CN106349148B - New indole class compound with anti-tumor metastasis and anti-inflammatory activity, synthesis and application - Google Patents

New indole class compound with anti-tumor metastasis and anti-inflammatory activity, synthesis and application Download PDF

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CN106349148B
CN106349148B CN201510409682.6A CN201510409682A CN106349148B CN 106349148 B CN106349148 B CN 106349148B CN 201510409682 A CN201510409682 A CN 201510409682A CN 106349148 B CN106349148 B CN 106349148B
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indoles
ethoxy
obzl
double
methoxy
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CN106349148A (en
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赵明
彭师奇
吴建辉
王玉记
甘太平
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Capital Medical 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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Abstract

The invention discloses 20 kinds of 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-AA-OBzl that general formula I is represented, disclose their preparation method, it discloses them and inhibits tumor cell invasion and transferance, the activity that they inhibit the weight gain of S-180-bearing mice knurl is disclosed, their antitumor Lung metastases activity and anti-inflammatory activity are disclosed.The compound of the present invention is preparing anti-tumor drug, has a good application prospect in medicine for anti transfer of tumor and anti-inflammatory drug.

Description

New indole class compound with anti-tumor metastasis and anti-inflammatory activity, synthesis and Using
Technical field
The present invention relates to 20 kinds of 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-AA- OBzl is related to their preparation method, is related to them and inhibits tumor cell invasion and transferance, is related to them and inhibits lotus S180 The activity of tumor mouse tumor body weight gains is related to their antitumor Lung metastases activity and anti-inflammatory activity.It is prepared by the compound of the present invention It has a good application prospect in anti-tumor drug, medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biological medicine necks Domain.
Background technique
Malignant tumour has seriously threatened the life and health of the mankind.Wherein lung cancer is one of most invasive human cancer. For the patient in patients with lung cancer advanced stage, the people of usual 10%-15% can only survive 5 years.This difficulty in past 30 years Situation not yet significantly makes moderate progress.In many clinical cases, lung cancer is transferred into surrounding tissue before being diagnosed.Hand Art, radiotherapy, chemotherapy may result in serious side effects, cause the quality of life of patient low.Therefore, there is an urgent need to find effectively and Safe drugs, this disadvantage in treatment to improve lung cancer.
Our early period invents (103539722 A of patent application publication CN, application number 201310278480.3) table Bright, double ethychlozate derivatives of aryl substituted methyl group connection have significant antitumor curative effect, and without apparent cell Toxicity or toxic side effect can be used as the candidate compound of anti-tumor drug.In more deep experimental study, inventor's discovery Double heteroauxins are changed into double indoles ethyl alcohol, to the CH for connecting double indoles ethyl alcohol2Salicyloy lamino acid benzyl ester is introduced, it can not only Enough enhance anti-tumor activity, additionally it is possible to obtain anti-tumor metastasis and anti-inflammatory activity, it can bring technical effect outstanding.Root According to these discoveries, 20 kinds of 5- of the invention (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- hydroxyl is inventors herein proposed Benzoyl-AA-OBzl and their preparation and anti-tumor drug is being prepared, in medicine for anti transfer of tumor and anti-inflammatory medicaments Using.
Summary of the invention
First content of the invention is to provide 20 kinds of 5- (bis- (3- (2- ethoxy) -1H- indoles -2) of general formula I representative Methyl) -2- (2-hydroxybenzoyl)-AA-OBzl (AA=Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro in formula, Met, Cys (Bzl), Ser, Thr, Gln, Asn, Asp (OBzl), Glu (OBzl), NG-NO2- Arg and The residue)；
Second content of the invention is to provide 20 kinds of 5- (bis- (3- (2- ethoxy) -1H- indoles-of the representative of general formula I 2) methyl) -2- (2-hydroxybenzoyl)-AA-OBzl (AA=Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr in formula, Pro, Met, Cys (Bzl), Ser, Thr, Gln, Asn, Asp (OBzl), Glu (OBzl), NG-NO2- Arg and The residue) system Preparation Method, this method are made of following steps:
1) it is reacted in tetrahydrofuran in Catalyzed by p-Toluenesulfonic Acid and 60 DEG C of indoles ethyl alcohol with 5- formylsalicylic acid methyl esters, it is raw As 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2 hydroxybenzoic acid methyl esters；
2) by 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2 hydroxybenzoic acid first in 4N NaOH solution Ester saponification, obtains 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2 hydroxybenzoic acid；
3) 5- formylsalicylic acid exists in the presence of dicyclohexylcarbodiimide (DCC) and N- hydroxy benzo triazole (HOBt) It is reacted in anhydrous tetrahydro furan with l-amino acid benzyl ester, generates 5- formyl -2- Hydroxy-benzoyIcarbamo-AA-OBzl, AA=in formula Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Cys (Bzl), Ser, Thr, Gln, Asn, Asp (OBzl), Glu (OBzl), NG-NO2- Arg and The residue；
4) indoles ethyl alcohol and 5- formyl -2- Hydroxy-benzoyIcarbamo-AA-OBzl in the presence of Catalyzed by p-Toluenesulfonic Acid and 60 DEG C It is reacted in tetrahydrofuran, generates 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-AA-OBzl, AA=Gly in formula, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Cys (Bzl), Ser, Thr, Gln, Asn, Asp (OBzl), Glu (OBzl), NG-NO2- Arg and The residue.
Third content of the invention is to evaluate 20 kinds of 5- (bis- (3- (2- ethoxy) -1H- indoles-of the representative of general formula I 2) methyl) -2- (2-hydroxybenzoyl)-AA-OBzl inhibit tumor cell proliferation effect；
4th content of the invention is to evaluate 20 kinds of 5- (bis- (3- (2- ethoxy) -1H- indoles-of the representative of general formula I 2) methyl) -2- (2-hydroxybenzoyl)-AA-OBzl inhibit lotus S180 mice with tumor tumour growth effect；
5th content of the invention is to evaluate 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- of general formula I (2-hydroxybenzoyl)-Trp-OBzl inhibits Lewis lung cancer in mice in-vivo tumour transfer activity；
6th content of the invention is to evaluate 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- of general formula I The ability of (2-hydroxybenzoyl)-Trp-OBzl inhibition tumor cell migration；
7th content of the invention is 5- (bis- (3- (2- ethoxy) -1H- indoles -2) first of evaluation evaluation general formula I Base) -2- (2-hydroxybenzoyl)-Trp-OBzl inhibit tumor cell invasion ability；
8th content of the invention is 5- (bis- (3- (2- ethoxy) -1H- indoles -2) first of evaluation evaluation general formula I Base) -2- (2-hydroxybenzoyl)-Trp-OBzl inhibit dimethylbenzene induction mouse ear swelling activity；
9th content of the invention is 20 kinds of 5- (bis- (3- (2- the ethoxy) -1H- indoles-for the representative for illustrating general formula I 2) methyl) -2- (2-hydroxybenzoyl)-AA-OBzl (AA=Gly, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro in formula, Met, Cys (Bzl), Ser, Thr, Gln, Asn, Asp (OBzl), Glu (OBzl), NG-NO2- Arg and The residue) it is anti-in preparation Tumour medicine, the application in medicine for anti transfer of tumor and anti-inflammatory drug.
Detailed description of the invention
Synthetic route i) DCC, HOBt, NMM of Fig. 1 compound；Ii) p-methyl benzenesulfonic acid, 60 DEG C；iii)4N NaOH； 1a With AA=in AA=Ile, 1e and 2e in AA=Leu, 1d and 2d in AA=Ala, 1c and 2c in AA=Gly in 2a, 1b and 2b In AA=Tyr in AA=Lys, 1i and 2i in AA=Phe, 1h and 2h in AA=Trp in Val, 1f and 2f, 1g and 2g, 1j and 2j AA=Thr, 1o in AA=Ser, 1n and 2n in AA=Cys (Bzl) in AA=Met in Pro, 1k and 2k, 11 and 21,1m and 2m With AA=Glu (OBzl), 1s in AA=Asp (OBzl), 1r and 2r in AA=Asn, 1q and 2q in AA=Gln in 2o, 1p and 2p With AA=N in 2sG-NO2AA=The residue in-Arg, 1t and 2t.
