (m, 2H, Ar-H), 6.89-6.76 (m, 3H, Ar-H), 5.46 (s, 2H, CH2),3.71 (s,3H,CH3),3.58(s,8H,CH2).ES-MS 395.1(M+H)+。
Compound 14b, methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-carboxyl indole between 1-
Between preparation 1-methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-carboxyl indole be use methoxycarbonyl group benzyl between 1-- 5-(morpholine 4-carbonyl)-3-formyl indole is raw material, the same 18a of method, white solid 0.45g, and yield is 85%. m.p.224.4-226.0℃；1H NMR(400MHz,DMSO)δ12.24(s,1H,COOH),8.37(s,1H,Ar-H),8.07 (d, J=1.1,1H, Ar-H), 7.93 (s, 1H, Ar-H), 7.87 (dt, J=7.6,1.4,1H, Ar-H), 7.58 (dd, J= 11.2,8.2,2H, Ar-H), 7.50 (t, J=7.6,1H, Ar-H), 7.25 (dd, J=8.5,1.6,1H, Ar-H), 5.62 (s, 2H,CH2),3.83(s,3H,CH3),3.57(s,8H,CH2).ES-MS423.1(M+H)+。
Compound 15a, 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-[(2-ethoxy) carbamoyl] indole
Preparation 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-[(2-ethoxy) carbamoyl] indole is to use 1-meta-methoxy benzyl-5-(morpholine 4-carbonyl)-3-carboxyl indole is raw material, method same 12, colorless oil 125mg, yield It is 86%；1H NMR (400MHz, DMSO) δ 8.22 (d, J=1.1,1H, Ar-H), 8.20 (s, 1H, Ar-H), 7.99 (t, J= 4.4,1H, NH), 7.60 (d, J=8.5,1H, Ar-H), 7.28-7.19 (m, 2H, Ar-H), 6.90-6.75 (m, 3H, Ar-H), 5.44(s,2H,CH2),4.72(s,1H,OH),3.72(s,3H,CH3), 3.55 (d, J=22.7,8H, CH2),3.49(s,2H, CH2), 3.14 (d, J=23.0,2H, CH2).ES-MS 438.2(M+H)+。
Compound 15b, methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-[(2-ethoxy) carbamoyl] Yin between 1- Diindyl
Between preparation 1-, methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-[(2-ethoxy) carbamoyl] indole is to adopt Being raw material with methoxycarbonyl group benzyl-5-(morpholine 4-carbonyl)-3-carboxyl indole between 1-, method, with 12, white solid 149mg, is received Rate is 97%；1H NMR (400MHz, DMSO) δ 8.23 (d, J=1.1Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H), 8.00 (t, J=5.6,1H, NH), 7.92-7.84 (m, 2H, Ar-H), 7.60 (d, J=8.5,1H, Ar-H), 7.57-7.47 (m, 2H, Ar- H), 7.23 (ddd, J=7.9,6.2,1.6,1H, Ar-H), 5.58 (s, 2H, CH2),3.83(s,3H,CH3),3.58(s,8H, CH2),3.53-3.49(m,2H,CH2),3.12(s,2H,CH2).ES-MS 466.2(M+H)+。
(6) preparation of compound 19a, 19b, 19c, 19d, 19e, 19f
Compound 17a, 1-are to methoxycarbonyl group benzyl-6-methoxyl group-3-formyl indole
Preparation 1-is to use 6-methoxyl group-3-formyl indole to methoxycarbonyl group benzyl-6-methoxyl group-3-formyl indole For raw material, the same 2a of method, white solid 0.61g, yield is 66%.m.p.111.8-113.2℃；1H NMR(400MHz, DMSO) δ 9.88 (s, 1H, CHO), 8.34 (s, 1H, Ar-H), 7.96 (m, 3H, Ar-H), 7.40 (d, J=8.2,2H, Ar-H), 7.11 (d, J=2.1,1H, Ar-H), 6.90 (dd, J=8.6,2.2,1H, Ar-H), 5.62 (s, 2H, CH2),3.82(s,3H, CH3),3.75(s,3H,CH3).ES-MS 324.1(M+H)+。
Compound 17b, methoxycarbonyl group benzyl-6-methoxyl group-3-formyl indole between 1-
