CN106349148A - Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound - Google Patents

Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound Download PDF

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CN106349148A
CN106349148A CN201510409682.6A CN201510409682A CN106349148A CN 106349148 A CN106349148 A CN 106349148A CN 201510409682 A CN201510409682 A CN 201510409682A CN 106349148 A CN106349148 A CN 106349148A
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indoles
obzl
ethoxy
double
compound
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CN106349148B (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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  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
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Abstract

The invention discloses 20 kinds of 5-(bi(3-(2-ethoxy)-1H-indol-2)methyl)-2-hydroxy benzoyl-AA-OBzl, discloses a preparation method of the 5-(bi(3-(2-ethoxy)-1H-indol-2)methyl)-2-hydroxy benzoyl-AA-OBzl, discloses an effect of the 5-(bi(3-(2-ethoxy)-1H-indol-2)methyl)-2-hydroxy benzoyl-AA-OBzl in inhibiting invasion and metastasis of a tumor cell, discloses an activity of the 5-(bi(3-(2-ethoxy)-1H-indol-2)methyl)-2-hydroxy benzoyl-AA-OBzl in inhibiting weight gain of a tumor body of a S180-bearing mouse, and discloses an anti-tumor pulmonary metastasis activity and an anti-inflammatory activity. The compound has an excellent application prospect in preparing an antitumor drug, an anti-tumor metastasis drug and an anti-inflammatory drug.

Description

There is the new indole class compound of anti-tumor metastasis and anti-inflammatory activity, it synthesizes and applies
Technical field
The present invention relates to 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2- (2-hydroxybenzoyl)-aa-obzl, it is related to it Preparation method, be related to them and suppress tumor cell invasions and transferance, be related to them and suppress lotus s180 knurl mouse tumor bodies The activity of weightening, is related to their antitumor Lung metastases activity and anti-inflammatory activity.The compound of the present invention preparing antineoplastic, Have a good application prospect in medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biomedicine field.
Background technology
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 late period, the people of usual 10%-15% can only be survived 5 years.This difficult situation in 30 years of past Not yet significantly make moderate progress.In a lot of clinical cases, lung cancer was transferred into surrounding tissue before being diagnosed.Operation, Radiotherapy, chemotherapy may result in serious side effects, leads to the quality of life of patient low.Therefore, in the urgent need to find effectively and Safe drugs, to improve this shortcoming in the treatment of lung cancer.
Our early stage invention (patent application publication cn 103539722 a, application number 201310278480.3) shows, virtue Base substituent methyl connect double ethychlozate derivatives there is significant antitumor curative effect, and do not have obvious cytotoxicity or Toxic and side effect, can be used as the candidate compound of antineoplastic.In more deep experimental study, inventor finds double Yin Indolylbutyric acid is changed into double indoles ethanol, to the ch connecting double indoles ethanol2Introduce Salicyloy lamino acid benzyl ester, can not only increase Powerful antitumor activity is additionally it is possible to obtain anti-tumor metastasis and anti-inflammatory activity, you can to bring prominent technique effect.According to These find, inventors herein propose 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- (2-hydroxybenzoyl) of the present invention - aa-obzl, and their preparation and preparing antineoplastic, the application in medicine for anti transfer of tumor and anti-inflammatory medicaments.
Content of the invention
First content of the present invention is 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- hydroxyl providing formula i to represent Base benzoyl-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)；
Second content of the present invention is 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- of the representative providing formula i (2-hydroxybenzoyl)-aa-obzl (aa=gly, ala, leu, ile, val, trp, phe, lys, tyr, pro, met in formula, Cys (bzl), ser, thr, gln, asn, asp (obzl), glu (obzl), ng-no2- arg and the residue) preparation method, The method is made up of following steps:
1) react in oxolane with 5- formylsalicylic acid methyl esters in Catalyzed by p-Toluenesulfonic Acid and 60 DEG C of indoles ethanol, be generated as 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2 hydroxybenzoic acid methyl esters；
2) by 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2 hydroxybenzoic acid methyl esters saponification in 4n naoh solution, obtain To 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2 hydroxybenzoic acid；
3) in the presence of dicyclohexylcarbodiimide (dcc) and n- hydroxy benzo triazole (hobt) 5- formylsalicylic acid anhydrous four React with l- amino-acid benzyl ester in hydrogen furans, generation 5- formyl -2- Hydroxy-benzoyIcarbamo-aa-obzl, aa=gly, ala in formula, 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) in the presence of Catalyzed by p-Toluenesulfonic Acid and 60 DEG C indoles ethanol and 5- formyl -2- Hydroxy-benzoyIcarbamo-aa-obzl in tetrahydrochysene furan Mutter middle reaction, generate 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2- (2-hydroxybenzoyl)-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.