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
1 liquid phase peptide reaction of embodiment leads to method
The exposed compound in carboxylic end is dissolved with anhydrous tetrahydro furan (THF), N- hydroxy benzenes a pair of horses going side by side three is added in obtained solution Nitrogen azoles (HOBt) is slowly added to the N dissolved with anhydrous THF, N- dicyclohexylcarbodiimide (DCC), 0 DEG C of stirring under ice bath 15min obtains reaction solution (I).The amino acid of carboxylic end protection is also dissolved with anhydrous THF, adjusts pH 9 with N-methylmorpholine (NMM), Then it is mixed with reaction solution (I), maintains pH 9 with N-methylmorpholine, 10h is stirred at room temperature, TLC monitors reaction process.Raw material point disappears After mistake, reaction mixture filtering, filtrate decompression concentration obtains sticky mass ethyl acetate or methylene chloride dissolution, obtains Solution successively use 5%NaHCO3Aqueous solution is washed, 5%KHSO4Aqueous solution is washed, and saturation NaCl aqueous solution is washed, ethyl acetate or dichloro Methane is added to anhydrous sodium sulfate and dries, filters, and filtrate decompression is concentrated to give target compound.
Embodiment 2 prepares 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2 hydroxybenzoic acid methyl esters (3)
1.66g (10mmol) 5- formylsalicylic acid methyl esters, 3.22g (20mmol) indoles ethyl alcohol and 0.17g (1mmol) are right Toluenesulfonic acid is dissolved with 50mLTHF, and after 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears It loses, stops reaction, be cooled to room temperature, be concentrated to dryness, residue is dissolved with methylene chloride, chromatographs to obtain by silicagel column column Buff powder 3.8g (78%).IR:3375,3055,1672,1487,1456,1208,1088,738cm-1； FT-MS(m/ E): 485.20627 [M+H]+(calculated:484.19982)；1δ=10.52 H NMR (800MHz, DMSO-d6) (s, 2H), 10.47 (s, 1H), 7.58 (s, 1H), 7.50 (d, J=8.0Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 7.25 (d, J =8.8Hz, 2H), 7.04 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.95 (d, J=8.8Hz, 1H), 6.08 (s, 1H), 3.80 (s, 3H), 3.53 (m, 2H), 3.49 (m, 2H), 2.86 (m, 4H).
Embodiment 3 prepares 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2 hydroxybenzoic acid (4)
1.2g (2.4mmol) 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2 hydroxybenzoic acid first under ice bath Ester (3) is dissolved with methanol, and 4N NaOH aqueous solution is added, and is adjusted pH value to 12, is reacted 48h, TLC plate monitors (CH2Cl2∶ CH3OH=20: 1) raw material point disappears, fully reacting.With saturation KHSO under ice bath4Reaction solution is adjusted to neutrality, is concentrated under reduced pressure and removes Methanol, residue continues to adjust pH value to 3, is extracted with ethyl acetate 3 times, combined ethyl acetate phase, dry with anhydrous sodium sulfate, Filtering, is concentrated under reduced pressure to give 1.08g (93%) target compound, is light gray solid.IR:3367,1667,1457,1215, 1038,740cm-1；FT-MS (m/e): 469.17775 [M-H]-(calculated:470.18417)；1H NMR (800MHz, DMSO-d6) δ=10.53 (s, 2H), 7.53 (s, 1H), 7.50 (d, J=8.0Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 7.26 (d, J=8.8Hz, 2H), 7.03 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.92 (d, J=8.8Hz, 1H), 6.07 (s, 1H), 3.53 (m, 2H), 3.49 (m, 2H), 2.85 (t, J=7.2Hz, 4H).
Embodiment 4 prepares 5- formyl -2- (2-hydroxybenzoyl)-glycine benzyl ester (1a)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.05g (12mmol) glycine benzyl hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 12h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 2.4g (72.8%) title compound, is pale yellow powder.ESI-MS (m/e): 314[M+H]+。
Embodiment 5 prepares 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-glycine benzyl ester (2a)
3.13g (10mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-glycine benzyl ester (1a), 3.22g (20mmol) indoles second Pure and mild 0.17g (1mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 4.8g (78%) target compound.IR:3329,3031,1736,1642,1456,1192,1038, 1008,695cm-1；FT-MS (m/e): 618.26100 [M+H]+(calculated:617.25259)；1H NMR (800MHz, DMSO-d6) δ=11.75 (s, 1H), 10.53 (s, 2H), 9.02 (s, 1H), 7.74 (d, J=2.4Hz, 1H), 7.50 (d, J= 8.0Hz, 2H), 7.38 (m, 4H), 7.33 (m, 3H), 7.17 (m, 1H), 7.04 (t, J=7.2Hz, 2H), 6.97 (t, J= 7.2Hz, 2H), 6.91 (d, J=8.0Hz, 1H), 6.04 (s, 1H), 5.15 (s, 2H), 4.73 (t, J=4.8Hz, 2H), 3.51 (m, 4H), 2.97 (m, 4H).
Embodiment 6 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-alanine benzyl ester (1b)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, after stirring 0.5h, 4.25g (12mmol) alanine benzyl ester hydrochloride is added, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, and shows fully reacting.It filters out DCU, reaction mixture are concentrated to dryness, residue with 150mL ethyl acetate dissolve, filter out insoluble matter, obtained solution according to It is secondary to use 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, acetic acid Methacrylate layer anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness.Residue chromatographs (CH by silicagel column column2Cl2∶ CH3OH=60: 1) purifying, obtain 2.7g (82%) target compound, is buff powder.ESI-MS (m/e): 328 [M+H]+。
Embodiment 7 prepares 5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-alanine benzyl Ester (2b)
0.98g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-alanine benzyl ester (1b), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mL THF dissolves, and 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears.Stop reaction, be cooled to room temperature, reaction mixture is concentrated to dryness, and residue is with two Chloromethanes dissolution chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) purifying, obtain 0.6g (79%) target compound, For grayish powder.IR:3330,1735,1641,1537,1456,1215,1040, 803cm-1；FT-MS (m/e): 632.27346 [M+H]+(calculated:631.26824)；1H NMR (800MHz, DMSO- D6) δ=10.49 (s, 2H), 7.78 (s, 1H), 7.48 (d, J=7.2Hz, 2H), 7.36 (m, 4H), 7.28 (m, 3H), 7.11 (dd, J1=8.0Hz, J2=8.8Hz, 1H), 7.02 (t, J=7.2Hz, 2H), 6.96 (t, J=7.2Hz, 2H), 6.90 (d, J =8.8Hz, 1H), 6.02 (s, 1H), 5.14 (q, J=4.8Hz, 2H), 4.53 (q, J=7.2Hz, 1H), 3.49 (m, 4H), 3.34 (m, 4H), 1.40 (d, J=7.2Hz, 3H).
Embodiment 8 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-leucine benzyl ester (1c)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.70g (12mmol) leucine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.0g (81.8%) title compound, is pale yellow powder.ESI-MS (m/e): 370[M+H]+。
Embodiment 9 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-leucine benzyl Ester (2c)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-leucine benzyl ester (1c), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mL THF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residue methylene chloride Dissolution chromatographs (CH by silicagel column column2Cl2∶CH3OH=60: 1) it purifies, obtains 0.52g (80.8%) target compound, be Grayish powder.IR:3349,2952,1735,1643,1457,1216,738cm-1；FT-MS (m/e): 674.31798 [M+H]+(calculated:673.31519)；1H NMR (800MHz, DMSO-d6) δ= 11.69 (s, 1H), 10.51 (d, J=6.4Hz, 2H), 8.86 (d, J=7.2Hz, 2H), 7.79 (d, J=2.4Hz, 1H), 7.49 (d, J=8.0Hz, 2H), 7.35 (m, 4H), 7.27 (m, 3H), 7.13 (dd, J1=8.0 Hz, J2=2.4Hz, 2H), 7.03 (t, J=7.2Hz, 2H), 6.98 (t, J=7.2Hz, 2H), 6.91 (d, J=8.0Hz, 1H), 6.03 (s, 1H), 5.76 (s, 1H), 5.21 (m, 2H), 4.55 (m, 1H), 3.57 (m, 4H), 2.95 (m, 4H), 1.72 (m, 1H), 1.62 (m, 2H), 0.87 (d, J=6.4Hz, 3H), 0.85 (d, J=6.4Hz, 3H).