Between preparation 1-, methoxycarbonyl group benzyl-6-methoxyl group-3-formyl indole is to use 6-methoxyl group-3-formyl indole For raw material, the same 2a of method, white solid 0.46g, yield is 83%.m.p.122.6-124.2℃；1H NMR(400MHz, DMSO) δ 9.88 (s, 1H, CHO), 8.35 (s, 1H, Ar-H), 7.97 (d, J=8.7,2H, Ar-H), 7.88 (dt, J=7.6, 1.3,1H, Ar-H), 7.58 (d, J=7.8,1H, Ar-H), 7.51 (t, J=7.7,1H, Ar-H), 7.18 (d, J=2.1,1H, Ar-H), 6.90 (dd, J=8.7,2.2,1H, Ar-H), 5.60 (s, 2H, CH2),3.83(s,3H,CH3),3.77(s,3H, CH3).ES-MS 324.1(M+H)+。
Compound 17c, 1-are to methoxy-benzyl-6-methoxyl group-3-formyl indole
Preparation 1-is that employing 6-methoxyl group-3-formyl indole is to methoxy-benzyl-6-methoxyl group-3-formyl indole Raw material, the same 2a of method, white solid 0.36g, yield is 72%.m.p.83.3-86℃；1H NMR(400MHz,DMSO)δ9.84 (s, 1H, CHO), 8.28 (s, 1H, Ar-H), 7.95 (d, J=8.6,1H, Ar-H), 7.31 (d, J=8.6,2H, Ar-H), 7.18 (d, J=2.2,1H, Ar-H), 6.93-6.85 (m, 3H, Ar-H), 5.41 (s, 2H, CH2),3.78(s,3H,CH3),3.71(s, 3H,CH3).ES-MS 296.1(M+H)+。
Compound 17d, 1-meta-methoxy benzyl-6-methoxyl group-3-formyl indole
Preparation 1-meta-methoxy benzyl-6-methoxyl group-3-formyl indole is that employing 6-methoxyl group-3-formyl indole is Raw material, the same 2a of method, yellow grain solid 0.43g, yield is 85%.m.p.114.6-115.5℃；1H NMR(400MHz, DMSO) δ 9.87 (s, 1H, CHO), 8.31 (s, 1H, Ar-H), 7.97 (d, J=8.6,1H, Ar-H), 7.30-7.22 (m, 1H, Ar-H), 7.17 (d, J=2.2,1H, Ar-H), 6.95-6.84 (m, 4H, Ar-H), 5.46 (s, 2H, CH2),3.78(s,3H, CH3),3.72(s,3H,CH3).ES-MS 296.1(M+H)+。
Compound 17e, 1-are to trifluoromethyl benzyl-6-methoxyl group-3-formyl indole
Preparation 1-is that employing 6-methoxyl group-3-formyl indole is to three fluorine-based benzyl-6-methoxyl group-3-formyl indoles Raw material, the same 2a of method, white flaky solid 0.41g, yield is 87%.m.p.122.8-123.8℃；1H NMR(400MHz, DMSO) δ 9.88 (s, 1H, CHO), 8.35 (s, 1H, Ar-H), 7.98 (d, J=8.6,1H, Ar-H), 7.73 (d, J=8.1,2H, Ar-H), 7.48 (d, J=8.1,2H, Ar-H), 7.14 (d, J=2.1,1H, Ar-H), 6.90 (dd, J=8.7,2.2,1H, Ar- H),5.63(s,2H,CH2),3.76(s,3H,CH3).ES-MS334.1(M+H)+。
Compound 17f, 1-m-trifluoromethyl benzyl-6-methoxyl group-3-formyl indole
Between preparation 1-, three fluorine-based benzyl-6-methoxyl group-3-formyl indoles are that employing 6-methoxyl group-3-formyl indole is Raw material, the same 2a of method, white solid 0.84g, yield is 88%.m.p.136.5-138.1℃；1HNMR(400MHz,DMSO)δ 9.88 (s, 1H, CHO), 8.39 (s, 1H, Ar-H), 7.96 (d, J=8.6,1H, Ar-H), 7.82 (s, 1H, Ar-H), 7.67 (d, J=7.2,1H, Ar-H), 7.55-7.60 (m, 2H, Ar-H), 7.21 (d, J=2.2,1H, Ar-H), 6.89 (dd, J=8.7, 2.2,1H,Ar-H),5.62(s,2H,CH2),3.77(s,3H,CH3).ES-MS334.1(M+H)+。
Compound 18a, 1-are to methoxycarbonyl group benzyl-6-methoxyl group-3-carboxyl indole
1-is added the tert-butyl alcohol to methoxycarbonyl group benzyl-6-methoxyl group-3-formyl indole 100mg (0.309mmol) In 1.54ml, sequentially add 2-methyl 2-butylene 1.54ml, NaClO2279mg (3.09mmol) and NaH2PO4278mg (2.31mmol) water 1.54ml solution, stirring reaction.After reaction terminates, separate organic layer, water layer methylene chloride/methanol (95:5) extraction, merges organic layer, is spin-dried for rear DCM/ methanol (95:5)-normal hexane recrystallization, obtains yellow solid 70mg, and yield is 67%.m.p.230.9-232.6℃；1H NMR (400MHz, DMSO) δ 11.99 (s, 1H, COOH), 8.08 (s, 1H, Ar-H), 7.90 (m, 3H, Ar-H), 7.36 (d, J=8.3,2H, Ar-H), 7.04 (d, J=2.1,1H, Ar-H), 6.83 (dd, J=8.7, 2.2,1H,Ar-H),5.56(s,2H,CH2),3.82(s,3H,CH3),3.73(s,3H,CH3).ES-MS 340.1(M+H)+。