3rd content of the present invention is 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) first of the representative evaluating formula i Base) -2- (2-hydroxybenzoyl)-aa-obzl suppress tumor cell proliferation effect；
4th content of the present invention is 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) first of the representative evaluating formula i Base) -2- (2-hydroxybenzoyl)-aa-obzl suppress lotus s180 mice with tumor tumour growth effect；
5th content of the present invention is to evaluate 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- hydroxy benzenes first of formula i Acyl-trp-obzl suppresses lewis lung cancer in mice in-vivo tumour transfer activity；
6th content of the present invention is to evaluate 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- hydroxy benzenes first of formula i Acyl-trp-obzl suppresses the ability of tumor cell migration；
7th content of the present invention is to evaluate 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- hydroxyl of formula i Benzoyl-trp-obzl suppresses the ability of tumor cell invasion；
8th content of the present invention is to evaluate 5- (double (3- (2- ethoxy) -1h- indoles -2) the methyl) -2- hydroxyl of formula i Benzoyl-trp-obzl suppresses the mice ear activity of dimethylbenzene induction；
9th content of the present invention is 20 kinds of 5- (double (3- (2- ethoxy) -1h- indoles -2) first of the representative illustrating formula i Base) -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) in preparation Antineoplastic, the application in medicine for anti transfer of tumor and anti-inflammatory drug.
Brief description
Fig. 1. the synthetic route i) dcc of compound, hobt, nmm；Ii) p-methyl benzenesulfonic acid, 60 DEG C；iii)4n naoh； Aa=gly in 1a and 2a, aa=ala in 1b and 2b, aa=leu in 1c and 2c, aa=ile, 1e in 1d and 2d With aa=val in 2e, aa=trp in 1f and 2f, aa=phe in 1g and 2g, aa=lys, 1i in 1h and 2h With aa=tyr in 2i, pro in 1j and 2j, aa=cys (bzl), 1m and 2m in aa=met in 1k and 2k, 11 and 21 Middle aa=ser, aa=thr in 1n and 2n, aa=gln in 1o and 2o, aa=asn in 1p and 2p, in 1q and 2q Aa=asp (obzl), aa=glu (obzl), aa=n in 1s and 2s in 1r and 2rg-no2In-arg, 1t and 2t Aa=the residue.
Specific embodiment
In order to the present invention is expanded on further, a series of embodiments are given below.These embodiments are entirely illustrative, they Only it is used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 liquid phase peptide reaction leads to method
Compound exposed for carboxylic end anhydrous tetrahydro furan (thf) is dissolved, the solution obtaining adds n- hydroxyl benzotriazole (hobt), it is slowly added to the n with anhydrous thf dissolving, n- dicyclohexylcarbodiimide (dcc), 0 DEG C of stirring 15min under ice bath Obtain reactant liquor (i).The amino acid of carboxylic end protection is also dissolved with anhydrous thf, adjusts ph 9 with n- methyl morpholine (nmm), so Mix with reactant liquor (i) afterwards, maintain ph 9 with n- methyl morpholine, 10h is stirred at room temperature, tlc monitors reaction process.Raw material After point disappears, reactant mixture filters, filtrate reduced in volume, obtains sticky mass ethyl acetate or dichloromethane dissolving, The solution obtaining uses 5%nahco successively3The aqueous solution is washed, 5%khso4The aqueous solution is washed, and the saturation nacl aqueous solution is washed, second Acetoacetic ester or dichloromethane are added to anhydrous sodium sulfate drying, filter, and filtrate reduced in volume obtains target compound.
Embodiment 2 prepares 5- (double (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 ethanol and 0.17g (1mmol) P-methyl benzenesulfonic acid 50mlthf dissolves, and after 60 DEG C of reaction 10h, (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) Raw material point disappears, and stops reaction, is cooled to room temperature, is evaporated to dry, and residue dichloromethane dissolves, by silica gel Post column chromatography obtains 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)；1H nmr (800mhz, dmso-d6) δ= 10.52 (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- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2 hydroxybenzoic acid (4)
1.2g (2.4mmol) 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2 hydroxybenzoic acid methyl esters (3) under ice bath With methyl alcohol dissolving, add the 4n naoh aqueous solution, adjust ph value to 12, react 48h, tlc plate is monitored (ch2cl2∶ch3Oh=20: 1) raw material point disappears, and reaction is completely.Saturation khso is used under ice bath4Reactant liquor is adjusted to neutrality, Reduced pressure concentration removes methyl alcohol, and residue continues to adjust ph value to 3, is extracted with ethyl acetate 3 times, combined ethyl acetate phase, With anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure to give 1.08g (93%) target compound, be 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.05g (12mmol) glycine benzyl ester after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so412h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 2.4g (72.8%) title compound, is pale yellow powder.Esi-ms (m/e): 314 [m+h]+.
Embodiment 5 prepares 5- (double (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 Alcohol and 0.17g (1mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 4.8g (78%) target compound, be grayish powder.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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, after stirring 0.5h, adds 4.25g (12mmol) alanine benzyl Ester hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point Disappear, display reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate Dissolving, filters insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4 The aqueous solution and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate subtracts Pressure is concentrated to dryness.Residue passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 2.7g (82%) target Compound, is buff powder.Esi-ms (m/e): 328 [m+h]+.
