CN105906602B - The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-acetogenin - Google Patents

The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-acetogenin Download PDF

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CN105906602B
CN105906602B CN201610266606.9A CN201610266606A CN105906602B CN 105906602 B CN105906602 B CN 105906602B CN 201610266606 A CN201610266606 A CN 201610266606A CN 105906602 B CN105906602 B CN 105906602B
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bases
reaction
ketone
dimethylxanthene
dimethylxanthene ketone
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CN105906602A (en
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张世杰
葛求富
黄滨南
胡惟孝
郭殿武
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HANGZHOU MINSHENG PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention provides a kind of preparation methods of 2 (5,6 dimethylxanthene ketone, 4 base) acetogenins.Reasonable design of the present invention prepares raw material sources and easily obtains extensively, and preparation method is simple and easy to operate, and reaction condition is mild, the high income of product, conducive to industrial-scale production.

Description

The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-acetogenin
The application is application No. is 201110125718.x, and the applying date is on May 16th, 2011, entitled " 2- (5, 6- dimethylxanthene ketone -4- bases)-acetic acid derivative and its preparation method and application " divisional application.
Technical field
The present invention relates to a kind of derivatives of xanthene ketone compounds and preparation method thereof, and in particular to a kind of 2- (5,6- Dimethylxanthene ketone -4- bases)-acetic acid derivative and its preparation method and application.
Background technology
Xanthene ketone compounds show extensive bioactivity according to the different substituents of its parent nucleus, including antibacterial, resist Virus, anti-hypertension, anti-oxidant, antithrombotic, antitumor isoreactivity.Xanthene ketone compounds play the action target spot of bioactivity Also because the performance of architectural difference itself is far different, target spot includes a variety of enzymes, ion channel, receptor protein etc..Nearest decades, medicine The xanthene ketone compounds of object chemist extensive concern different structure, are desirably to obtain the new drug with active anticancer.
In these xanthene ketone compounds, what most negative Sheng was hoped surely belongs to Vadimezan, and the chemical name of the compound is 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid, molecular formula C17H14O4, molecular weight 282.29, structural formula is：
Vadimezan is a kind of vascular endothelial cell proliferation inhibitor, Baguley, and B.C. research groups find the chemical combination Object have excellent active anticancer, action target spot is tumor vessel, can to tumor vessel generate destruction (《Lancet Oncology》, 2003,4,141,《Nature Reviews Cancer》, 2005,5,4234,《Cancer》, 2010,116, 1859).Compare tubulin binding agent CA-4P, AVE8062, ZD6126, TZT1027, Oxi4503 etc., and Vadimezan is more Generated tumor vessel can be destroyed, the tumour cell nutrition supply channel of blood vessel is thoroughly cut through, rather than just inhibition Tumor neogenetic blood vessels.
Wilson, W.R. and Siim, B.G. are disclosed and may be used also in United States Patent (USP) of the patent publication No. for US 7863321 With other a variety of anti-cancer agent in combination medications, as carboplatin, gemcitabine, cis-platinum, 5 FU 5 fluorouracil, cyclophosphamide, Etoposide, Vincristine, adriamycin, Irinotecan etc. can play collaboration facilitation.In terms of clinical research, McKeage, M.J., Reck, M. and Jameson, M.B. et al. are then non-small for treatment late period in the drug combination of Vadimezan and carboplatin, taxol The II phase clinical effectiveness of cell lung cancer NSCLC shows that the therapeutic scheme can effectively delay tumor progression, extends patient vitals (《Lung Cancer》, 2009,65,192.).In addition, the human hairs such as Wang, L.C.S., Ching, L.M. and Paxton, J.W. Existing, Vadimezan can also be combined with non-steroidal anti-inflammatory drugs, improved the effect of its antineoplastic vascular, delayed tumour growth significantly (《Investigational New Drugs》, 2009,27,280.).At present, which has enter into the III phases and faces Bed experiment (《Expert Opinion on Investigational Drugs》, 2010,19,295.).