Embodiment 10 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-isoleucine benzyl ester (1d)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.70g (12mmol) isoleucine benzyl ester hydrochloride is added after stirring 0.5h, PH to 9 is adjusted with NMM, reacts 8h, TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.It filters out DCU, reaction mixture are concentrated to dryness, residue with 150mL ethyl acetate dissolve, filter out insoluble matter, obtained solution according to It is secondary to use 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, acetic acid Methacrylate layer anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil passes through silicagel column column Chromatograph (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3g (81.7%) title compound, is pale yellow powder.ESI-MS(m/ E): 370 [M+H]+。
Embodiment 11 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-isoleucine Benzyl ester (2d)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-isoleucine benzyl ester (1d), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 0.6g (82.7%) target compound, is grayish powder.(c=0.6, CH3OH)；IR:3321, 2928,1729,1641,1456,1191,738cm-1；FT-MS (m/e): 674.31936 [M+H]+(calculated: 673.31519)；1δ=11.47 (s, 1H) H NMR (800MHz, DMSO-d6), 10.52 (s, 2H), 8.85 (d, J=8.0Hz, 1H), 7.73 (s, 1H), 7.50 (d, J=8.0Hz, 2H), 7.35 (m, 4H), 7.33 (m, 1H), 7.30 (d, J=8.0Hz, 2H), 7.13 (dd, J1=8.8Hz, J2=2.4Hz, 1H), 7.06 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.92 (d, J=8.8Hz, 1H), 6.04 (s, 1H), 5.16 (q, J=4.0Hz, 2H), 4.74 (s, 1H), 4.50 (dd, J1= 8.0Hz, J2=5.6Hz, 1H), 3.56 (m, 4H), 2.85 (m, 4H), 1.96 (m, 1H), 1.40 (m, 1H), 1.16 (m, 1H), 0.87 (d, J=7.2Hz, 3H), 0.84 (t, J=7.2Hz, 3H).
Embodiment 12 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-valine benzyl ester (1e)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.50g (12mmol) valine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.1g (87.3%) title compound, is pale yellow powder.ESI-MS (m/e): 355[M+H]+。
Embodiment 13 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-valine benzyl Ester (2e)
1.06g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-valine benzyl ester (1e), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 0.48g (80.3%) target compound, is grayish powder.(c=0.5, CH3OH)；IR: 3324,2932,1735,1640,1456,1038,738,696cm-1；FT-MS (m/e): 660.3026 [M+H]+ (calculated:659.29954)；1δ=11.48 (s, 1H) H NMR (800MHz, DMSO-d6), 10.52 (s, 2H), 8.84 (s, 1H), 7.74 (s, 1H), 7.50 (d, J=8.0Hz, 2H), 7.36 (m, 4H), 7.39 (m, 3H), 7.13 (dd, J1= 8.8Hz, J2=2.4Hz, 1H), 7.03 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.93 (d, J=8.8Hz, 1H), 6.04 (s, 1H), 5.16 (dd, J=37.6,12Hz, 2H), 4.62 (s, 2H), 4.44 (d, J=7.2Hz, 1H), 3.61 (m, 4H), 2.85 (m, 4H), 2.18 (m, 1H), 0.90 (d, J=7.2Hz, 3H), 0.88 (d, J=7.2Hz, 3H).
Embodiment 14 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-tryptophan benzyl ester (1f)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 3.97g (12mmol) tryptophan benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.5g (79.1%) title compound, is pale yellow powder.ESI-MS (m/e): 443[M+H]+。
Embodiment 15 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-tryptophan benzyl Ester (2f)
1.33g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-tryptophan benzyl ester (1f), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 1.82g (81.3%) target compound, is grayish powder.(c=0.8, CH3OH)；IR: 3396,3056,1736,1642,1456,1215,737,696cm-1；FT-MS (m/e): 747.31278 [M+H]+ (calculated:746.31044)；1δ=10.81 (s, 1H) H NMR (800MHz, DMSO-d6), 10.49 (s, 2H), 7.75 (s, 1H), 7.49 (d, J=12Hz, 2H), 7.47 (d, J=9.6Hz, 1H), 7.34 (d, J=8.0Hz, 1H), 7.29 (m, 5H), 7.20 (m, 2H), 7.09 (m, 2H), 7.06 (m, 3H), 6.99 (t, J=7.2Hz, 2H), 6.94 (t, J=7.2Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.01 (s, 1H), 5.09 (q, J=12Hz, 2H), 4.74 (t, J=7.2Hz, 1H), 3.54 (m, 4H), 3.28 (m, 2H), 2.83 (m, 4H).
Embodiment 16 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-phenylalanine benzyl ester (1g)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.27g (12mmol) phenylalanine benzyl ester hydrochloride is added after stirring 0.5h, PH to 9 is adjusted with NMM, reacts 8h, TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.It filters out DCU, reaction mixture are concentrated to dryness, residue with 150mL ethyl acetate dissolve, filter out insoluble matter, obtained solution according to It is secondary to use 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, acetic acid Methacrylate layer anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil passes through silicagel column column Chromatograph (CH2Cl2∶CH3OH=60: 1) purifying, obtain 2.4g (67.9%) title compound, is pale yellow powder.ESI-MS (m/e): 404 [M+H]+。
Embodiment 17 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-phenylalanine Benzyl ester (2g)
1.2g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-phenylalanine benzyl ester (1g), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 1.69g (79.5%) target compound, is grayish powder.(c=0.6, CH3OH)；IR: 3331,3032,1740,1678,1455,1215,738,694cm-1；FT-MS (m/e): 708.30314 [M+H]+ (calculated:707.29954)；1δ=11.48 (s, 1H) H NMR (800MHz, DMSO-d6), 10.49 (s, 2H), 8.90 (d, J=7.2Hz, 1H), 7.75 (s, 1H), 7.49 (d, J=8.0Hz, 2H), 7.33 (m, 7H), 7.17 (m, 5H), 7.09 (dd, J1=8.0Hz, J2=2.4Hz, 2H), 7.05 ((t, J=8Hz, 2H), 6.97 (t, J=8.0Hz, 2H), 6.88 (d, J= 8.8Hz, 1H), 6.02 (s, 1H), 5.75 (s, 2H), 4.74 (m, 1H), 3.54 (m, 4H), 3.16 (dd, J1=13.6 Hz, J2= 5.6Hz, 1H), 3.10 (dd, J1=8Hz, J2=5.6Hz, 1H), 2.83 (m, 4H).
Embodiment 18 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-lysine benzyl ester (1h)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.5g (12mmol) Lys (Boc)-OBzl is added after stirring 0.5h, with NMM tune PH to 9 is saved, 8h is reacted, TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, reaction is mixed It closes liquid to be concentrated to dryness, residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution successively uses 5% NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate layer Use anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.4g (70.8%) title compound, is pale yellow powder.ESI-MS (m/e): 485[M+H]+。
Embodiment 19 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-lysine Benzyl ester (2h)
1.5g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-lysine benzyl ester (1h), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid with 50mLTHF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 2.01g (85%) target compound.(c=0.8, CH3OH)；IR:3323,2930, 1736,1643,1456,1365,738,696cm-1；FT-MS (m/e): 789.38138 [M+H]+(calculated: 788.32609)；1δ=11.65 (s, 1H) H NMR (800MHz, DMSO-d6), 10.53 (s, 2H), 8.87 (d, J=7.2Hz, 1H), 7.77 (s, 1H), 7.49 (d, J=8.0Hz, 2H), 7.36 (m, 4H), 7.32 (m, 3H), 7.12 (d, J=1.6Hz, 1H), 7.01 (t, J=7.2Hz, 2H), 6.95 (t, J=7.2Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.61 (t, J= 7.2Hz, 1H), 6.03 (s, 1H), 5.15 (q, J=12Hz, 2H), 4.72 (m, 2H), 4.48 (m, 1H), 3.53 (m, 4H), 2.95 (m, 6H), 1.82 (m, 1H), 1.75 (m, 1H), 1.34 (s, 10H), 1.24 (m, 2H).