Compound 18b, methoxycarbonyl group benzyl-6-methoxyl group-3-carboxyl indole between 1-
Between preparation 1-, methoxycarbonyl group benzyl-6-methoxyl group-3-carboxyl indole is to use methoxycarbonyl group benzyl-6-methoxy between 1- Base-3-formyl indole is raw material, the same 18a of method, yellow solid 0.6g, and yield is 82%.m.p.200.0-203.1℃；1H NMR (400MHz, DMSO) δ 11.98 (s, 1H, COOH), 8.11 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.87 (d, J= 8.5,2H, Ar-H), 7.48-7.57 (m, 2H, Ar-H), 7.11 (d, J=2.1,1H, Ar-H), 6.83 (dd, J=8.7,2.2, 1H,Ar-H),5.55(s,2H,CH2),3.82(s,3H,CH3), 3.76 (d, J=6.7Hz, 3H, CH3).ES-MS 340.1(M+ H)+。
Compound 18c, 1-are to methoxy-benzyl-6-methoxyl group-3-carboxyl indole
Methoxy-benzyl-6-methoxyl group-3-formyl indole 100mg (0.338mmol) is added in 5ml acetone by 1-, It is subsequently adding potassium permanganate 160mg (1.017mmol) and is dissolved in the 2ml solution of water gained, stirring reaction 10h.Add 1.4ml10% H2O2, rotation is evaporated off acetone, adds 2M HCl and adjusts pH to 2-3, and sucking filtration is dried to obtain light yellow solid 52mg, and yield is 49%. m.p.148.6-152.9℃；1H NMR(400MHz,DMSO)δ11.97(s,1H,COOH),8.02(s,1H,Ar-H),7.85 (d, J=8.7,1H, Ar-H), 7.32-7.24 (m, 2H, Ar-H), 7.12 (d, J=2.2,1H, Ar-H), 6.95-6.87 (m, 2H, Ar-H), 6.83 (dd, J=8.7,2.3,1H, Ar-H), 5.36 (s, 2H, CH2),3.78(s,3H,CH3),3.71(s,3H, CH3).ES-MS 312.1(M+H)+。
Compound 18d, 1-meta-methoxy benzyl-6-methoxyl group-3-carboxyphenyl indole
Preparation 1-meta-methoxy benzyl-6-methoxyl group-3-carboxyl indole be use 1-meta-methoxy benzyl-6-methoxyl group- 3-formyl indole is raw material, the same 18c of method, light yellow solid 230mg, and yield is 55%.m.p.159.4-164.6℃；1H NMR (400MHz, DMSO) δ 11.96 (s, 1H, COOH), 8.04 (s, 1H, Ar-H), 7.86 (d, J=8.7,1H, Ar-H), 7.24 (t, J=7.9,1H, Ar-H), 7.10 (d, J=2.1,1H, Ar-H), 6.89 (s, 1H, Ar-H), 6.81-6.86 (m, 3H, Ar- H),5.40(s,2H,CH2),3.76(s,3H,CH3),3.71(s,3H,CH3).ES-MS 312.1(M+H)+。
Compound 18e, 1-are to trifluoromethyl benzyl-6-methoxyl group-3-carboxyl indole
Preparation 1-to three fluorine-based benzyl-6-methoxyl group-3-carboxyl indoles be use 1-to three fluorine-based benzyl-6-methoxyl groups- 3-formyl indole is raw material, the same 18a of method, yellow solid 140mg, and yield is 56%.m.p.181.7-184.1℃；1H NMR (400MHz, DMSO) δ 12.04 (s, 1H, COOH), 8.11 (s, 1H, Ar-H), 7.88 (d, J=8.7,1H, Ar-H), 7.71 (d, J=8.2,2H, Ar-H), 7.44 (d, J=8.1,2H, Ar-H), 7.08 (d, J=2.1Hz, 1H, Ar-H), 6.84 (dd, J =8.7,2.2Hz, 1H, Ar-H), 5.58 (s, 2H, CH2),3.74(s,3H,CH3).ES-MS 350.1(M+H)+。
Compound 18f, 1-m-trifluoromethyl benzyl-6-methoxyl group-3-carboxyl indole