Embodiment 7 prepares 5- (double (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 ethanol Dissolve with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50ml thf, 60 DEG C of reaction 10h, tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears.Stop reaction, be cooled to room temperature, reactant mixture be evaporated to dry, Residue dichloromethane dissolves, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 0.6g (79%) Target compound, is 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.70g (12mmol) leucine benzyl ester after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.0g (81.8%) title compound, is pale yellow powder.Esi-ms (m/e): 370 [m+h]+.
Embodiment 9 prepares (5- (double (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 second Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50ml thf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears.Stop reaction, be cooled to room temperature, reactant mixture be evaporated to dry, Residue dichloromethane dissolves, by silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 0.52g (80.8%) target compound, is 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.70g (12mmol) isoleucine benzyl after stirring 0.5h Ester hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point Disappear, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3g (81.7%) title compound, is pale yellow powder.Esi-ms (m/e): 370 [m+h]+.
Embodiment 11 prepares (5- (double (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 Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 0.6g (82.7%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.47 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.50g (12mmol) valine benzyl ester after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.1g (87.3%) title compound, is pale yellow powder.Esi-ms (m/e): 355 [m+h]+.
Embodiment 13 prepares (5- (double (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 Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 0.48g (80.3%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.48 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 3.97g (12mmol) tryptophan benzyl ester after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.5g (79.1%) title compound, is pale yellow powder.Esi-ms (m/e): 443 [m+h]+.
Embodiment 15 prepares (5- (double (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 Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.82g (81.3%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=10.81 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.27g (12mmol) phenylalanine benzyl after stirring 0.5h Ester hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point Disappear, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 2.4g (67.9%) title compound, is pale yellow powder.Esi-ms (m/e): 404 [m+h]+.
Embodiment 17 prepares (5- (double (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 Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.69g (79.5%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.48 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.5g (12mmol) lys (boc)-obzl after stirring 0.5h, Adjust ph to 9 with nmm, react 8h, (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, reaction Completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters insoluble Thing, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and saturation Nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume, to dry, obtains The pale yellow oil arriving passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.4g (70.8%) mark Topic compound, is pale yellow powder.Esi-ms (m/e): 485 [m+h]+.
Embodiment 19 prepares (5- (double (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 second Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 2.01g (85%) target compound, be grayish powder.(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)；1H nmr (800mhz, dmso-d6) δ=11.65 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 5.3g (12mmol) tyrosine benzyl ester salt after stirring 0.5h Hydrochlorate, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, Reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters Insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and Saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume is extremely Dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.6g (85.7%) title compound, is pale yellow powder.Esi-ms (m/e): 420 [m+h]+.
Embodiment 21 prepares (5- (double (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 ethanol Dissolve with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf, 60 DEG C of reaction 10h, tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.76g (81.0%) target compound, be grayish powder.(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)；1H nmr (800mhz, dmso-d6) δ=11.47 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 2.9g (12mmol) proline benzyl ester salt after stirring 0.5h Hydrochlorate, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, Reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters Insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and Saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume is extremely Dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.1g (84.2%) title compound, is pale yellow powder.Esi-ms (m/e): 354 [m+h]+.
Embodiment 23 prepares (5- (double (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 ethanol Dissolve with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf, 60 DEG C of reaction 10h, tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.63g (81.5%) target compound, be grayish powder. (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)；1H nmr (800mhz, dmso-d6) δ=10.58 (s, 2h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 4.9g (12mmol) methionine benzyl ester salt after stirring 0.5h Hydrochlorate, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, Reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters Insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and Saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume is extremely Dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.0g (83.7%) title compound, is pale yellow powder.Esi-ms (m/e): 358 [m+h]+.
Embodiment 25 prepares (5- (double (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 ethanol Dissolve with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50ml thf, 60 DEG C of reaction 10h, tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.71g (82.3%) target compound, be grayish powder. (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)；1H nmr (800mhz, dmso-d6) δ=11.67 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 1.7g (4.9mmol) cysteine benzyl after stirring 0.5h Ether benzyl ester hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) former Shots disappear, and reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate Dissolving, filters insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4 The aqueous solution and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate subtracts Pressure is concentrated to dryness, and the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 2.1g (65.8%) title compound, is pale yellow powder.Esi-ms (m/e): 450 [m+h]+.
Embodiment 27 prepares (5- (double (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 ethanol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50ml thf dissolve, 60 DEG C of reactions 10h, tlc (ch monitored by plate2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, instead Mixture is answered to be evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, 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)；1H nmr (800mhz, dmso-d6) δ=11.58 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 2.8g (12mmol) serine benzyl ester salt after stirring 0.5h Hydrochlorate, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, Reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters Insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and Saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume is extremely Dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 2.8g (81.4%) title compound, is pale yellow powder.Esi-ms (m/e): 344 [m+h]+.
