CN109485641A - Uracil-carbazoles conjugate, synthesis and its application of a kind of amide key connection - Google Patents

Uracil-carbazoles conjugate, synthesis and its application of a kind of amide key connection Download PDF

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CN109485641A
CN109485641A CN201810799322.5A CN201810799322A CN109485641A CN 109485641 A CN109485641 A CN 109485641A CN 201810799322 A CN201810799322 A CN 201810799322A CN 109485641 A CN109485641 A CN 109485641A
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uracil
dihydroxy
pyrimidine
ethyl acetate
methyl
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CN109485641B (en
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马东来
李斯
刘惠娴
李菁
李明杰
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Hebei Medical University
Hebei University of Chinese Medicine
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Hebei Medical University
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    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

Uracil-carbazoles conjugate, synthesis and its application of a kind of amide key connection, is related to chemical medicine field.Using carbazole and uracil as parent nucleus, splice principle using active structure, design has synthesized the uracil by amide chain link-carbazoles conjugate of series.The analog derivative is important heterocycle compound, has good anti-tumor activity, thus discloses their application prospects as anti-tumor drug, general structure is as follows:

Description

Uracil-carbazoles conjugate, synthesis and its application of a kind of amide key connection
Technical field
The present invention relates to chemical medicine fields, specifically using carbazole and uracil as starting material, have synthesized series A kind of amide key connection uracil-carbazoles conjugate, synthesis and its application.
Background technique
Carbazole analog derivative is a kind of nitrogenous organic heterocyclic molecule, has biggish planar conjugate structure, Neng Gouyu Between groove and base-pair in DNA double helical structure, DNA conformation is caused to change, therefore is widely applied to anti-swollen Tumor, antiviral, antihistamine, in anti-oxidant and anti-inflammatory etc. the synthesis of drugs.In recent years, carbazole compound has multiple chemical combination Object enters clinical investigation phase, as Murrayafolin A (1) and Carbazomycin G (2) has stronger antimycotic work With；Ondansetron (Ondansetron, 3) is highly selective 5-hydroxytryptamine receptor antagonist, is able to suppress or controls by changing Treat and radiotherapy caused by small intestine and CTZ receptor it is stimulated caused by Nausea and vomiting etc.；Ellipticine (4) has suppression DNA topoisomerase II activity processed, is mainly used for treating lymphocytic leukemia；Conducton (Carazolol, 5) is used for The drug for treating hypertension.
In addition, uracil (Uracil, 6) is a kind of pyrimidines antimetabolic object, the Antitumor test of such compound is wide, is The choice drug of the kinds cancers such as clinical treatment gastric cancer, the carcinoma of the rectum, breast cancer.Herein on the basis of previous research work, with click Azoles and uracil are parent nucleus, splice principle using active structure, and design has synthesized serial new by different amide chain links Uracil carbazole conjugate, and it is white to people using MTT cytotoxicity assay method (MTT) detection part target compound The anti tumor activity in vitro of blood disease (K562), human lung cancer (A549) and human cervical carcinoma (Hela) cell.
Summary of the invention
The object of the present invention is to provide one kind to have anti-tumor activity uracil-carbazoles conjugate and its synthetic method, Using carbazole and uracil as parent, splices principle using active structure, synthesize uracil-carbazoles conjugate.The present invention is main Uracil-carbazoles conjugate that a kind of amide is keyed is synthesized by four-step reaction from carbazole and uracil, such change Closing object has anti-tumor activity, and general structure is as follows:
Wherein, the uracil-carbazoles conjugate for the series that general formula UV-S is represented, the R in formula are H, F or CH3；N=1- 6 natural number.
Uracil-carbazoles conjugate of one kind amide key connection of the invention, synthetic route are as follows:
Wherein, R H, F or CH3；The natural number of n=1-6.
Uracil-carbazoles conjugate of the present invention a kind of amide key connection with anti-tumor activity, synthesis step It is as follows:
Step (1): the synthesis of N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine
In reaction flask, acetonitrile, uracil compounds is added, under nitrogen protection, is stirred at room temperature down and three is added dropwise simultaneously Ethamine and benzyl chloroformate, are added dropwise, and are stirred to react at least 2h, stop reaction, and ethyl acetate is added, has been washed with brine Machine phase after rotating out ethyl acetate, is separated using silica gel column chromatography after organic phase is dry, obtains title compound, preferably wash De- liquid is V (ethyl acetate): V (petroleum ether)=1: 6.