Between preparation 1-three fluorine-based benzyl-6-methoxyl group-3-carboxyl indoles be use three fluorine-based benzyl-6-methoxyl groups between 1-- 3-formyl indole is raw material, the same 18a of method, yellow solid 0.32g, and yield is 61%.m.p.173.1-175.0℃；1H NMR (400MHz, DMSO) δ 12.01 (s, 1H, COOH), 8.14 (s, 1H, Ar-H), 7.87 (d, J=8.7Hz, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.65 (d, J=7.6,1H, Ar-H), 7.60-7.49 (m, 2H, Ar-H), 7.14 (d, J=2.2,1H, Ar-H), 6.84 (dd, J=8.7,2.2,1H, Ar-H), 5.56 (s, 2H, CH2),3.75(s,3H,CH3).ES-MS 350.1(M+ H)+。
Compound 19a, 1-are to methoxycarbonyl group benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole
Preparation 1-is to use 1-pair to methoxycarbonyl group benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole Methoxycarbonyl group benzyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, and yellow oil 60mg, yield is 77%；1H NMR (400MHz, DMSO) δ 8.03-7.91 (m, 4H, Ar-H), 7.87 (t, J=5.6,1H, NH), 7.33 (d, J=8.3,2H, Ar-H), 7.05 (d, J=2.1,1H, Ar-H), 6.79 (dd, J=8.8,2.2,1H, Ar-H), 5.52 (s, 2H, CH2),4.73 (t, J=5.5,1H, OH), 3.82 (s, 3H, CH3),3.73(s,3H,CH3), 3.49 (dd, J=11.9,6.1,2H, CH2), 3.29 (q, J=6.0,2H, CH2).ES-MS 383.1(M+H)+。
Compound 19b, methoxycarbonyl group benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole between 1-
Between preparation 1-, methoxycarbonyl group benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole is to use between 1- Methoxycarbonyl group benzyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, and yellow oil 86mg, yield is 66%；1H NMR (400MHz, DMSO) δ 8.01 (d, J=8.7Hz, 1H, Ar-H), 7.98 (s, 1H, Ar-H), 7.91-7.82 (m, 3H, Ar- H), 7.50 (d, J=5.4,2H, Ar-H), 7.11 (d, J=2.2,1H, Ar-H), 6.79 (dd, J=8.8,2.2,1H, Ar-H), 5.51(s,2H,CH2), 4.72 (t, J=5.5,1H, OH), 3.83 (s, 3H, CH3),3.76(s,3H,CH3), 3.50 (q, J= 6.1,2H,CH2), 3.31 (q, J=6.0,2H, CH2).ES-MS 383.1(M+H)+。
Compound 19c, 1-are to methoxy-benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole
Preparation 1-is to use first between 1-to methoxy-benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole Oxygen carbonyl benzyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, yellow oily 89mg, and yield is 56%；1H NMR (400MHz, DMSO) δ 8.00-7.97 (m, 2H, Ar-H), 7.94 (s, 1H, Ar-H), 7.84 (t, J=5.6,1H, NH), 7.25- 7.21 (m, 2H, Ar-H), 7.10 (d, J=2.2,1H, Ar-H), 6.92-6.88 (m, 2H, Ar-H), 6.77 (dd, J=8.7, 2.3,1H,Ar-H),5.31(s,2H,CH2), 3.77 (d, J=2.0,3H, CH3),3.71(s,3H,CH3), 3.49 (t, J= 6.1,2H,CH2),3.31-3.28(m,2H,CH2).ES-MS355.1(M+H)+。
Compound 19d, 1-meta-methoxy benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole
Preparation 1-meta-methoxy benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole is to use first between 1- Oxy-benzyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, light yellow solid 80mg, and yield is 59%. m.p.116.8-121.1℃；1H NMR (400MHz, DMSO) δ 8.00 (d, J=8.7,1H, Ar-H), 7.96 (s, 1H, Ar-H), 7.86 (t, J=5.5,1H, NH), 7.25 (dd, J=8.8,7.8,1H, Ar-H), 7.10 (d, J=2.1,1H, Ar-H), 6.89- 6.74(m,4H,Ar-H),5.37(s,2H,CH2), 4.73 (t, J=5.5,1H, OH), 3.76 (s, 3H, CH3),3.71(s,3H, CH3), 3.50 (q, J=6.0,2H, CH2), 3.30 (q, J=6.0,2H, CH2).ES-MS 355.1(M+H)+。