Embodiment 20 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-tyrosine benzyl ester (1i)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 5.3g (12mmol) tyrosine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.6g (85.7%) title compound, is pale yellow powder.ESI-MS (m/e): 420[M+H]+。
Embodiment 21 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-tyrosine Benzyl ester (2i)
1.2g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-tyrosine benzyl ester (1i), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid with 50mLTHF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 1.76g (81.0%) target compound.(c=0.6, CH3OH)；IR:3324,2969, 1735,1641,1456,1358,1215,738,696cm-1；FT-MS (m/e): 724.30316 [M+H]+(calculated: 723.29445)；1δ=11.47 (s, 1H) H NMR (800MHz, DMSO-d6), 10.53 (s, 2H), 9.25 (s, 1H), 8.85 (s, 1H), 7.73 (s, 1H), 7.49 (m, 2H), 7.34 (m, 4H), 7.28 (m, 3H), 7.14 (m, 1H), 7.03 (t, J= 7.2Hz, 2H), 6.96 (m, 2H), 6.92 (m, 2H), 6.88 (d, J=7.2Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 6.03 (s, 1H), 5.76 (s, 2H), 5.11 (m, 2H), 4.69 (m, 2H), 3.53 (m, 4H), 3.05 (m, 2H), 2.91 (m, 4H).
Embodiment 22 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-proline benzyl ester (1j)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 2.9g (12mmol) proline benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.1g (84.2%) title compound, is pale yellow powder.ESI-MS (m/e): 354[M+H]+。
Embodiment 23 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-proline Benzyl ester (2j)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-proline benzyl ester (1j), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid with 50mLTHF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 1.63g (81.5%) target compound.(c=0.5, CH3OH)；IR:3297,3030, 1736,1574,1455,1365,1216,737,696cm-1；FT-MS (m/e): 658.28914 [M+H]+(calculated: 657.28389)；1δ=10.58 (s, 2H) H NMR (800MHz, DMSO-d6), 10.00 (s, 1H), 7.50 (d, J=7.2Hz, 2H), 7.38-7.21 (m, 8H), 7.03 (t, J=7.2Hz, 3H), 6.94 (t, J=7.2Hz, 4H), 6.92 (s, 1H), 6.85 (d, J=8.0Hz, 1H), 6.02 (s, 1H), 5.08 (q, J=12.0Hz, 2H), 4.64 (s, 2H), 4.45 (t, J=4.8Hz, 1H), 3.55 (m, 4H), 2.86 (m, 4H), 2.28 (m, 1H), 1.86 (m, 4H).
Embodiment 24 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-methionine benzyl ester (1k)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 4.9g (12mmol) methionine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.0g (83.7%) title compound, is pale yellow powder.ESI-MS (m/e): 358[M+H]+。
Embodiment 25 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-methionine benzyl Ester (2k)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-methionine benzyl ester (1k), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mL THF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 1.71g (82.3%) target compound.(c=1.0, CH3OH)；IR:3321,3031, 1735,1641,1457,1216,739,696cm-1；FT-MS (m/e): 692.27857 [M+H]+(calculated: 691.27161)；1δ=11.67 (s, 1H) H NMR (800MHz, DMSO-d6), 10.51 (s, 2H), 8.93 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 7.49 (d, J=8.0Hz, 2H), 7.37 (m, 4H), 7.30 (m, 3H), 7.13 (dd, J1=8.8Hz, J2 =2.4Hz, 1H), 7.02 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.91 (d, J=8.8Hz, 1H), 6.03 (s, 1H), 5.16 (dd, J1=29.6Hz, J2=12.8Hz, 2H), 4.72 (s, 2H), 4.66 (m, 1H), 3.53 (m, 4H), 2.83 (m, 4H), 2.47 (m, 2H), 2.13 (m, 2H), 1.96 (s, 3H).
Embodiment 26 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-cysteine benzyl oxide benzyl ester (1l)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 1.7g (4.9mmol) cysteine benzyl oxide benzyl ester hydrochloric acid is added after stirring 0.5h Salt adjusts pH to 9 with NMM, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.It filters out DCU, reaction mixture are concentrated to dryness, residue with 150mL ethyl acetate dissolve, filter out insoluble matter, obtained solution according to It is secondary to use 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, acetic acid Methacrylate layer anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil passes through silicagel column column Chromatograph (CH2Cl2∶CH3OH=60: 1) purifying, obtain 2.1g (65.8%) title compound, is pale yellow powder.ESI-MS (m/e): 450 [M+H]+。
Embodiment 27 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-cysteine Benzyl oxide benzyl ester (21)
1.3g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-cysteine benzyl oxide benzyl ester (1l), 0.75g (4.5mmol) Indoles ethyl alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mL THF dissolve, 60 DEG C of reaction 10h, the monitoring of TLC plate (CH2Cl2∶CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture decompression It is concentrated to dryness, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH= 50: 1) purifying, obtain 1.76g (78.0%) target compound, be grayish powder.(c=0.7, CH3OH)； IR:3322,3030,1737,1642,1455,1216,738,696cm-1；FT-MS (m/e): 754.29240 [M+H]+ (calculated:753.28726)；1δ=11.58 (s, 1H) H NMR (800MHz, DMSO-d6), 10.77 (s, 2H), 9.11 (s, 1H), 7.75 (s, 1H), 7.50 (dd, J1=12.0Hz, J2=8.0Hz, 3H), 7.35 (m, 4H), 7.28 (m, 3H), 7.24 (m, 2H), 7.22 (m, 1H), 7.16 (m, 2H), 7.08 (m, 2H), 6.97 (t, J=7.2Hz, 2H), 6.92 (d, J=8.0Hz, 1H), 6.04 (s, 1H), 5.15 (q, J=4.8Hz, 2H), 4.78 (td, J1=7.2Hz, J2=5.6Hz, 1H), 4.73 (s, 2H), 4.60 (s, 1H), 3.73 (s, 2H), 3.65 (t, J=7.2Hz, 2H), 3.56 (m, 4H), 2.84 (m, 4H).
Embodiment 28 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-serine benzyl ester (1m)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 2.8g (12mmol) serine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 2.8g (81.4%) title compound, is pale yellow powder.ESI-MS (m/e): 344[M+H]+。
Embodiment 29 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-serine benzyl Ester (2m)
1.3g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-serine benzyl ester (1m), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mL THF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 1.56g (81.3%) target compound.(c=0.9, CH3OH)；IR:3335, 2940,1737,1642,1456,1259,738,695cm-1；FT-MS (m/e): 648.26903 [M+H]+(calculated: 647.26315)；1δ=11.42 (s, 1H) H NMR (800MHz, DMSO-d6), 10.53 (s, 2H), 9.05 (s, 1H), 7.76 (s, 1H), 7.49 (d, J=7.2Hz, 2H), 7.38 (m, 4H), 7.28 (m, 3H), 7.21 (m, 2H), 7.15 (dd, J=8.8, 2.4Hz, 1H), 7.05 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.90 (d, J=8.0Hz, 1H), 6.04 (s, 1H), 5.16 (s, 2H), 4.65 (m, 1H), 3.88 (d, J=7.2Hz, 1H), 3.75 (d, J=7.2Hz, 1H), 3.58 (m, 4H), 2.84 (m, 4H).
Embodiment 30 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-threonine benzyl ester (1n)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 2.9g (12mmol) threonine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.0g (83.7%) title compound, is pale yellow powder.ESI-MS (m/e): 358[M+H]+。
Embodiment 31 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-threonine Benzyl ester (2n)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-threonine benzyl ester (1n), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mL THF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH30H=50: 1) it purifies, obtains It is grayish powder to 1.65g (83.1%) target compound.(c=0.6, CH3OH)；IR:3322, 2969,1736,1641,1456,1228,738,696cm-1；FT-MS (m/e): 662.28382 [M+H]+(calculated: 661.27880)；1δ=11.27 (s, 1H) H NMR (800MHz, DMSO-d6), 10.54 (s, 2H), 8.96 (s, 1H), 7.73 (s, 1H), 7.50 (d, J=8.0Hz, 2H), 7.37 (m, 4H), 7.29 (m, 3H), 7.11 (dd, J1=8.8Hz, J2=2.4Hz, 1H), 7.05 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.93 (d, J=8.0Hz, 1H), 6.05 (s, 1H), 5.15 (dd, J1=16.8Hz, J2=12.8Hz, 2H), 4.74 (s, 2H), 4.49 (dd, J1=8.0Hz, J2=2.4Hz, 1H), 3.58 (m, 4H), 2.86 (t, J=7.2Hz, 4H), 1.11 (d, J=7.2Hz, 3H).