Further preferred: the every 15ml of acetonitrile corresponds to uracil 3mmol, triethylamine 4.5mmol benzyl chloroformate 4.5mmol.
Step (2): N3Benzyloxycarbonyl group -5- methyl-N1The synthesis of (n`-n alkanoic acid base) -2,4- dihydroxy-pyrimidine:
In reaction flask, DMF, N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine, potassium carbonate and two end groups are added and take The end group bromine n alkyl acid in generation stirs lower heating reflux reaction 6h under nitrogen protection；Stop reacting and being cooled to room temperature, add Enter ethyl acetate, is washed with brine organic phase and after rotating out ethyl acetate, is separated using silica gel column chromatography after organic phase is dry Target compound, preferably eluent are V (ethyl acetate): V (petroleum ether)=1: 5.
It is preferred that the every 15ml of DMF corresponds to 15 mmol of N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine, potassium carbonate The end group bromine n alkyl acid 22.5mmol that 45mmol, two end groups replace.
Step (3): the uracil with protecting group-carbazoles conjugate N1(N`- (9``- ethyl-carbazole -3``- base) - Acetamido)-N3The structural formula of benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine is as follows:
In reaction flask, DMF, N is added3Benzyloxycarbonyl group -5- methyl-N1(n`-n alkanoic acid base) -2,4- dihydroxy-pyrimidine, DCC (dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine), 3-amino-9-ethyl carbazole under nitrogen protection, are stirred It mixes, reacts at room temperature at least 4h；Stop reacting and being cooled to room temperature, ethyl acetate is added, is washed with brine organic phase, organic phase After drying, after steaming ethyl acetate, using silica gel column chromatography isolating target compound, preferably eluent is V (ethyl acetate): V (petroleum ether)=1: 6；
It is further preferred: the every 10ml of DMF, corresponding N3Benzyloxycarbonyl group -5- methyl-N1(n`- n alkanoic acid base) -2,4- dihydroxy Yl pyrimidines 10mmol, DCC 20mmol, DMAP 20mmol, 3-amino-9-ethyl carbazole 15mmol.
Step (4): uracil-carbazoles conjugate, that is, N of amide key connection1(N`- (9``- Ethy-Carbazole -3``- Base)-acetamido) -5- methyl -2,4- dihydroxy-pyrimidine synthesis:
In reaction flask, N is added1(N`- (9``- Ethy-Carbazole -3``- base)-acetamido)-N3Benzyloxycarbonyl group- Reaction at least 2h is stirred at room temperature in atmosphere of hydrogen in 5- methyl -2,4- dihydroxy-pyrimidine, Pd/C, methanol；After completion of the reaction, It is filtered to remove Pd/C；After steaming methanol, using silica gel column chromatography isolating target compound, preferably eluent is V (ethyl acetate) : V (petroleum ether)=1: 4], faint yellow solid.
Gained compound of the invention is used to prepare anti-tumor drug.
The invention has the advantages that target compound synthesized by the present invention has both the biological nature of uracil and carbazole, with And special uracil-carbazoles conjugate skeleton structure with advantage, in addition, stable planar structure can with protein, DNA etc. forms hydrogen bond and action site, increases the stability of conformation, significantly increases the synergistic effect of active group, drug Bioavilability and drug effect.
Specific embodiment
The content of present invention is further described below with reference to embodiment, but is not with restriction of the invention.