Embodiment 29 prepares (5- (double (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 second Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50ml thf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.56g (81.3%) target compound, be grayish powder. (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)；1H nmr (800mhz, dmso-d6) δ=11.42 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 2.9g (12mmol) threonine benzyl ester salt after stirring 0.5h Hydrochlorate, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, Reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters Insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and Saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume is extremely Dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.0g (83.7%) title compound, is pale yellow powder.Esi-ms (m/e): 358 [m+h]+.
Embodiment 31 prepares (5- (double (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 ethanol Dissolve with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50ml thf, 60 DEG C of reaction 10h, tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch30h=50: 1) purify, obtain 1.65g (83.1%) target compound, be grayish powder. (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)；1H nmr (800mhz, dmso-d6) δ=11.27 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 5.0g (12mmol) glutamine benzyl ester after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.0g (77.9%) title compound, is pale yellow powder.Esi-ms (m/e): 385 [m+h]+.
Embodiment 33 prepares (5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2- (2-hydroxybenzoyl)-glutamine benzyl ester (2o)
1.4g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamine benzyl ester (1o), 0.75g (4.5mmol) indoles second Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.74g (83.8%) target compound, be 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)；-1H nmr (800mhz, dmso-d6) δ=11.75 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 3.5g (12mmol) asparagine benzyl ester after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.1g (74.1%) title compound, is pale yellow powder.Esi-ms (m/e): 371 [m+h]+.
Embodiment 35 prepares (5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2- (2-hydroxybenzoyl)-asparagine benzyl ester (2p)
1.1g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-asparagine benzyl ester (1p), 0.75g (4.5mmol) indoles second Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.59g (79.3%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.74 (s, 1h), 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).
The double benzyl ester (1q) of embodiment 36 preparation 5- formyl -2- Hydroxy-benzoyIcarbamo-aspartic acid
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds the double benzyl of 4.2g (12mmol) aspartic acid after stirring 0.5h Ester hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point Disappear, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 4g (86.9%) title compound, is pale yellow powder.Esi-ms (m/e): 462 [m+h]+.
Embodiment 37 prepares ((the double benzyl ester (2q) of 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2- (2-hydroxybenzoyl)-aspartic acid
The double benzyl ester (1q) of 1.4g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-aspartic acid, 0.75g (4.5mmol) indoles Ethanol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is supervised Survey (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reaction is mixed Compound is evaporated to dry, residue dichloromethane dissolving, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.82g (79.4%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.52 (s, 1h), 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).
The double benzyl ester (1r) of embodiment 38 preparation 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamic acid
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds the double benzyl ester of 4.4g (12mmol) glutamic acid after stirring 0.5h Hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears Lose, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 4.1g (88.4%) title compound, is pale yellow powder.Esi-ms (m/e): 476 [m+h]+.
Embodiment 39 prepares ((the double benzyl ester (2r) of 5- (double (3- (2- ethoxy) -1h- indoles -2) methyl) -2- (2-hydroxybenzoyl)-glutamic acid
The double benzyl ester (1r) of 1.4g (3mmol) 5- formyl -2- Hydroxy-benzoyIcarbamo-glutamic acid, 0.75g (4.5mmol) indoles second Alcohol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, and tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ ch3Oh=50: 1) purify, obtain 1.94g (83.3%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.67 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 5.8g (12mmol) Nitro-Arginine benzyl after stirring 0.5h Ester hydrochloride, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point Disappear, reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, Filter insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4Water-soluble Liquid and saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate decompression is dense It is reduced to dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 3.2g (71.1%) title compound, is pale yellow powder.Esi-ms (m/e): 458 [m+h]+.
Embodiment 41 prepares (((5- (double (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) Yin Diindyl ethanol and 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf dissolve, 60 DEG C of reaction 10h, tlc plate Monitoring (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reaction Mixture is evaporated to dry, residue dichloromethane dissolving, and sample mixed by column chromatography brick glue, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.85g (81.3%) target compound, be 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)；1H nmr (800mhz, dmso-d6) δ=11.66 (s, 1h), 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)
Under ice bath, 1.66g (10mmol) 5- formylsalicylic acid is dissolved with anhydrous thf, be initially charged 1.35g (10mmol) Hobt, is subsequently adding 2.26g (11mmol) dcc, adds 3.1g (12mmol) theanine benzyl ester salt after stirring 0.5h Hydrochlorate, adjusts ph to 9 with nmm, reacts 8h, and (ch monitored by tlc plate2cl2∶ch3Oh=30: 1) raw material point disappears, Reaction is completely.Filter dcu, reaction mixture is evaporated to dry, residue 150ml ethyl acetate dissolving, filters Insoluble matter, the solution obtaining uses 5%nahco successively3The aqueous solution, the saturation nacl aqueous solution, 5%khso4The aqueous solution and Saturation nacl solution washing 3 times, the anhydrous na of ethyl acetate layer2so42h is dried, filters, filtrate reduced in volume is extremely Dry, the pale yellow oil obtaining passes through silicagel column column chromatography (ch2cl2∶ch3Oh=60: 1) purify, obtain 2.5g (46.3%) title compound, is pale yellow powder.Esl-ms (m/e): 413 [m+h]+.