In existing patent, the European patent of Publication No. EP 0278176 is the basic substance structure patent of Vadimezan, Disclose below formula structure and preparation method thereof：
Mainly it is transformed to form a series of derivatives by carrying out Vadimezan on parent nucleus the substituent group of different substitution positions Object is not directed to and the carboxylic group on Vadimezan phenyl ring is transformed；The China of Publication No. CN 101195609A is specially Profit also provides the derivative and its preparation prepared by the Vadimezan compounds with antitumor activity, the general formula of derivative Structure (I) is as follows：
Wherein, R " is expressed as the substituent group of 2 on 1,2,3,7,8 active positions, is also not directed at carboxyl position Modification transformation, and synthesis route is complicated, yield is low and is difficult to industrial-scale production.
In addition, looking into new discovery by CA structures, it is related to only modifying at the carboxyl position of Vadimezan and is transformed, is published There are four Vadimezan derivatives are main：1. CA accession number be 1035912-44-7,2. CA accession number be 1070196-50-7, 3. CA accession number is 1070196-53-0,4. CA accession number is 162070-60-2, compound structure difference is as follows：
Wherein 1. CA accession number is 1035912-44-7 (i.e. 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid first to structure Ester) it is similar with Vadimezan derivant structures according to the present invention.
Invention content
2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid the purpose of the present invention is to provide a kind of structure novel spreads out Biology by modifying the substitution at 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid carboxyl position, synthesizes and filters out a system Compound of the row with antitumor activity.
The technical solution adopted by the present invention is：
The derivative of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid provided by the invention, has the following structure general formula：
Wherein：
R is O (CH2)mR1、NHR2、NH(CH2)nR2、NHNHC(S)NHR3、NHNH2、NHNHC(O)R3、
R1For CH3, ← HC=CH2、←C≡CH、C3-6Cycloalkyl,
R2For CH3、C3-6Cycloalkyl, halogenated pyridyl, COOR4、
R3For C1-6Alkyl, C1-6Alkenyl,
Wherein substituent group X, Y, Z H, halogen, COOR4、CF3、NO2、OH、C1-6Alkoxy, C1-6Alkyl, C3-6Cycloalkanes Base, amino, CN, (CO) R5、NR6R7、C(O)NR8R9、(CH2)pR2、S(O)2NR6R7In one kind；
R4For H, C1-6Alkyl, C1-6Alkoxy, OH, NO2Or amino；
R5、R6、R7、R8、R9For H, OH, C1-6Alkyl or C3-6Cycloalkyl；
M is 7~17 natural number, and n is 1~17 natural number, and p is 1~17 natural number.
Preferred derivative is R in general formula structure1For CH3, ← HC=CH2、←C≡CH、C3-6Cycloalkyl or R2For CH3、C3-6Cycloalkyl, halogenated pyridyl, COOR4OrR3For C1-6Alkyl, C1-6Alkenyl orR4For H or C1-6Alkyl, wherein substituent group X, Y, Z H, halogen, COOR4、CF3、NO2、OH、 OCH3In one kind；
M is 7~17 natural number；N is 1~17 natural number.
Preferred derivative is that R is NH (CH in general formula structure2)nR2, wherein R2For CH3OrSubstituent group X, one kind in Y, Z H, halogen, n are 1~17 natural number.
Preferred derivative is that R is in general formula structureWherein substituent group X, Y, Z H, halogen Element, CF3、NO2、OH、OCH3In one kind.