Embodiment 1
The synthesis of N- benzyloxycarbonyl group -2,4- dihydroxy-pyrimidine (1):
In the single-necked flask of 100mL, acetonitrile 15ml is added, uracil (3mmol) is stirred at room temperature under nitrogen protection Down while triethylamine (4.5mmol) and chlorobenzoyl chloride (4.5mmol) is added dropwise, is added dropwise, is stirred to react 2h.Stop reaction, adds Enter 100 mL of ethyl acetate, be washed with brine organic phase (50mL × 8), after organic phase is dry, steams second using Rotary Evaporators It after acetoacetic ester, is separated using silica gel column chromatography, obtains title compound, eluent is V (ethyl acetate): V (petroleum ether)=1: 6。
Embodiment 2
The synthesis of N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine (2):
In the single-necked flask of 100mL, acetonitrile 15ml, methyl uracil (3 mmol), under nitrogen protection, room is added Temperature stirring is lower while triethylamine (4.5mmol) and chlorobenzoyl chloride (4.5mmol) is added dropwise, and is added dropwise, is stirred to react 2h.Stop Reaction is added ethyl acetate 100mL, is washed with brine organic phase (50mL × 8), after organic phase is dry, utilizes rotary evaporation It after instrument steams ethyl acetate, is separated using silica gel column chromatography, obtains title compound, eluent is V (ethyl acetate): V (stone Oily ether)=1: 6.
Embodiment 3
N3Benzyloxycarbonyl group -5- methyl-N1The synthesis of (2`- acetate) -2,4- dihydroxy-pyrimidine (3):
In the single-necked flask of 100mL, DMF 15ml, N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine (2) is added (15mmol), potassium carbonate (45mmol) and 2- bromoacetic acid (22.5 mmol) stir lower heating reflux reaction under nitrogen protection 6h.Stop reacting and being cooled to room temperature, ethyl acetate 100mL is added, is washed with brine organic phase (50mL × 8), organic phase After drying, after steaming ethyl acetate using Rotary Evaporators, using silica gel column chromatography isolating target compound, eluent V (ethyl acetate): V (petroleum ether)=1: 5, white solid, yield 67.2%.MS(ESI),m/Z:310.3[M]+.
Embodiment 4
N3Benzyloxycarbonyl group-N1The synthesis of (3`- propionyloxy) -2,4- dihydroxy-pyrimidine (4):
It according to the method for embodiment 3, is reacted from compound (1) and 3- bromo-propionic acid, obtains title compound, be white solid, Yield 70.8%.MS(ESI),m/Z:318.7[M+H]+.
Embodiment 5
N3Benzyloxycarbonyl group -5- methyl-N1The synthesis of (3`- butyric acid base) -2,4- dihydroxy-pyrimidine (5):
It according to the method for embodiment 3, is reacted from compound (1) and 4- bromo-butyric acid, obtains title compound, be white solid, Yield 63.4%.MS(ESI),m/Z:332.2[M+H]+.
Embodiment 6
N3Benzyloxycarbonyl group -5- methyl-N1The synthesis of (6`- caproyl) -2,4- dihydroxy-pyrimidine (6):
It according to the method for embodiment 3, is reacted from compound (2) and 6- bromocaproic acid, obtains title compound, white solid produces Rate 66.8%.MS(ESI),m/Z:475.7[M+H]+.
Embodiment 7
N1(N`- (9``- Ethy-Carbazole -3``- base)-acetamido)-N3Benzyloxycarbonyl group -5- methyl -2,4- dihydroxy The synthesis of pyrimidine (7):
In the single-necked flask of 100mL, DMF 10ml, compound (3) (10 mmol), DCC (dicyclohexyl carbon two is added Imines), DMAP (4-dimethylaminopyridine) and 3-amino-9-ethyl carbazole (15mmol), under nitrogen protection, stirring, reflux is anti- Answer 4h.Stop reacting and being cooled to room temperature, ethyl acetate 100mL is added, is washed with brine organic phase (50mL × 8), it is organic Mutually after drying, after steaming ethyl acetate using Rotary Evaporators, using silica gel column chromatography isolating target compound, eluent V (ethyl acetate): V (petroleum ether)=1: 6, faint yellow solid, yield 50.4%.1H NMR(CD3OH, 500MHz): δ=1.39 (t, 3H,CH3),1.81(s,3H,CH3),3.24(t,2H,CH2),4.33(t,2H,CH2),5.04(s, 2H,CH2),6.94 (t,1H,ArH),7.08(s,1H,ArH),7.22(t,3H,ArH),7.24(t, 3H,ArH),7.39(d,2H,ArH),7.43 (t,2H,ArH),7.87(d,1H,ArH)； MS(ESI),m/Z:510.3[M+H]+.