Embodiment 32 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamine benzyl ester (1o)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 5.0g (12mmol) glutamine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.0g (77.9%) title compound, is pale yellow powder.ESI-MS (m/e): 385[M+H]+。
Embodiment 33 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-glutamy Amine benzyl ester (2o)
1.4g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamine benzyl ester (1o), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 1.74g (83.8%) target compound, is grayish powder.(c=0.7, CH3OH)；IR: 3291,1736,1643,1456,1358,1262,739,696cm-1；FT-MS (m/e): 689.29622 [M+H]+ (calculated:688.28970)；-1δ=11.75 (s, 1H) H NMR (800MHz, DMSO-d6), 10.51 (s, 2H), 8.99 (s, 1H), 7.80 (s, 1H), 7.49 (d, J=8.0Hz, 2H), 7.38 (m, 4H), 7.29 (m, 3H), 7.13 (dd, J1= 8.0Hz, J2=5.6Hz, 1H), 7.06 (t, J=7.2Hz, 2H), 6.99 (t, J=7.2Hz, 2H), 6.91 (d, J=8.8Hz, 1H), 6.73 (s, 1H), 6.03 (s, 1H), 5.15 (s, 2H), 4.73 (s, 2H), 4.52 (ddd, J1=8.8Hz, J2=7.2Hz, J3=5.6Hz, 2H), 3.50 (m, 4H), 2.83 (t, J=7.2Hz, 4H), 2.17 (t, J=7.2Hz, 2H), 2.10 (m, 1H), 1.92 (m, 1H).
Embodiment 34 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-asparagine benzyl ester (1p)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 3.5g (12mmol) asparagine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.1g (74.1%) title compound, is pale yellow powder.ESI-MS (m/e): 371[M+H]+。
Embodiment 35 prepares (5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-asparagus fern acyl Amine benzyl ester (2p)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-asparagine benzyl ester (1p), 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 1.59g (79.3%) target compound, is grayish powder.(c=0.7, CH3OH)；IR: 3323,2939,1736,1643,1456,1213,739,696cm-1；FT-MS (m/e): 675.28117 [M+H]+ (calculated:674.27405)；1δ=11.74 (s, 1H) H NMR (800MHz, DMSO-d6), 10.51 (s, 2H), 8.99 (s, 1H), 7.80 (s, 1H), 7.49 (d, J=8.0Hz, 2H), 7.38 (m, 4H), 7.29 (m, 3H), 7.13 (dd, J1= 8.0Hz, J2=5.6Hz, 1H), 7.06 (t, J=7.2Hz, 2H), 6.99 (t, J=7.2Hz, 2H), 6.91 (d, J=8.8Hz, 1H), 6.72 (s, 1H), 6.03 (s, 1H), 5.14 (s, 2H), 4.73 (s, 2H), 4.52 (m, 1H), 3.50 (m, 4H), 2.83 (t, J=7.2Hz, 4H), 2.10 (m, 1H), 1.92 (m, 1H).
Embodiment 36 prepares the double benzyl esters (1q) of 5- formyl -2- Hydroxy-benzoyIcarbamo-aspartic acid
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, the double benzyl ester hydrochlorides of 4.2g (12mmol) aspartic acid are added after stirring 0.5h, PH to 9 is adjusted with NMM, reacts 8h, TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.It filters out DCU, reaction mixture are concentrated to dryness, residue with 150mL ethyl acetate dissolve, filter out insoluble matter, obtained solution according to It is secondary to use 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, acetic acid Methacrylate layer anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil passes through silicagel column column Chromatograph (CH2Cl2∶CH3OH=60: 1) purifying, obtain 4g (86.9%) title compound, is pale yellow powder.ESI-MS(m/ E): 462 [M+H]+。
Embodiment 37 prepares ((5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-asparagus fern ammonia Sour double benzyl esters (2q)
The double benzyl esters (1q) of 1.4g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-aspartic acid, 0.75g (4.5mmol) indoles Ethyl alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid are dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 1.82g (79.4%) target compound, is grayish powder.(c=0.7, CH3OH)；IR: 3348,2936,1735,1642,1456,1215,738,695cm-1；FT-MS (m/e): 766.30833 [M+H]+ (calculated:765.30502)；1δ=11.52 (s, 1H) H NMR (800MHz, DMSO-d6), 10.54 (s, 2H), 9.24 (d, J=7.2Hz, 1H), 7.74 (s, 1H), 7.51 (d, J=8.0Hz, 2H), 7.32 (m, 12H), 7.17 (m, 1H), 7.08 (m, 2H), 6.97 (t, J=7.2Hz, 2H), 6.92 (d, J=8.8Hz, 1H), 6.04 (s, 1H), 5.12 (s, 2H), 5.06 (q, J=2.4Hz, 2H), 4.98 (dd, J1=7.2Hz, J2=5.6Hz, 1H), 4.72 (s, 2H), 3.58 (m, 4H), 3.02 (qd, J1 =16.8Hz, J2=5.6Hz, 2H), 2.89 (m, 4H).
Embodiment 38 prepares the double benzyl esters (1r) of 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamic acid
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, the double benzyl ester hydrochlorides of 4.4g (12mmol) glutamic acid are added after stirring 0.5h, use NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 4.1g (88.4%) title compound, is pale yellow powder.ESI-MS (m/e): 476[M+H]+。
Embodiment 39 prepares ((5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-glutamic acid Double benzyl esters (2r)
The double benzyl esters (1r) of 1.4g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamic acid, 0.75g (4.5mmol) indoles second Pure and mild 0.16g (0.3mmol) p-methyl benzenesulfonic acid is dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶ CH3OH=50: 1) pure Change, obtain 1.94g (83.3%) target compound, is grayish powder.(c=0.5, CH3OH)；IR: 3348,3059,1727,1643,1456,1214,738,696cm-1；FT-MS (m/e): 780.32448 [M+ H]+ (calculated:779.32607)；1δ=11.67 (s, 1H) H NMR (800MHz, DMSO-d6), 10.52 (s, 2H), 8.93 (s, 1H), 7.79 (s, 1H), 7.49 (dd, J1=8.0Hz, J2=4.8Hz, 2H), 7.32 (m, 12H), 7.12 (dd, J1= 8.0Hz, J2=2.4Hz, 1H), 7.03 (t, J=7.2Hz, 2H), 6.98 (dt, J1=8.8Hz, J2=7.2Hz, 2H), 6.91 (d, J=8.8Hz, 2H), 6.04 (s, 1H), 5.14 (q, J=4.8Hz, 2H), 5.06 (s, 2H), 4.59 (dd, J1=8.8Hz, J2=5.6Hz, 1H), 3.58 (m, 4H), 2.83 (m, 4H), 2.48 (m, 2H), 2.18 (m, 1H), 1.97 (m, 1H).
Embodiment 40 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-Nitro-Arginine benzyl ester (1s)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 5.8g (12mmol) Nitro-Arginine benzyl ester hydrochloride is added after stirring 0.5h, PH to 9 is adjusted with NMM, reacts 8h, TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.It filters out DCU, reaction mixture are concentrated to dryness, residue with 150mL ethyl acetate dissolve, filter out insoluble matter, obtained solution according to It is secondary to use 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, acetic acid Methacrylate layer anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil passes through silicagel column column Chromatograph (CH2Cl2∶CH3OH=60: 1) purifying, obtain 3.2g (71.1%) title compound, is pale yellow powder.ESI-MS (m/e): 458 [M+H]+。
Embodiment 41 prepares (((5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-nitro Arginine benzyl ester (2s)
1.3g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-Nitro-Arginine benzyl ester (1s), 0.75g (4.5mmol) indoles Ethyl alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid are dissolved with 50mLTHF, 60 DEG C of reaction 10h, and TLC plate monitors (CH2Cl2∶ CH3OH=25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated under reduced pressure into Dry, residue is dissolved with methylene chloride, and column chromatography brick glue mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) pure Change, obtain 1.85g (81.3%) target compound, is grayish powder.(c=0.9, CH3OH)；IR:3320, 3058,1980,1728,1633,1456,1372,740,696cm-1；FT-MS (m/e): 762.32238 [M+H]+ (calculated:761.31731)；1δ=11.66 (s, 1H) H NMR (800MHz, DMSO-d6), 10.52 (s, 2H), 7.78 (s, 2H), 7.49 (d, J=8.0Hz, 2H), 7.36 (m, 4H), 7.31 (m, 3H), 7.12 (dd, J1=8.8Hz, J2=2.4Hz, 1H), 7.03 (t, J=7.2Hz, 2H), 6.97 (t, J=7.2Hz, 2H), 6.91 (d, J=7.2Hz, 1H), 6.03 (s, 1H), 5.15 (q, J=4.8Hz, 2H), 4.58 (m, 1H), 3.62 (m, 4H), 3.17 (m, 2H), 2.83 (m, 2H), 1.79 (m, 1H), 1.76 (m, 1H).