Compound 19e, 1-are to trifluoromethyl benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole
Preparation 1-is to use 1-to three to three fluorine-based benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole Fluorine-based benzyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, white solid 85mg, and yield is 64%.m.p.174- 174.9℃；1H NMR (400MHz, DMSO) δ 8.03-7.95 (m, 2H, Ar-H), 7.86 (t, J=5.6,1H, NH), 7.72 (d, J=8.2,2H, Ar-H), 7.40 (d, J=8.1,2H, Ar-H), 7.08 (d, J=2.2,1H, Ar-H), 6.79 (dd, J=8.8, 2.3,1H,Ar-H),5.54(s,2H,CH2), 4.72 (t, J=5.5,1H, OH), 3.73 (s, 3H, CH3), 3.49 (q, J=6.1, 2H,CH2), 3.30 (dd, J=11.8,5.9,2H, CH2).ES-MS 392.1(M+H)+。
Compound 19f, 1-m-trifluoromethyl benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole
Between preparation 1-, three fluorine-based benzyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole are to use between 1-three Fluorine-based benzyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, and yellow crystals 190mg, yield is 68%. m.p.90.1-95.6℃；1H NMR (400MHz, DMSO) δ 8.01 (d, J=9.2,2H, Ar-H), 7.85 (t, J=5.6,1H, NH), 7.72 (s, 1H, Ar-H), 7.66 (d, J=7.8,1H, Ar-H), 7.58 (t, J=7.7,1H, Ar-H), 7.46 (d, J= 7.7,1H, Ar-H), 7.12 (d, J=2.2,1H, Ar-H), 6.80 (dd, J=8.8,2.2,1H, Ar-H), 5.54 (s, 2H, CH2), 4.71 (t, J=5.5,1H, OH), 3.75 (s, 3H, CH3), 3.51 (q, J=6.1,2H, CH2), 3.31 (q, J=6.1, 2H,CH2).ES-MS 392.1(M+H)+。
Compound 20, methoxycarbonyl group benzyl-6-methoxyl group-3-hydroxyCarbamoyl indole between 1-
Methoxycarbonyl group benzyl-6-methoxyl group-3-carboxyl indole 180mg (0.53mmol) between 1-is added in 2ml DMF, so Rear addition BOP 269mg (0.637mmol), NEt30.3ml (2.12mmol), 0 DEG C of stirring reaction 0.5h.Add oxammonium hydrochloride 55.65mg (0.795mmol), is warmed to room temperature stirring reaction 20h.Ethyl acetate extracts, and anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains Crude product, through column chromatography, eluant is ethyl acetate/petroleum ether (1:8), obtains colorless oil object 40.1mg, and yield is 29% ；1H NMR(400MHz,DMSO)δ10.59(s,1H,OH),8.21(s,1H,Ar-H),7.89-7.84(m,3H,Ar-H),7.65 (s, 1H, Ar-H), 7.50 (d, J=7.5,2H, Ar-H), 7.08 (d, J=2.2,1H, Ar-H), 6.78 (dd, J=8.7,2.2, 1H,Ar-H),5.49(s,2H,CH2),3.82(s,3H,CH3),3.76(s,3H,CH3).ES-MS 355.1(M+H)+。
(7) compound 23 and the preparation of compound 27
Compound 21,1-methoxycarbonyl-methyl-6-methoxyl group-3-formyl indole
Preparation 1-methoxycarbonyl-methyl-6-methoxyl group-3-formyl indole is that employing 6-methoxyl group-3-formyl indole is Raw material, the same 2a of method, white solid 0.4g, yield is 94%.m.p.134.3-137.3℃；1H NMR(400MHz,DMSO)δ 9.87 (s, 1H, CHO), 8.15 (s, 1H, Ar-H), 7.95 (d, J=8.6,1H, Ar-H), 7.16 (d, J=2.2,1H, Ar-H), 6.90 (dd, J=8.6,2.2,1H, Ar-H), 5.27 (s, 2H, CH2),3.79(s,3H,CH3),3.71(s,3H,CH3).ES-MS 248.1(M+H)+。
Compound 22,1-methoxycarbonyl-methyl-6-methoxyl group-3-carboxyl indole