Embodiment 8
N1(N`- (9``- Ethy-Carbazole -3``- base)-propionamido-)-N3Benzyloxycarbonyl group -5- methyl -2,4- dihydroxy The synthesis of pyrimidine (8):
According to the method for embodiment 7, is reacted from compound (4) and 3-amino-9-ethyl carbazole (15 mmol), obtain title Compound, faint yellow solid, yield 51.1%.1H NMR (CD3OH, 500MHz): δ=1.36 (t, 2H, CH2),1.42(t, 3H,CH3),3.83(t,2H, CH2),4.33(t,2H,CH2),5.04(s,2H,CH2),6.91(t,1H,ArH),7.09(d, 2H, ArH),7.20(t,2H,ArH),7.22(t,3H,ArH),7.38(d,2H,ArH),7.47(t,2H, ArH),7.91(d, 1H,ArH)；MS(ESI),m/Z:511.3[M]+.
Embodiment 9
N1(N`- (9``- Ethy-Carbazole -3``- base)-amide-based small)-N3Benzyloxycarbonyl group -2,4- dihydroxy-pyrimidine (9) Synthesis:
According to the method for embodiment 7, is reacted from compound (5) and 3-amino-9-ethyl carbazole (15 mmol), obtain title Compound, faint yellow solid, yield 52.2%.1H NMR (CD3OH, 500MHz): δ=1.34 (t, 2H, CH2),1.41(t, 3H,CH3),1.70(t,2H, CH2),3.21(t,2H,CH2),4.34(t,2H,CH2),5.05(s,2H,CH2),6.93(t,1H, ArH),7.13(s,1H,ArH),7.21(q,3H,ArH),7.25(t,3H,ArH),7.40(d, 2H,ArH),7.45(t,2H, ArH),7.89(d,1H,ArH)；MS(ESI),m/Z:525.7 [M+H]+.
Embodiment 10
N1(N`- (9``- Ethy-Carbazole -3``- base)-hexanoyl amido)-N3Benzyloxycarbonyl group -5- methyl -2,4- dihydroxy The synthesis of pyrimidine (10):
According to the method for embodiment 7, is reacted from compound (6) and 3-amino-9-ethyl carbazole (15 mmol), obtain title Compound, faint yellow solid, yield 49.8%.1H NMR (CD3OH, 500MHz): δ=1.35 (t, 2H, CH2),1.41(t, 3H,CH3),1.45(t,3H, CH3),1.68(t,2H,CH2),1.81(s,3H,CH3),1.96(t,2H,CH2),3.23(t,2H, CH2),4.35(t,2H,CH2),5.05(s,2H,CH2),6.92(t,1H,ArH),7.13(s,1H, ArH),7.20(t,3H, ArH),7.23(t,3H,ArH),7.41(d,2H,ArH),7.43(t,2H, ArH),7.90(d,1H,ArH)；MS(ESI),m/ Z:567.4[M+H]+.
Embodiment 11
N1(N`- (9``- Ethy-Carbazole -3``- base)-acetamido) -5- methyl -2,4- dihydroxy-pyrimidine (10) Synthesis:
In the single-necked flask of 100mL, be added compound (7) (10mmol), Pd/C (0.1g), in methanol 10ml, in hydrogen During atmosphere is enclosed, reaction 2h is stirred at room temperature.After completion of the reaction, it is filtered to remove Pd/C.After steaming methanol using Rotary Evaporators, adopt With silica gel column chromatography isolating target compound, eluent is V (ethyl acetate): V (petroleum ether)=1: 4], faint yellow solid, Yield 94.8%.1H NMR(CD3OH, 500MHz): δ=1.39 (t, 3H, CH3),1.81(s,3H,CH3),3.20(t,2H, CH2),3.37(t,2H,CH2),4.34(t,2H, CH2),5.04(s,2H,CH2),6.91(t,1H,ArH),7.12(t,1H, ArH),7.26(q,4H, ArH),7.35(t,2H,ArH),7.42(d,2H,ArH),7.51(d,2H,ArH)7.91(d,1H, ArH)；13C NMR(CD3OH, 125MHz): δ=12.4,15.3,25.5,44.2,51.3,97.4 101.8,108.2, 110.8,118.4,122.3,126.5,147.0,150.7,164.2； MS(ESI),m/Z:377.0[M+H]+.