Embodiment 42 prepares 5- formyl -2- Hydroxy-benzoyIcarbamo-theanine benzyl ester (1t)
The anhydrous THF of 1.66g (10mmol) 5- formylsalicylic acid is dissolved under ice bath, 1.35g (10mmol) first is added Then 2.26g (11mmol) DCC is added in HOBt, 3.1g (12mmol) theanine benzyl ester hydrochloride is added after stirring 0.5h, uses NMM adjusts pH to 9, reacts 8h, and TLC plate monitors (CH2Cl2∶CH3OH=30: 1) raw material point disappears, fully reacting.DCU is filtered out, Reaction mixture is concentrated to dryness, and residue 150mL ethyl acetate dissolves, and filters out insoluble matter, obtained solution is successively used 5%NaHCO3Aqueous solution, saturation NaCl aqueous solution, 5%KHSO4Aqueous solution and saturation NaCl aqueous solution wash 3 times, ethyl acetate Layer uses anhydrous Na2SO4Dry 2h, filtering, filtrate decompression are concentrated to dryness, and obtained light yellow oil is chromatographed by silicagel column column (CH2Cl2∶CH3OH=60: 1) purifying, obtain 2.5g (46.3%) title compound, is pale yellow powder.ESl-MS (m/e): 413[M+H]+。
Embodiment 43 prepares (((5- (bis- (3- (2- ethoxy) -1H- indoles -2) methyl) -2- (2-hydroxybenzoyl)-theanine Benzyl ester (2t)
1.3g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-theanine benzyl ester (1t), 0.75g (4.5mmol) indoles ethyl alcohol It is dissolved with 0.16g (0.3mmol) p-methyl benzenesulfonic acid with 50mLTHF, 60 DEG C of reaction 10h, TLC plate monitors (CH2Cl2∶CH3OH =25: 1) raw material point disappears, and shows fully reacting.Stop reaction, is cooled to room temperature, reaction mixture is concentrated to dryness, residual Object is stayed to be dissolved with methylene chloride, column chromatography silica gel mixes sample, chromatographs (CH by silicagel column column2Cl2∶CH3OH=50: 1) it purifies, obtains It is grayish powder to 1.76g (82.3%) target compound.(c=0.9, CH3OH)；IR:3299, 2969,1736,1640,1456,1216,738,696cm-1；FT-MS (m/e): 717.32977 [M+H]+(calculated: 716.32100)；1δ=11.76 (s, 1H) H NMR (800MHz, DMSO-d6), 10.51 (s, 2H), 9.01 (s, 1H), 7.80 (dd, J1=8.0Hz, J2=2.4Hz, 2H), 7.49 (d, J=8.0Hz, 2H), 7.34 (m, 4H), 7.28 (m, 3H), 7.13 (dd, J1=8.8Hz, J2=2.4Hz, 1H), 7.03 (t, J=7.2Hz, 2H), 6.96 (t, J=7.2Hz, 2H), 6.91 (d, J =8.0Hz, 1H), 6.03 (s, 1H), 5.14 (s, 2H), 4.73 (q, J=7.2Hz, 2H), 4.52 (ddd, J1=8.8Hz, J2= 7.2Hz, J3=5.6Hz, 1H), 3.59 (m, 4H), 2.83 (m, 4H), 2.23 (m, 2H), 2.11 (m, 1H), 1.99 (m, 1H), 0.95 (t, J=7.2Hz, 3H).
Respectively that growth conditions are good, the A549 (human lung carcinoma cell) in logarithmic growth phase, (human leukemia is thin by K562 Born of the same parents), MCF-7 (human breast cancer cell), Bel-7402 (human liver cancer cell) and HeLa (human cervical carcinoma cell).According to 5 × 104 The density of a cell/mL is inoculated in 96 orifice plates, every 100 μ L of hole.At 37 DEG C, 5%CO24h is cultivated in incubator, by concentration gradient The 2a-t of 100 μM, 50 μM, 25 μM, the 10 μM and 1 μM sterilized processing of addition, is compared with adriamycin.Continue after cultivating 48h, often Hole adds 25 μ L concentration to be the MTT solution of 5mg/mL, is placed in 37 DEG C of incubation 4h, and carefully removing supernatant, (suspension cell is after being centrifuged Removing supernatant) 100 μ L DMSO (dimethyl sulfoxide) of every hole addition, oscillation about 15min dissolve precipitating afterwards.Immediately in microplate reader OD (absorbance) value is measured under upper 570nm wavelength.Following formula finds out the sample under each concentration to the inhibiting rate of tumour cell:
Growth inhibition ratio=[(control group mean OD value a sample group mean OD value)/blank group mean OD value] × 100%, Experiment is repeated 3 times, and inhibiting rate maps to drug concentration, seeks IC50(half effective inhibition concentration) value.Experimental result is shown in Table 1.Data Show compound 4 without the activity of significantly inhibition tumor cell proliferation, compound 2a-t is demonstrated by certain inhibition tumour The activity of cell Proliferation.The inhibitory activity of wherein compound 2b-f, i are preferable.
1 2a-t anti-tumour cell proliferative activity of table
N=3；
The anti-tumor activity of the evaluation of experimental example 2 2a-t
It is taken under aseptic condition and is inoculated in ICR mouse 10 days S180 sarcomas, appropriate normal saline tumor cells are added Suspension makes cell number 2 × 107/ mL, it is subcutaneous to be inoculated in healthy male ICR mouse forelimb armpit, and every mouse injects 0.2mL.It connects After planting for 24 hours, (dosage is 2 μm of ol/ to treatment group mouse by oral 0.2mL compound 4 (dosage is 8.9 μm of ol/kg) or 2a-t daily Kg aqueous solution).Naive mice takes orally 0.2mL physiological saline daily.With adriamycin (intraperitoneal injection dosage is 2 μm of ol/kg) Make positive control.Experiment was carried out to the 10th day, claimed mouse weight, and took the tumour weighing of each group mouse, finally counted each group The tumour inhibiting rate of animal.The curative effect of solid tumor inhibits percentage to indicate with knurl weight, calculates as follows: tumor-like hyperplasia %=(1- administration Group knurl weight/blank group knurl weight) × 100%.Indicate that the activity of compound, data are included in table 2 with knurl weight or percentage tumour inhibiting rate.Data Show that compound 4 and 2a-t are demonstrated by good anti-tumor activity.Wherein the activity of compound 2f is best.Due to compound 4 Dosage be 8.9 μm of ol/kg, and the dosage of 2a-t be 2 μm of ol/kg, so structural modification makes effective dose reduce 4.4 Times.Anti-tumor activity and adriamycin of the compound 2f when taking orally to 2 μm of ol/kg are in the antitumor of 2 μm of ol/kg of intraperitoneal injection Active suitable (P > 0.05).Statistics indicate that present invention obtains unexpected technical effects.
Influence of 2 2a-t of table to mice bearing S180 tumor weight
N=12；A) the P < 0.01 compared with NS；B) the P > 0.05 compared with Dox.
The relationship of experimental example 3 evaluation compound 2f anti-tumor activity and dosage
It is administered orally according to the method for experimental example 2.Blank control is physiological saline, and 2f chooses 2 μm of ol/kg (height), 0.2 μ Mol/kg (in) and 0.02 μm of ol/kg (low), three dosage.As a result it is included in table 3.It is closed statistics indicate that 2f shows apparent dose-effect System.