Embodiment 43 prepares (((5- (double (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 ethanol Dissolve with 0.16g (0.3mmol) p-methyl benzenesulfonic acid 50mlthf, 60 DEG C of reaction 10h, tlc plate is monitored (ch2cl2∶ch3Oh=25: 1) raw material point disappears, and display reaction is completely.Stop reaction, be cooled to room temperature, reactant mixture It is evaporated to dry, residue dichloromethane dissolves, and column chromatography silica gel mixes sample, by silicagel column column chromatography (ch2cl2∶ch3Oh=50: 1) purify, obtain 1.76g (82.3%) target compound, be grayish powder. (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)；1H nmr (800mhz, dmso-d6) δ=11.76 (s, 1h), 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, it is in the a549 (human lung carcinoma cell) of exponential phase, k562 (human leukemia cell), Mcf-7 (human breast cancer cell), bel-7402 (human liver cancer cell) and hela (human cervical carcinoma cell).According to 5 × 104Individual thin The density of born of the same parents/ml is inoculated in 96 orifice plates, every hole 100 μ l.At 37 DEG C, 5%co24h is cultivated, by concentration in incubator 100 μm of gradient, 50 μm, 25 μm, the 2a-t of the 10 μm and 1 μm sterilized process of addition, compared with adriamycin.Continue After continuous culture 48h, every hole adds the mtt solution that 25 μ l concentration are 5mg/ml, is placed in 37 DEG C of incubation 4h, carefully removes Supernatant (suspension cell removes supernatant after centrifugation) is gone to add 100 μ l dmso (dimethyl sulfoxide (DMSO)) in every hole afterwards, vibration is about 15min dissolution precipitation.Od (absorbance) value is measured under 570nm wavelength immediately on the ELIASA.Obtained each with following formula The inhibiting rate to tumour cell for the sample under individual concentration:
Growth inhibition ratio=[(the average od value of control group average od value one sample sets)/blank group average od value] × 100%, Experiment is repeated 3 times, and inhibiting rate is mapped to drug concentration, seeks ic50(half effective inhibition concentration) value.Experimental result is shown in Table 1. As shown by data, compound 4 does not significantly suppress the activity of tumor cell proliferation, and compound 2a-t is all demonstrated by certain suppression The activity of tumor cell proliferation processed.Wherein compound 2b-f, the inhibitory activity of i is preferable.
Table 1 2a-t anti-tumour cell proliferative activity
N=3；
Experimental example 2 evaluates the antitumor activity of 2a-t
Take under aseptic condition and be inoculated in the icr mouse s180 sarcoma of 10 days, add appropriate normal saline tumor cells suspension, Cell number is made to be 2 × 107/ ml, be inoculated in health male icr mouse forelimb armpit subcutaneous, every injected in mice 0.2ml.Inoculation After 24h, treatment group mouse is administered orally 0.2ml compound 4 (dosage is 8.9 μm of ol/kg) or 2a-t daily, and (dosage is 2 μm ol/kg) the aqueous solution.Naive mice is administered orally 0.2ml physiological saline daily.With adriamycin, (lumbar injection dosage is for 2 μm ol/kg) make positive control.Experiment was carried out to the 10th day, claimed Mouse Weight, and take the tumour of each group mouse to weigh, Count the tumour inhibiting rate of each group animal afterwards.The curative effect of solid tumor is represented with knurl weight inhibition percentage, is calculated as follows: tumor-like hyperplasia %=(1- administration group knurl weight/blank group knurl weight) × 100%.Represent the activity of compound with knurl weight or percentage tumour inhibiting rate, data arranges Enter table 2.As shown by data, compound 4 and 2a-t are all demonstrated by good antitumor activity.The activity of wherein compound 2f is best. Because the dosage of compound 4 is 8.9 μm of ol/kg, and the dosage of 2a-t is 2 μm of ol/kg, so structural modification makes effectively Dosage reduces 4.4 times.The antitumor activity when being administered orally to 2 μm of ol/kg for the compound 2f and adriamycin are in lumbar injection 2 The antitumor activity of μm ol/kg is quite (p ＞ 0.05).As shown by data is present invention obtains unexpected technique effect.
The impact to lotus s180 mouse tumor weight for table 2 2a-t
N=12；A) p ＜ 0.01 compared with ns；B) p ＞ 0.05 compared with dox.
Experimental example 3 evaluates the relation of compound 2f antitumor activity and dosage
Method oral administration according to experimental example 2.Blank is physiological saline, and 2f chooses 2 μm of ol/kg (high), 0.2 μm of ol/kg (in) and three dosage of 0.02 μm of ol/kg (low).Result lists table 3 in.As shown by data 2f shows obvious dose-effect relationship.