Embodiment 12
N1The synthesis of (N`- (9``- Ethy-Carbazole -3``- base)-propionamido-) -2,4- dihydroxy-pyrimidine (12):
According to the method for embodiment 11, is reacted from compound (8) and Pd/C (0.1g), obtain title compound, pale yellow colored solid Body, yield 93.2%.1H NMR(CD3OH, 500MHz): δ=1.38 (t, 3H, CH3),1.67(t,2H,CH2),4.42(t, 2H,CH2),5.04(s,2H, CH2),6.92(t,1H,ArH),7.12(t,1H,ArH),7.22(d,2H,ArH),7.24(t, 2H, ArH),7.33(t,2H,ArH),7.39(d,2H,ArH),7.55(d,2H,ArH),7.92(d, 1H,ArH)；13C NMR (CD3OH, 125MHz): δ=12.7,25.4,33.4,41.1,44.6,91.5,104.3,105.1,110.4,115.1, 118.0,121.1,127.6,146.8.150.4,164.5； MS(ESI),m/Z:376.2[M+H]+.
Embodiment 13
N1The conjunction of (N`- (9``- Ethy-Carbazole -3``- base)-amide-based small) fluoro- 2,4- dihydroxy-pyrimidine (13) of -5- At:
According to the method for embodiment 11, is reacted from compound (9) and Pd/C (0.1g), obtain title compound, pale yellow colored solid Body, yield 93.5%.1H NMR(CD3OH, 500MHz): δ=1.35 (t, 2H, CH3),1.38(t,3H,CH3),1.65(t, 2H,CH2),3.23(t,2H, CH2),4.35(t,2H,CH2),5.04(s,2H,CH2),6.93(t,1H,ArH),7.14(t, 1H, ArH),7.23(d,2H,ArH),7.31(q,2H,ArH),7.36(d,2H,ArH),7.90(d, 1H,ArH)；13C NMR (CD3OH, 125MHz): δ=12.3,25.4,26.5,44.2,97.7,102.4,108.1,117.6,119.7,121.3, 127.3,146.3,150.4,164.2；MS(ESI), m/Z:391.1[M+H]+.
Embodiment 14
Compound Cytotoxicity test
5 amide key connections compound (such as table 1) are dissolved with liquid medium respectively, and are diluted to required concentration, 4 DEG C of guarantors It deposits.The cell that K562, A549 and Hela cell grow into logarithmic phase is collected respectively, is adjusted above-mentioned cell to outstanding with culture medium Liquid concentration is 1 × 104A/mL, and be inoculated on 96 well culture plates, it is put into containing 5%CO2In incubator, 37 DEG C of cultures are for 24 hours. Liquid medium is removed, being separately added into the prepare liquid of known concentration, (ultimate density is 10-7~10-4Mol/L, each concentration weight Multiple 6 times) on 96 well culture plates, separately plus blank control group and using cis-platinum as positive controls.It is put into containing 5%CO2Incubator In, 37 DEG C of culture 48h.After culture, 20 μ l 5mg/mL MTT dyeing agent solution is added in each hole, continues to train in 37 DEG C Support 4h.Liquid is discarded supernatant, 100 μ L DMSO solutions are injected in every hole, after mixing, are detected above-mentioned solution with microplate reader and are existed Optical density (OD value) at 570nm calculates the inhibition rate of tumor cell of sample by formula (1).
Inhibition rate of tumor cell (%)=(1-ODtreated/ODcontrol)×100(1)
As it can be seen from table 15 carbazoles-uracil conjugate to Hela, K562 and A549 cell strain all show compared with Strong cytotoxicity.The connection chain of carbazole and uracil it is too long or it is too short for compound inhibit three kinds of tumour cells effect It is weaker；Carbazole-uracil the conjugate wherein connected with propionamido- is most strong to the inhibitory effect of three kinds of tumor cell lines, and It is better than positive control drug cis-platinum.
1 part of compounds cell toxicity data of table

Claims (7)

1. uracil-carbazoles conjugate of a kind of amide key connection, general structure are as follows:
Wherein, the uracil-carbazoles conjugate for a kind of amide key connection that general formula UV-S is represented, the R in formula are H, F or CH3； The natural number of n=1-6.