Preferred derivative is mainly selected from following compound：
2- (5,6- dimethylxanthene ketone -4- bases)-N- propyl acetamides, structural formula are：
2- (5,6- dimethylxanthene ketone -4- bases)-phenyl acetanilide,Phenacetylaniline, structural formula are：
N- (4- chlorphenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide, structural formula are：
N- (3- chlorphenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide, structural formula are：
N'- (5- chlorine-2-hydroxyl benzene methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide, structural formula are：
In addition to above-mentioned five more have the compound of choosing, 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid in the present invention spreads out Biology is further selected from following preferred compound：
2- (5,6- dimethylxanthene ketone -4- bases)-heptyl acetate；2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid 18 Ester；2- (5,6- dimethylxanthene ketone -4- bases)-allyl acetate；2- (5,6- dimethylxanthene ketone -4- bases)-propargyl acetate； 2- (5,6- dimethylxanthene ketone -4- bases)-phenylmethyl acetate；2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid-(4- chlorobenzenes First) ester；2- (5,6- dimethylxanthene ketone -4- bases)-N- butyl acetamides；N- (3,4- dichlorophenyls) -2- (5,6- dimethyl Xanthones Ton ketone -4- bases)-acetamide；N- (the chloro- 4- fluorophenyls of 3-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide；N- (3- tri- Methyl fluoride -4- nitrobenzophenones) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide；N- (the chloro- pyridine -2- bases of 5-) -2- (5, 6- dimethylxanthene ketone -4- bases)-acetamide；N- (the bromo- pyridine -2- bases of 5-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetyl Amine；N- (4- hydroxy 3-methoxybenzenes base) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide；2- (2- (5,6- dimethyl Xanthone -4- bases) acetamido) ethyl acetate；3- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl propionate； 4- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl benzoate；2- (5,6- dimethylxanthene ketone -4- bases)-second Hydrazides；N'- (2- hydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide；N'- (4- hydroxy benzenes methylenes Base) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide；N'- (3- methoxybenzenes methene) -2- (5,6- dimethylxanthenes Ketone -4- bases)-acethydrazide；N'- (4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide；N'-(3, 4,5- trimethoxy-benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide；N'- (3,4- dihydroxy benzenes methylenes Base) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide；N'- (4- hydroxy 3-methoxybenzenes methene) -2- (5,6- diformazans Base xanthone -4- bases)-acethydrazide；N'- (4- hydroxy-3-methoxy -2- nitrobenzoyls alkenyl) -2- (5,6- dimethylxanthenes Ketone -4- bases)-acethydrazide；N'- (3- hydroxyl -4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acetyl Hydrazine；N'- (benzo [d] [1,3] dioxolane -5- methenes) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide；4- allyls Base -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) thiosemicarbazides；(R) -1- (2- (5,6- dimethylxanthene ketone -4- bases) Acetyl) -4- (1- phenyl) thiosemicarbazides；(S) -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) amino Thiocarbamide；(E)-N'-3- hexenoyls-N-2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide.
In addition, in addition to above-mentioned 34 preferred compounds, 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid in the present invention Derivative is further included such as lower structure, is similarly made using following preparation methods：
The 2- (5,6- dimethylxanthene ketone -4- bases) prepared as shown in above-mentioned general structure the present invention also provides a kind of - The method of the derivative of acetic acid, including chemically reacting as follows：
(1) reaction equation A：
2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid is flowed back with alcohol in toluene solvant, through catalyst esterification Derivative I a is obtained, is reacted to reflux temperature, the reaction time is 2~10 hours；
Catalyst is selected from the concentrated sulfuric acid, p-methyl benzenesulfonic acid, dicyclohexylcarbodiimide (DCC), diphenylamines fluoroform sulphonate One or more of (DPAT)；
(2) reaction equation B：
2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid and arylamine or alkanamine are heated in organic solvent, it is anti-through amidation Answer reagent that derivative I b is obtained by the reaction, reaction temperature is 50~70 DEG C, and the reaction time is 4~24 hours；
Organic solvent is selected from one kind in dichloromethane, dimethylformamide (DMF), amidation process reagent choosing From dicyclohexylcarbodiimide (DCC), 1- ethyls -3- (3- dimethylamine propyls) carbodiimide (EDCI), three nitrogen of 1- hydroxy benzos One or more of azoles (HOBt), 4-dimethylaminopyridine (DMAP)；
(3) reaction equation C：
By 2- (5,6- dimethylxanthene ketone -4- bases)-ethyl acetate and hydrazine hydrate back flow reaction in absolute ethyl alcohol, obtain Derivative I c, that is, 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid hydrazides；Derivative I c again with aldehyde in ethanol solution through condensation Derivative I d is obtained by the reaction, reaction temperature is 80 DEG C, and the reaction time is 2~12 hours；
(4) reaction equation D：
Derivative I c made from reaction equation C and isothiocyanates back flow reaction in ethanol solution will be utilized, will be derived Object Ie, reaction temperature are 80 DEG C, and the reaction time is 6~12 hours；
(5) reaction equation E：
Derivative I c made from reaction equation C will be utilized to be heated with carboxylic acid in organic solvent, reacted through amidation process reagent Derivative I f is obtained, reaction temperature is 50~60 DEG C, and the reaction time is 4~24 hours；
Organic solvent is selected from one kind in dichloromethane, dimethylformamide (DMF), amidation process reagent choosing From dicyclohexylcarbodiimide (DCC), 1- ethyls -3- (3- dimethylamine propyls) carbodiimide (EDCI), three nitrogen of 1- hydroxy benzos One or more of azoles (HOBt), 4-dimethylaminopyridine (DMAP)；
R in above-mentioned reaction equation A, reaction equation B, reaction equation C, reaction equation D and reaction equation E1For CH3, ← HC=CH2、←C ≡CH、C3-6Cycloalkyl,R2For CH3、C3-6Cycloalkyl, halogenated pyridyl, COOR4、R3For C1-6Alkyl, C1-6Alkenyl, R4For H, C1-6Alkyl, C1-6Alkoxy, OH, NO2Or amino, R5、R6、R7、R8、R9For H, OH, C1-6 Alkyl or C3-6Cycloalkyl；
Wherein substituent group X, Y, Z H, halogen, COOR4、CF3、NO2、OH、C1-6Alkoxy, C1-6Alkyl, C3-6Cycloalkanes Base, amino, CN, (CO) R5、NR6R7、C(O)NR8R9、(CH2)pR2、S(O)2NR6R7In one kind；
M is 7~17 natural number, and n is 1~17 natural number, and p is 1~17 natural number.