Table 3 compound 2f antitumor activity and the relation of dosage
N=12；A) with physiological saline and 0.2 μm of ol/kg 2f than p ＜ 0.01；B) with physiological saline than p ＜ 0.01, with 0.02 μm of ol/kg 2f is than p ＜ 0.05；C) with physiological saline than p ＞ 0.05.
Experimental example 4 evaluates the acute toxicity of compound 2f
1) evaluation method
Single-dose, observes the state of mouse, Continuous Observation 14 days, and records the change of Mouse Weight；Claimed in the 15th day Pluck eyeball and take blood after weight, and core, liver,spleen,kidney, brain are weighed, the difference of statistics 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 blood Clear Enzyme target, to evaluate the toxicity to mouse for the compound 2f.
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 liquid or physiology salt Water, n=12.
3) result lists table 4 and table 5 in
As shown by data, 200 μm of ol/kg of Mouse oral (100 times of effective dose) compound 2f, 14 days no dead and abnormal behaviors Deng toxic reaction, internal organs and body weight and saline control group do not have difference, show 200 μm of ol/kg compounds of Mouse oral 2f does not have overt toxicity.Serum enzyme detection display, administration group serum alt, ast and creatinine content and physiological saline group phase Ratio indifference, illustrates that compound 2f has no adverse effects to mouse liver and renal function.
Table 4 is administered orally the impact to body weight and internal organs weight for 200 μm of ol/kg compound 2f
Table 5 is administered orally the impact to sero-enzyme for 200 μm of ol/kg compound 2f
Experimental example 5 evaluates compound 2f anti-mouse lewis lung cancer metastasis activity
1) dosage and administering mode
Oral dose is 2 μm of ol/kg, according to the every 10g of Mouse Weight to 0.1ml liquid or physiological saline, n=10.
2) foundation of Mouse With Lewis Lung Cancer model
Lewis murine lung cancer cell (llc), purchased from atcc.From dmem culture medium, wherein contain 10% warp Inactivation hyclone, 1 × 105U/l penicillin and 100mg/l streptomysin.According to attached cell cultural method, every two It passes on once, enrichment of cell.Whne cell growth state good, be in exponential phase when, vitellophag.Use physiology salt Water adjustment cell concentration is to 1 × 107Individual/ml, placenta indigo plant (tryanblue) dyeing counting, viable count ＞ 95%.Take inbred strais C57bl/6 male mice, left hand fixes mouse, and with 75% ethanol disinfection mouse right fore skin of axillary fossa, the right hand holds 1ml Asepsis injector is in mouse armpit hypodermic injection llc tumor cell suspension 0.2ml/ only.Can grow within 10 days after mouse inoculation The tumour of diameter about 4-5mm, standby as knurl source.
3) foundation of lewis lung cancer metastasis model
Take 8-10 days well-grown lewis lung cancer tumor-bearing mices of inoculation, etherization, de- cervical vertebra is put to death, with 75% Ethanol soaking disinfection 10min, peels off knurl body, the good tumor tissues of growth selection, in sterilized petri dishes on superclean bench In shred, be positioned in glass tissue homogenizer, in tumor mass weight (g): physiological saline volume (ml) be 1: 3 ratio add The physiological saline of 4 DEG C of precoolings is lightly ground, and makes cell suspension, crosses 200 mesh cell sieves and makes single cell suspension, uses physiology Salt solution adjustment cell concentration is to 1.5 × 107Individual/ml, placenta indigo plant (tryanblue) dyeing counting, viable count ＞ 95%.
Take inbred strais c57bl/6 male mice, left hand fixes mouse, with 75% ethanol disinfection mouse right fore skin of axillary fossa, The right hand holds 1ml asepsis injector in mouse armpit hypodermic injection tumor cell suspension 0.2ml.Inoculate latter 10 days and grow diameter about The tumour of 4-5mm, measures gross tumor volume, by tumor average volume random packet.
Start within 11st day to be administered from inoculated tumour, be administered 11 times altogether, measure every three days and record gross tumor volume.22nd day After measurement knurl volume, etherization, de- cervical vertebra is put to death, and takes out tumour and weighs, and records lung's rate of transform and the transfer of tumour Burrknot number.
4) result lists table 6 and table 7 in
The as shown by data of table 6, compound 2f has good inhibitory action to transplantable tumor.The as shown by data of table 7, compound 2f There is good inhibitory action to tumor-bearing mice Lung metastases rate and lung surface metastatic tumor tubercle number.According to table 2 as a result, it is possible to drill Unraveling silk other compounds also has corresponding technique effect.
The impact to transplanting tumor weight for the table 6 compound 2f
N=10；A) with physiological saline than p ＜ 0.01.
The impact to tumor-bearing mice lung surface metastatic tumor tubercle number for the table 7 compound 2f
N=10；A) p ＜ 0.01 compared with physiological saline.