Preparation 1-methoxycarbonyl-methyl-6-methoxyl group-3-carboxyl indole be use 1-methoxycarbonyl-methyl-6-methoxyl group- 3-formyl indole is raw material, the same 18c of method, white solid 56mg, and yield is 47%.m.p.201.4-203.6℃；1H NMR (400MHz, DMSO) δ 11.94 (s, 1H, COOH), 7.91 (s, 1H, Ar-H), 7.86 (d, J=8.7,1H, Ar-H), 7.08 (d, J=2.2,1H, Ar-H), 6.84 (dd, J=8.7,2.2,1H, Ar-H), 5.20 (s, 2H, CH2),3.78(s,3H,CH3),3.70 (s,3H,CH3).ES-MS 264.1(M+H)+。
Compound 23,1-methoxycarbonyl-methyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole
Preparation 1-methoxycarbonyl-methyl-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole is to use 1-methoxy Carbonvlmethyl-6-methoxyl group-3-carboxyl indole is raw material, and method is with 12, and colorless oil 102mg, yield is 88%；1H NMR (400MHz, DMSO) δ 7.97 (d, J=8.7,1H, Ar-H), 7.80-7.82 (m, 2H, Ar-H and NH), 7.03 (d, J= 2.2,1H, Ar-H), 6.79 (dd, J=8.7,2.3,1H, Ar-H), 5.17 (s, 2H, CH2), 4.71 (t, J=5.5,1H, OH), 3.78(s,3H,CH3),3.70(s,3H,CH3), 3.50 (q, J=6.1,2H, CH2), 3.10 (q, J=7.2,2H, CH2).ES- MS 307.1(M+H)+。
Compound 25,1-(2-morpholinyl-2-acetyl group)-6-methoxyl group-3-formyl indole
By 1-methoxycarbonyl-methyl-6-methoxyl group-3-formyl indole 350mg (1.42mmol) add 1mlMeOH with In 4mlTHF, the rear 6N NaOH0.76ml that adds, stirring reaction 10h, 6N HCl adjust PH-2, and ethyl acetate extracts, saturated NaCl Washing, washing, anhydrous sodium sulfate is dried, and concentrated by rotary evaporation obtains crude yellow solid 314mg.Referring next to the method for compound 7, directly Reacting to obtain yellow solid 284mg with morpholine, yield is 73%.m.p.204.1-208.0℃；1H NMR(400MHz,DMSO)δ 9.85 (s, 1H, CHO), 8.07 (s, 1H, Ar-H), 7.95 (d, J=8.6Hz, 1H, Ar-H), 7.08 (d, J=2.2Hz, 1H, Ar-H), 6.89 (dd, J=8.6,2.2Hz, 1H, Ar-H), 5.30 (s, 2H, CH2),3.80(s,3H,CH3), 3.70 (d, J= 4.8,2H,CH2), 3.60 (d, J=4.5Hz, 4H, CH2), 3.47 (d, J=4.9Hz, 2H, CH2).ES-MS 303.1(M+H)+。
Compound 26,1-(2-morpholinyl-2-acetyl group)-6-methoxyl group-3-carboxyl indole
Preparation 1-(2-morpholinyl-2-acetyl group)-6-methoxyl group-3-carboxyl indole is to use 1-(2-morpholinyl-2-acetyl Base)-6-methoxyl group-3-formyl indole is raw material, the same 18c of method, yellow solid 144mg, yield is 46%.m.p.256.7- 259.0.5℃；1H NMR (400MHz, DMSO) δ 7.85 (d, J=8.7,1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.01 (d, J =2.1,1H, Ar-H), 6.83 (dd, J=8.7,2.2,1H, Ar-H), 5.22 (s, 2H, CH2),3.79(s,3H,CH3),3.72- 3.56(m,8H,CH2).ES-MS 319.1(M+H)+。
Compound 27,1-(2-morpholinyl-2-acetyl group)-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole Preparation 1-(2-morpholinyl-2-acetyl group)-6-methoxyl group-3-[(2-ethoxy) carbamoyl] indole is to use 1-(2- Quinoline base-2-acetyl group)-6-methoxyl group-3-carboxyl indole is raw material, method is with 12, and colorless oil 70mg, yield is 48%. m.p.256.3-256.5℃；1H NMR (400MHz, DMSO) δ 7.98 (d, J=8.7,1H, Ar-H), 7.77 (m, 2H, Ar- Hand NH), 6.98 (d, J=2.2,1H, Ar-H), 6.77 (dd, J=8.7,2.3,1H, Ar-H), 5.19 (s, 2H, CH2), 4.71 (t, J=5.5,1H, OH), 3.78 (s, 3H, CH3), 3.64 (d, J=35.7,8H, CH2),3.52-3.47(m,2H, CH2), 3.17 (d, J=5.2,2H, CH2).ES-MS 362.1(M+H)+。