Preferred catalyst is diphenylamines fluoroform sulphonate in reaction equation A.
Preferred organic solvent is dimethylformamide in reaction equation B, and amidation process reagent is sub- for dicyclohexyl carbon two Amine and 1- hydroxy benzo triazoles.
Preferred organic solvent is dimethylformamide in reaction equation E, and amidation process reagent is sub- for dicyclohexyl carbon two Amine and 1- hydroxy benzo triazoles.
The derivative of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid that the present invention is prepared is preparing prevention or is controlling Treat the application in the drug of tumor disease.They are found to various tumor cell strains by in-vitro screening, including people's endometrium Cancer Ishikawa, human lung cancer A549, human choriocarcinoma Bewo, human cervical carcinoma HeLa and Siha, human breast carcinoma MCF-7, people are white Blood disease HL-60, Human hepatocarcinoma cell line SMMC-7721, human lung cancer NCI-460, people's sdenocarcinoma of stomach BGC-823 etc. are respectively provided with antitumor cell hyperplasia Activity.Simultaneously as described in background the invention, it is pair similar with structure in technical solution of the present invention in screening in vitro (1. CA accession number is 1035912-44- to structure to Vadimezan derivatives 2- (5,6- dimethylxanthene ketone -4- bases)-methyl acetate 7) carry out in vitro test control, in vitro test shows that the compound does not have antitumor activity, to Ishikawa, A549, Bewo, The IC of HeLa, Siha, MCF-7, HL-60, BEL-7402, NCI-460 and BGC-82350It is all higher than 100 μM.
The invention has the advantages that：
The present invention with 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid with antitumor activity be lead compound, it is right Its carboxyl position carries out various structures modification transformation, obtain the 2- (5,6- dimethylxanthene ketone -4- bases) of structure novels a series of - Acetogenin is compared with existing Vadimezan or derivatives thereof 2- (5,6- dimethylxanthene ketone -4- bases)-methyl acetate etc., There is inhibiting effect to kinds of tumor cells using the partial derivatives obtained by the present invention, especially swell to lung cancer and leukaemia Oncocyte inhibiting rate is higher, and antitumor activity of compound is notable.
Reasonable design of the present invention prepares raw material sources and easily obtains extensively, and preparation method is simple and easy to operate, reaction condition temperature With the high income of product, conducive to industrial-scale production.
Specific embodiment
The present invention is described further in conjunction with the embodiments.Following embodiment illustrates the present invention rather than with any Mode limits the present invention.