2. preparing uracil-carbazoles conjugate method of a kind of amide key connection described in claim 1, feature exists In, comprising the following steps:
Step (1): the synthesis of N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine
In reaction flask, acetonitrile, uracil compounds is added, under nitrogen protection, is stirred at room temperature down while being added dropwise triethylamine And benzyl chloroformate, it is added dropwise, is stirred to react at least 2h, stop reaction, ethyl acetate is added, is washed with brine organic phase, After organic phase is dry, after rotating out ethyl acetate, is separated using silica gel column chromatography, obtain title compound；
Step (2): N3Benzyloxycarbonyl group -5- methyl-N1The synthesis of (n`-n alkanoic acid base) -2,4- dihydroxy-pyrimidine:
In reaction flask, it is added what DMF, N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine, potassium carbonate and two end groups replaced End group bromine n alkyl acid stirs lower heating reflux reaction 6h under nitrogen protection；Stop reacting and being cooled to room temperature, acetic acid is added Ethyl ester is washed with brine organic phase, after organic phase is dry, after rotating out ethyl acetate, separates targeted using silica gel column chromatography Close object；
Step (3): the uracil with protecting group-carbazoles conjugate N1(N`- (9``- Ethy-Carbazole -3``- base)-acetamide Base)-N3The structural formula of benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine is as follows:
In reaction flask, DMF, N is added3Benzyloxycarbonyl group -5- methyl-N1(n`-n alkanoic acid base) -2,4- dihydroxy-pyrimidine, DCC (dicyclohexylcarbodiimide), DMAP (4-dimethylaminopyridine), 3-amino-9-ethyl carbazole, under nitrogen protection, stirring, room Temperature reaction at least 4h；Stop reacting and being cooled to room temperature, ethyl acetate is added, is washed with brine organic phase, after organic phase is dry, After steaming ethyl acetate, using silica gel column chromatography isolating target compound；
Step (4): N1The conjunction of (N`- (9``- Ethy-Carbazole -3``- base)-acetamido) -5- methyl -2,4- dihydroxy-pyrimidine At:
In reaction flask, N is added1(N`- (9``- Ethy-Carbazole -3``- base)-acetamido)-N3Benzyloxycarbonyl group -5- first Reaction at least 2h is stirred at room temperature in atmosphere of hydrogen in base -2,4- dihydroxy-pyrimidine, Pd/C, methanol；After completion of the reaction, it crosses and filters out Remove Pd/C；After steaming methanol, using silica gel column chromatography isolating target compound.
3. according to the method for claim 2, which is characterized in that step (1) eluent is V (ethyl acetate): V (petroleum ether) =1: 6；The every 15ml of acetonitrile corresponds to uracil 3mmol, triethylamine 4.5mmol, benzyl chloroformate 4.5mmol.
4. according to the method for claim 2, which is characterized in that step (2), eluent are V (ethyl acetate): V (petroleum Ether)=1: 5；The every 15ml of DMF corresponds to N- benzyloxycarbonyl group -5- methyl -2,4- dihydroxy-pyrimidine 15mmol, potassium carbonate 45mmol, two The end group bromine n alkyl acid 22.5mmol that end group replaces.
5. according to the method for claim 2, which is characterized in that step (3) scheme 2, eluent are V (ethyl acetate): V (petroleum ether)=1: 6；Every 10ml DMF corresponds to N3Benzyloxycarbonyl group -5- methyl-N1(n`-n alkanoic acid base) -2,4- dihydroxy-pyrimidine 10mmol, DCC 20mmol, DMAP 20mmol, 3-amino-9-ethyl carbazole 15mmol.
6. according to the method for claim 2, which is characterized in that step (4) eluent is V (ethyl acetate): V (petroleum ether) =1: 4.
7. uracil-carbazoles conjugate application of one kind amide key connection described in claim 1, is used to prepare antitumor Drug.
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JPS5663966A (en) * 1979-10-29 1981-05-30 Tokyo Kinzoku Kogyo Kk Pyrimidine derivative and its preparation
WO2010036821A1 (en) * 2008-09-24 2010-04-01 Hydra Biosciences, Inc. Methods and compositions for treating respiratory disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5663966A (en) * 1979-10-29 1981-05-30 Tokyo Kinzoku Kogyo Kk Pyrimidine derivative and its preparation
WO2010036821A1 (en) * 2008-09-24 2010-04-01 Hydra Biosciences, Inc. Methods and compositions for treating respiratory disorders

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