Wherein, organic solvent A is selected from THF, dioxane,
Organic solvent B is selected from methanol, ethanol, isopropanol,
Organic solvent C is selected from DMF, DMSO,
Reducing agent is selected from NaBH4, KBH4, sodium triacetoxy borohydride, sodium cyanoborohydride
Amine is selected from triethylamine, diethylamine, trimethylamine, dimethylamine, N, N-diisopropylethylamine.

Claims (9)

1. a new indole analog derivative, chemical structure of general formula such as following formula (I, II):
Wherein,
R1Selected from-OCH3With
R2Selected from the alkyl of 1-4 carbochain, including methyl, ethyl, n-pro-pyl, isopropyl, cyclopropyl, normal-butyl, sec-butyl, Isobutyl group, the tert-butyl group,
R3Selected from alkyl or tolyl, ethylbenzene, the phenyl of 1-4 carbochain,
R4Selected from-COOCH3、-COOC2H5、
N is the integer of 0-4.
New indole analog derivative the most according to claim 1, it is characterised in that:
Wherein, R1The position of substitution of group is 5 or 6.
New indole analog derivative the most according to claim 1, it is characterised in that:
Wherein, R1In group
For
New indole analog derivative the most according to claim 1, it is characterised in that:
Wherein, R2Selected from methyl.
New indole analog derivative the most according to claim 1, it is characterised in that:
Wherein, R3Selected from methyl, phenyl.
New indole analog derivative the most according to claim 1, it is characterised in that:
Wherein, R4Selected from-COOCH3、
New indole analog derivative the most according to claim 1, it is characterised in that:
Wherein, n is 0,1,2.
New indole analog derivative the most according to claim 1, it is characterised in that selected from the compound of following structural:
9. the method for the new indole analog derivative synthesized in claim 1-8 described in any one, it is characterised in that close Become route as follows:
The process of operation a comprises the following steps: by raw material I-0 and NH2R2Will after stirring reaction a period of time in organic solvent A Solvent is evaporated, and adds stirring reaction after organic solvent B and reducing agent；
The process of operation b comprises the following steps: raw material II-0 and Ka Te condensing agent BOP, amine are dissolved in organic solvent C reaction one Add after the section timeRear stirring reaction,
Wherein, organic solvent A is selected from THF, dioxane,
Organic solvent B is selected from methanol, ethanol, isopropanol,
Organic solvent C is selected from DMF, DMSO,
Reducing agent is selected from NaBH4、KBH4, sodium triacetoxy borohydride, sodium cyanoborohydride,
Amine is selected from triethylamine, diethylamine, trimethylamine, dimethylamine, N, N-diisopropylethylamine.
CN201610624882.8A 2016-08-02 2016-08-02 New indole analog derivative and preparation method thereof Pending CN106243012A (en)

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