Experimental example 6 activity of transwell cell experimental evaluation compound 2f antitumor cell migration
1) experimental technique
Take growth conditions to be well in the a549 cell of exponential phase, 0.25% pancreatin digestion, Microscopic observation, add serum Terminate digestion 3000rpm centrifugation 3min, count, be made into single cell suspension, density is 5 × 105Individual/ml.transwell On cell, the every hole in room adds 100 μ l cell suspensions, is simultaneously introduced the solution of compound 2f, makes final concentration of 10 μm, 5 μm With 1 μm.Lower room adds 1640 culture mediums containing 10%fbs of 600 μ l, at 37 DEG C and 5%co2Train in incubator Support 6 hours.Wipe matrigel and upper indoor cell with cotton swab, fix cell 30min with 4% paraformaldehyde, absorb Fixer, washes 3 times with pbs；Crystal violet dye liquor with 0.1% dyes 15min, absorbs dyeing liquor, washes 3 times with pbs. Each cell choose 6 visuals field take pictures and count, cell number with (Individual) represent.
2) experimental result
The result of table 8 shows, compared with blank control group, 1 μm, 5 μm and 10 μm of compound 2f act on ventricular cell 6h, The suppression a549 cell migration of concentration dependent ground.According to table 2 as a result, it is possible to other compounds of deducing also have corresponding technology Effect.
Table 8 compound 2f antitumor cell migratory activity
N=3；A) with blank and 5 μm of compound 2f than p ＜ 0.01；B) with blank and 1 μm of compound 2f Than p ＜ 0.01；C) a) with blank than p ＜ 0.01.
Experimental example 7 activity of transwell cell experimental evaluation compound 2f antitumor cell invasion and attack
1) experimental technique
By frozen 4 DEG C of the matrigel in -20 DEG C of refrigerators overnight, become liquid.Take 720 μ l serum-free 1640 culture medium, Add 180 μ l matrigel, mix, add to room on the polycarbonate membrane of transwell cell (100 μ l/), put Enter 37 DEG C and 5%co2It is incubated 5h in incubator.Absorb residual liquid in cell, every hole adds 50 μ l 1640 culture medium, 37 DEG C and 5%co2It is incubated 30min in incubator.Growth conditions are taken well to be in the a549 cell of exponential phase, 0.25% Pancreatin digests, Microscopic observation, adds serum to terminate digestion, and 3000rpm centrifugation 3min, counts, and is made into unicellular outstanding Liquid, density is 2 × 105Individual/ml.On cell, the every hole in room adds 100 μ l cell suspensions, is simultaneously introduced the molten of compound 2f Liquid, makes final concentration of 10 μm, 5 μm, 1 μm.Lower room adds containing 10%fbs the 1640 of 600 μ l to support base, 37 DEG C, 5%co2Cultivate 24 hours in incubator.Wipe matrigel and upper indoor cell with cotton swab, with 4% poly first Aldehyde fixes cell 30min, absorbs fixer, is washed 3 times with pbs, and the crystal violet dye liquor with 0.1% dyes 15min, inhales Except dyeing liquor, wash 3 times with pbs.Each cell choose 6 visuals field take pictures, count, cell number with (Individual) table Show.
2) experimental result
The result of table 9 shows, compared with blank control group, 1 μm, 5 μm and 10 μm of compound 2f to act on room thin Born of the same parents 6h, concentration dependent ground suppression a549 cell invasion.According to table 2 as a result, it is possible to other compounds of deducing also have phase The technique effect answered.
Table 9 compound 2f antitumor cell invasion and attack activity
N=3；A) with blank and 5 μm of compound 2f than p ＜ 0.01；B) with blank and 1 μm of compound 2f Than p ＜ 0.01；C) a) with blank than p ＜ 0.01.
Experimental example 8 evaluates compound 2f suppression dimethylbenzene inducing mouse ear swelling activity
1) animal model
Icr male mice 30, body weight 18-22g, it is randomly divided into blank control group, aspirin group and compound 2f group, Every group 10.Each group according to dosage oral administration.After administration 30min, uniform application 30 μ l inside mouse left ear auricle Dimethylbenzene, etherization after 2h, cervical dislocation is put to death, and outer for left and right two ear auricle is cut and overlapped is stacked together, and uses The card punch of diameter 7mm beats circular auricle in same position, weighs, and calculates two ear weight differences as ear swelling degree, i.e. mouse Ear swelling degree=left ear circular piece weight-auris dextra circular piece weight, with (Mg) represent.
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
The result of table 10 shows, the ear swelling degree of saline-treated mice is noticeably greater than the ear swelling that compound 2f treats mouse Degree.According to table 2 as a result, it is possible to other compounds of deducing also have corresponding technique effect.
Table 10 compound 2f suppression dimethylbenzene inducing mouse ear swelling activity
N=10；A) with physiological saline than p ＜ 0.05.