The relationship of table 3 compound 2f anti-tumor activity and dosage
N=12；A) with physiological saline and 0.2 μm of ol/kg 2f ratio P < 0.01；B) and physiological saline ratio P < 0.01, with 0.02 μm of ol/kg 2f ratio P < 0.05；And physiological saline ratio p > 0.05 c).
The acute toxicity of the evaluation of experimental example 4 compound 2f
1) evaluation method
Single-dose observes the state of mouse, is observed continuously 14 days, and record the variation of mouse weight；Claimed in the 15th day Eyeball is plucked after weight and takes blood, and coring, liver,spleen,kidney, brain weighing, counts the difference of administration group and vehicle control group.Using corresponding Kit measurement creatinine in serum (creatinine), glutamic-pyruvic transaminase (ALT) and glutamic-oxalacetic transaminease (AST) these three sero-enzymes Index is learned, to evaluate compound 2f to the toxicity of mouse.
2) medication and dosage
The oral dose of compound 2f is 200 μm of ol/kg, according to the every 10g of mouse weight to 0.1mL medical fluid or physiology salt Water, n=12.
3) result is included in table 4 and table 5
Statistics indicate that 200 μm of ol/kg of Mouse oral (100 times of effective dose) compound 2f, 14 days without dead and behavior Toxic reactions, internal organs and the weight such as abnormal and saline control group do not have difference, show 200 μm of ol/kg chemical combination of Mouse oral Object 2f does not have overt toxicity.Serum enzyme detection display, administration group Serum ALT, AST and creatinine content and physiological saline group phase Than indifference, illustrate that compound 2f has no adverse effects to mouse liver and renal function.
Table 4 takes orally influence of 200 μm of ol/kg compound 2f to weight and internal organs weight
Table 5 takes orally influence of 200 μm of ol/kg compound 2f to sero-enzyme
Experimental example 5 evaluates compound 2f anti-mouse Lewis lung cancer metastasis activity
1) dosage and administration mode
Oral dose is 2 μm of ol/kg, according to the every 10g of mouse weight to 0.1mL medical fluid or physiological saline, n=10.
2) foundation of Mice Bearing Lewis Lung Cancer model
Lewis murine lung cancer cell (LLC) is purchased from ATCC.DMEM culture medium is selected, wherein containing the 10% tire ox through inactivating Serum, 1 × 105U/L penicillin and 100mg/L streptomysin.According to attached cell cultural method, passage in every two days is primary, enrichment Cell.It is good when cell growth state, when being in logarithmic growth phase, vitellophag.With physiological saline adjust cell concentration to 1 × 107A/mL, placenta indigo plant (Tryanblue) dyeing counting, viable count > 95%.Inbred strais C57BL/6 male mice is taken, it is left Hand fixes mouse, and with 75% ethanol disinfection mouse right fore skin of axillary fossa, the right hand holds 1mL asepsis injector in mouse armpit skin Lower injection LLC tumor cell suspension 0.2mL/ is only.The tumour that diameter about 4-5mm can be grown after mouse inoculation for 10 days, as tumor Source is spare.
3) foundation of Lewis lung cancer metastasis model
8-10 days well-grown Lewis lung cancer tumor-bearing mices of inoculation are taken, etherization, cervical dislocation is put to death, with 75% Ethyl alcohol soaking disinfection 10min, removes knurl on superclean bench, well-grown tumor tissues is selected, in sterilized petri dishes It shreds, is placed in glass tissue homogenizer, in tumor mass weight (g): the ratio that physiological saline volume (mL) is 1: 3 is added 4 DEG C in advance Cold physiological saline is lightly ground, and cell suspension is made, and crosses 200 mesh cell sieves and single cell suspension is made, adjusted with physiological saline Cell concentration is to 1.5 × 107A/mL, placenta indigo plant (Tryanblue) dyeing counting, viable count > 95%.
Take inbred strais C57BL/6 male mice, the fixed mouse of left hand, with 75% ethanol disinfection mouse right fore armpit skin Skin, the right hand hold 1mL asepsis injector and tumor cell suspension 0.2mL are subcutaneously injected in mouse armpit.Grow diameter about within 10 days after inoculation The tumour of 4-5mm measures gross tumor volume, is grouped at random by tumor average volume.
It is administered since inoculated tumour the 11st day, is administered 11 times altogether, measures and records gross tumor volume every three days.22nd day After measuring knurl product, etherization, cervical dislocation is put to death, and takes out tumour weighing, and record the lung's rate of transform and metastatic tumor of tumour Joint number.
4) result is included in table 6 and table 7
Table 6 statistics indicate that, compound 2f has good inhibiting effect to transplantable tumor.Table 7 statistics indicate that, compound 2f There is good inhibiting effect to tumor-bearing mice Lung metastases rate and lung surface metastatic tumor tubercle number.According to table 2 as a result, can deduce Other compounds also have corresponding technical effect.
Influence of the 6 compound 2f of table to transplanting tumor weight
N=10；And physiological saline ratio P < 0.01 a).
Influence of the 7 compound 2f of table to tumor-bearing mice lung surface metastatic tumor tubercle number
N=10；A) the P < 0.01 compared with physiological saline.
The activity that experimental example 6 is migrated with the cell Transwell experimental evaluation compound 2f antitumor cell
1) experimental method
Growth conditions are taken well to be in the A549 cell of logarithmic growth phase, blood is added under the microscope in the digestion of 0.25% pancreatin It is clear to terminate digestion and 3000rpm centrifugation 3min, it counts, is made into single cell suspension, density is 5 × 105A/mL.Transwell 100 μ L cell suspensions are added in upper chamber every hole in cell, while the solution of compound 2f is added, and make final concentration of 10 μM, 5 μM and 1 μ M.1640 culture mediums containing 10%FBS of 600 μ L are added in lower room, in 37 DEG C and 5%CO2It is cultivated 6 hours in incubator.Use cotton swab Matrigel and upper indoor cell are wiped, cell 30min is fixed with 4% paraformaldehyde, absorbs fixer, washed 3 times with PBS； 15min is dyed with 0.1% crystal violet dye liquor, dyeing liquor is absorbed, is washed 3 times with PBS.6 visuals field are chosen in each cell to take pictures And count, cell number with (It is a) it indicates.
2) experimental result
Table 8 the result shows that, compared with blank control group, 1 μM, 5 μM and 10 μM compound 2f acts on ventricular cell 6h, Inhibit to concentration dependent A549 cell migration.According to table 2 as a result, other compounds that can deduce also have corresponding technology to imitate Fruit.
8 compound 2f antitumor cell migratory activity of table
N=3；A) with blank control and 5 μM of compound 2f ratio P < 0.01；B) with blank control and 1 μM of compound 2f ratio P < 0.01；C) a) and blank control ratio P < 0.01.
The activity that experimental example 7 is invaded with the cell Transwell experimental evaluation compound 2f antitumor cell
1) experimental method
It will freeze in 4 DEG C of matrigel of -20 DEG C of refrigerators overnight, become liquid.720 μ L serum-free, 1640 culture medium is taken, 180 μ L Matrigel are added, mix, is added to the polycarbonate membrane upper chamber of the cell Transwell (100 μ L/), is put into 37 DEG C and 5%CO25h is incubated in incubator.Absorb residual liquid in cell, every hole is added 50 μ L, 1640 culture medium, 37 DEG C and 5%CO230min is incubated in incubator.Growth conditions are taken well to be in the A549 cell of logarithmic growth phase, 0.25% pancreatin disappears To change, under the microscope, serum is added and terminates digestion, and 3000rpm is centrifuged 3min, counts, is made into single cell suspension, density is 2 × 105A/mL.100 μ L cell suspensions are added in upper chamber every hole in cell, while the solution of compound 2f is added, and make final concentration of 10 μM, 5 μM, 1 μM.The feeding base in 1640 containing 10%FBS of 600 μ L is added in lower room, in 37 DEG C, 5%CO2It is cultivated 24 hours in incubator. Matrigel and upper indoor cell are wiped with cotton swab, cell 30min is fixed with 4% paraformaldehyde, absorbs fixer, use PBS It washes 3 times, dyes 15min with 0.1% crystal violet dye liquor, absorb dyeing liquor, washed 3 times with PBS.6 views are chosen in each cell Open country is taken pictures, count, cell number with (It is a) it indicates.