Experimental example 9 evaluates tnf- α and il-8 content in compound 2f paraxylene induction inflammation mice plasma
1) dosage and administering 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, body weight 18-22g, it is randomly divided into 4 groups, every group 6.Each group mouse according to dosage gavage. After administration 30 minutes, uniform application 30 μ l dimethylbenzene inside mouse ear, after 2 hours, pluck eyeball and take blood (0.45ml Plus 0.05ml 3.8% sodium citrate), it is centrifuged 10 minutes in 4 DEG C of 3000rpm immediately, take supernatant to be plasma sample.
3) tnf- α and il-8 content in detection mice plasma
The mensure of tnf- alpha content in mice plasma: setting gauge orifice, compound 2f hole and blank well.Gauge orifice adds 50 μ l Standard solution, what is all not added with blank well.Compound 2f hole adds 10 μ l and 40 μ l compound 2f dilutions.Except blank Outside hole, it is separately added into 50 μ l hpr reagent in each hole, stick plate patch after adding, be incubated 60 minutes in 37 DEG C.Carefully Take shrouding film off, discard liquid, wash plate 5 times with cleaning solution.Every hole is initially charged 50 μ l nitrite ion a, adds 50 μ l Nitrite ion b, gently concussion mixes, and 37 DEG C of lucifuges develop the color 15 minutes.Every hole adds 50 μ l terminate liquids, and terminating reaction is (now Blue standing turns yellow).With blank well zeroing, measure the optical density (o.d. value) in each hole under 450nm wavelength with ELIASA. OD value will be recorded and substitute into linear equation, and calculate tnf- α concentration, carry out t inspection.
The mensure of il-8 content in mice plasma: setting gauge orifice, compound 2f hole and blank well.Blank well adds 100 μ l samples Product dilution, standard sample wells adds 50 μ l standard solutions and streptavidin-hrp 50 μ l, and compound 2f hole adds 40 μ l Compound 2f solution, the anti-il-8 antibody of 10 μ l, sticks plate and pastes 37 DEG C of incubations 60 minutes.By 30 times of washing lotion distilled water 30 times of dilution, carefully takes shrouding film off, discards liquid, and after every hole adds cleaning solution, standing discarded after 30 seconds, repeated to wash plate 5 times, pat dry.Every hole is initially charged 50 μ nitrite ion a l, adds 50 μ l nitrite ion b, and gently concussion mixes, 37 DEG C Lucifuge develops the color 10 minutes.Every hole adds 50 μ l terminate liquid terminating reactions (now blue standing turns yellow).With blank well zeroing, use ELIASA measures the optical density (o.d. value) in each hole under 450nm wavelength.OD value will be recorded and substitute into linear equation, meter Calculate il-8 concentration, carry out t inspection.
4) experimental result
The result of table 11 shows, tnf- α that 2 μm ol/kg compound 2fs lower caused by dimethylbenzene xylene inflammation mice plasma is administered orally.According to Table 2 as a result, it is possible to other compounds of deducing also have corresponding technique effect.
The impact of tnf- α and il-8 in table 11 compound 2f paraxylene inducing acute inflammatory mice plasma
N=6；A) with physiological saline than p ＜ 0.05.

Claims (5)

1. formula i represents 20 kinds of double -3- ethoxy -1h- indoles -2- methoxy-salicylic acyl-aa-obzl, aa=gly in formula, Ala, leu, ile, val, trp, phe, lys, tyr, pro, met, bzl protect the cys of sulfydryl, ser, thr, 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 acyls that the formula i of preparation claim 1 represents The method of-aa-obzl, the method is made up of following steps:
1) react in oxolane with 5- formylsalicylic acid methyl esters in Catalyzed by p-Toluenesulfonic Acid and 60 DEG C of indoles ethanol, It is generated as double -3- ethoxy -1h- indoles -2- methoxy-salicylic acid methyl esters；
2) by sour for pair -3- ethoxy -1h- indoles -2- methoxy-salicylic methyl esters saponification in 4n naoh solution, double -3- hydroxyl second are obtained The acid of base -1h- indoles -2- methoxy-salicylic；
3) in the presence of dicyclohexylcarbodiimide and n- hydroxy benzo triazole 5- formylsalicylic acid in anhydrous tetrahydro furan React with l- amino-acid benzyl ester, generate 5- formyl -2- Hydroxy-benzoyIcarbamo-aa-obzl；
4) indoles ethanol and 5- formyl -2- Hydroxy-benzoyIcarbamo-aa-obzl in the presence of Catalyzed by p-Toluenesulfonic Acid and 60 DEG C Oxolane reacts, generates double -3- ethoxy -1h- indoles -2- methoxy-salicylic acyl-aa-obzl.
3. 20 kinds of claim 1 double -3- ethoxy -1h- indoles -2- methoxy-salicylic acyl-aa-obzl are preparing antineoplastic Application in thing.
4. 20 kinds of claim 1 double -3- ethoxy -1h- indoles -2- methoxy-salicylic acyl-aa-obzl are preparing antitumor turn Move the application in medicine.
5. 20 kinds of claim 1 double -3- ethoxy -1h- indoles -2- methoxy-salicylic acyl-aa-obzl are preparing anti-inflammatory agent Application in thing.
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