2) experimental result
Table 9 the result shows that, compared with blank control group, 1 μM, 5 μM and 10 μM compound 2f acts on ventricular cell 6h, Inhibit to concentration dependent A549 cell invasion.According to table 2 as a result, other compounds that can deduce also have corresponding technology to imitate Fruit.
9 compound 2f antitumor cell of table invasion activity
N=3；A) with blank control and 5 μM of compound 2f ratio P < 0.01；B) with blank control and 1 μM of compound 2f ratio P < 0.01；C) a) and blank control ratio P < 0.01.
Experimental example 8 evaluates compound 2f and inhibits dimethylbenzene inducing mouse ear swelling activity
1) animal model
ICR male mice 30, weight 18-22g, it is randomly divided into blank control group, aspirin group and compound 2f group, Every group 10.Each group is according to dosage administered orally.After 30min is administered, 30 μ L diformazans are uniformly smeared on the inside of the left ear auricle of mouse Benzene, etherization after 2h, cervical dislocation are put to death, and auricle will be cut and are overlapped and be stacked together outside two ears of left and right, with diameter 7mm's Punch beats round auricle in same position, and weighing calculates two ear weight differences as ear swelling, i.e. mouse ear swelling=left ear Round slice weight-auris dextra circle slice weight, with (Mg it) indicates.
2) dosage
Aspirin dose is 1.11mmol/kg, and compound 2f dosage is 2 μm of ol/kg, and physiological saline dosage is every 10g Mouse is to 0.1mL.
3) experimental result
Table 10 the result shows that, the ear swelling of saline-treated mice be noticeably greater than compound 2f treatment mouse ear Swelling.According to table 2 as a result, other compounds that can deduce also have corresponding technical effect.
10 compound 2f of table inhibits dimethylbenzene inducing mouse ear swelling activity
N=10；And physiological saline ratio P < 0.05 a).
Experimental example 9 evaluates TNF-α and IL-8 content in compound 2f paraxylene induction inflammation mice plasma
1) dosage and administration mode
The oral dose of aspirin is 1.11mmol/kg, and the oral dose of compound 2f is 2 μm of ol/kg, n=6.
2) animal model
ICR male mice 24, weight 18-22g, it is randomly divided into 4 groups, every group 6.The according to dosage stomach-filling of each group mouse.It gives After medicine 30 minutes, 30 μ L dimethylbenzene are uniformly smeared on the inside of mouse ear, after 2 hours, are plucked eyeball and are taken blood (0.45mL adds 3.8% sodium citrate of 0.05mL), it is centrifuged 10 minutes in 4 DEG C of 3000rpm immediately, taking supernatant is plasma sample.
3) TNF-α and IL-8 content in mice plasma are detected
The measurement of TNF-α content in mice plasma: setting gauge orifice, the hole compound 2f and blank well.Gauge orifice adds 50 μ L Standard solution, what is all not added blank well.The hole compound 2f adds 10 μ L and 40 μ L compound 2f dilutions.In addition to blank well, It is separately added into 50 μ L HPR reagents into each hole, plate patch is sticked after adding, is incubated for 60 minutes in 37 DEG C.Carefully take sealing plate film off, Liquid is discarded, with cleaning solution board-washing 5 times.50 μ L developing solution A are first added in every hole, add 50 μ L developing solution B, and gently concussion is mixed Even, 37 DEG C are protected from light colour developing 15 minutes.Every hole adds 50 μ L terminate liquids, terminates reaction (blue is vertical at this time turns yellow).With blank well tune Zero, the optical density (O.D. value) in each hole is measured under 450nm wavelength with microplate reader.OD value will be measured and substitute into linear equation, TNF-α concentration is calculated, t inspection is carried out.
The measurement of IL-8 content in mice plasma: setting gauge orifice, the hole compound 2f and blank well.Blank well adds 100 μ L Sample diluting liquid, standard sample wells add 50 μ L of 50 μ L standard solutions and Streptavidin-HRP, and the hole compound 2f adds 40 μ L Compound 2f solution, the anti-IL-8 antibody of 10 μ L stick plate and paste 37 DEG C of incubations 60 minutes.30 times of washing lotions distilled water is diluted 30 Times, it carefully takes sealing plate film off, discards liquid, discarded after standing 30 seconds after every hole addition cleaning solution, repeat board-washing 5 times, pat dry. 50 μ developing solution A L are first added in every hole, add 50 μ L developing solution B, and gently concussion mixes, and 37 DEG C are protected from light colour developing 10 minutes.Every hole Add 50 μ L terminate liquids to terminate reaction (blue is vertical at this time turns yellow).It is returned to zero with blank well, is measured under 450nm wavelength with microplate reader The optical density (O.D. value) in each hole.OD value will be measured and substitute into linear equation, calculate IL-8 concentration, carry out t inspection.
4) experimental result
Table 11 the result shows that, take orally the TNF-α that 2 μm of ol/kg compound 2f lower caused by dimethylbenzene xylene inflammation mice plasma.According to Table 2 as a result, other compounds that can deduce also have corresponding technical effect.
11 compound 2f paraxylene of table induces the influence of TNF-α and IL-8 in acute inflammation mice plasma
N=6；And physiological saline ratio P < 0.05 a).

Claims (6)

1. 20 kinds of double -3- ethoxy -1H- indoles -2- methoxy-salicylic acyl-AA-OBzl that general formula I is represented, AA=Gly in formula, Ala, Leu, Ile, Val, Trp, Phe, Lys, Tyr, Pro, Met, Bzl protect the Cys, Ser, Thr of sulfydryl, Gln, Asn, β-carboxylic Base-OBzl-Asp, γ-carboxyl-OBzl-Glu, NG-NO2- Arg and The residue
2. 20 kinds of double -3- ethoxy -1H- indoles -2- methoxy-salicylic acyl-AA-OBzl that the general formula I for preparing claim 1 is represented Method, this method is made of following steps:
1) in the presence of dicyclohexylcarbodiimide and N- hydroxy benzo triazole 5- formylsalicylic acid in anhydrous tetrahydro furan It is reacted with l-amino acid benzyl ester, generates 5- formyl -2- Hydroxy-benzoyIcarbamo-AA-OBzl；
2) at Catalyzed by p-Toluenesulfonic Acid and 60 DEG C, indoles ethyl alcohol and 5- formyl -2- Hydroxy-benzoyIcarbamo-AA-OBzl are in tetrahydro furan It mutters middle reaction, generates double -3- ethoxy -1H- indoles -2- methoxy-salicylic acyl-AA-OBzl.
3. the method for preparing double -3- ethoxy -1H- indoles -2- methoxy-salicylic acid, this method are made of following steps:
1) at Catalyzed by p-Toluenesulfonic Acid and 60 DEG C, indoles ethyl alcohol reacts in tetrahydrofuran with 5- formylsalicylic acid methyl esters, raw As double -3- ethoxy -1H- indoles -2- methoxy-salicylic acid methyl esters；
2) double -3- ethoxy -1H- indoles -2- methoxy-salicylic acid methyl esters are saponified in 4N NaOH solution, obtain double -3- hydroxyls Ethyl -1H- indoles -2- methoxy-salicylic acid.
4. double -3- ethoxy -1H- indoles -2- methoxy-salicylic acyl-the AA-OBzl of 20 kinds of claim 1 are preparing antineoplastic Application in object.
5. double -3- ethoxy -1H- indoles -2- methoxy-salicylic acyl-the AA-OBzl of 20 kinds of claim 1 are preparing antitumor turn Move the application in drug.
6. double -3- ethoxy -1H- indoles -2- methoxy-salicylic acyl-the AA-OBzl of 20 kinds of claim 1 are preparing anti-inflammatory agent Application in object.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539722A (en) * 2012-07-10 2014-01-29 永光制药有限公司 Aryl-substituted methyl-connected bis-indoleacetic acid derivative and preparation method and application thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539722A (en) * 2012-07-10 2014-01-29 永光制药有限公司 Aryl-substituted methyl-connected bis-indoleacetic acid derivative and preparation method and application thereof

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