Embodiment 1
Reaction equation A：
(1) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-heptyl acetate (Ia-1)
By 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid (141mg, 0.5mmol), n-heptanol (16mg, 1.0mmol) Be heated to reflux in toluene solvant (15mL) with catalyst diphenylamines fluoroform sulphonate (DPAT, 32mg, 0.1mmol), TLC with Track reacts to terminal, and the reaction time is 2~10 hours；Vacuum rotary steam removal solvent obtains crude product, then by crude product absolute ethyl alcohol Recrystallize to obtain white solid 2- (5,6- dimethylxanthene ketone -4- bases)-heptyl acetate (Ia-1)：Ia-1 mass be 167mg, yield 87.8%；mp：68-69℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:2949,1716,1650,1597,1411,1333,1230, 766；1H NMR(CDCl3,500MHz)δ:8.29(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.09 (d, J= 8.0Hz,1H,Ar-H8),7.64(dd,J1=1.5Hz, J2=7.0Hz, 1H, Ar-H3), 7.34 (t, J=7.5Hz, 1H, Ar- ), H2 7.21 (d, J=8.0Hz, 1H, Ar-H7), 4.11 (t, J=6.8Hz, 2H, OCH2),3.99(s,2H,Ar-CH2),2.45 (s,6H,2×Ar-CH3),1.59-1.56(m,2H,OCH2 CH2 ),1.21-1.19(m,6H,CH2CH2CH2 CH2CH3),1.13- 1.12(m,2H,CH 2CH3), 0.84 (t, J=7.3Hz, 3H, CH3)；EI-MS m/z (%):380(M+,25),282(16),239 (18),238(100),237(27),209(11)；EI- high resolution mass spectrums (C24H28O4):Measured value M+380.1972 (calculated values 380.1988)。
(2) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid octadecyl ester (Ia-2)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid octadecyl ester with (1), with positive octadecyl alcolol (270mg, It 1.0mmol) is reacted for raw material, TLC tracking reaction to terminal, obtains brown solid 2- (5,6- dimethylxanthene ketone -4- bases)-second Sour octadecyl ester
(Ia-2)：Ia-2 mass be 197mg, yield 73.7%；mp：57-59℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1: 2917,2849,1731,1602,1413,1336,1230,1182,760；1H NMR(CDCl3,500MHz)δ:8.28(dd,J1= 1.5Hz,J2=8.0Hz, 1H, Ar-H1), 8.09 (d, J=8.0Hz, 1H, Ar-H8), 7.64 (dd, J1=1.5Hz, J2= 7.5Hz, 1H, Ar-H3), 7.34 (t, J=7.5Hz, 1H, Ar-H2), 7.20 (d, J=8.5Hz, 1H, Ar-H7), 4.11 (t, J =6.8Hz, 2H, OCH2),3.99(s,2H,Ar-CH2),2.45(s,6H,2×Ar-CH3),1.59-1.55(m,2H, OCH2 CH2 ),1.35-1.14(m,30H,(CH2)1 5CH3), 0.88 (t, J=6.8Hz, 3H, CH3)；EI-MS m/z (%):534 (M+,25),283(34),238(100),237(21),225(14)；EI- high resolution mass spectrums (C35H50O4):Measured value M+ (534.3720 calculated value 534.3709).
(3) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-allyl acetate (Ia-3)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-allyl acetate with (1), with allyl alcohol (58mg, It 1.0mmol) is reacted for raw material, TLC tracking reaction to terminal, obtains brown solid 2- (5,6- dimethylxanthene ketone -4- bases)-second Allyl propionate (Ia-3)：Ia-3 mass be 93mg, yield 57.7%；mp:125-128℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1: 3081,2966,1734,1646,1602,1412,1333,1230,1175,761；1H NMR(CDCl3,500MHz)δ:8.29 (dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.09 (d, J=8.0Hz, 1H, Ar-H8), 7.65 (dd, J1=1.3Hz, J2=7.3Hz, 1H, Ar-H3), 7.35 (t, J=7.8Hz, 1H, Ar-H2), 7.20 (d, J=8.5Hz, 1H, Ar-H7), 5.89 (ddt,J1=6.0Hz, J2=10.5Hz, J3=17.0Hz, 1H,CH=CH2),5.27(dq,J1=1.3Hz, J2=17.0Hz, 1H, CH=CHH),5.20(dq,J1=1.3Hz, J2=10.5Hz, 1H, CH=CHH),4.64(dt,J1=1.3Hz, J2= 6.0Hz,2H,OCH2),4.03(s,2H,Ar-CH2),2.45(s,3H,Ar-CH3),2.44(s,3H,Ar-CH3)；EI-MS m/z (%):322(M+,72),281(68),254(18),253(100),238(18),237(93),209(42),165(31)；Element Analyze (C20H18O4):Measured value:C,74.55；H, 5.62%；Calculated value:C,74.52；H, 5.63%.
(4) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-propargyl acetate (Ia-4)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-propargyl acetate with (1), with propargyl alcohol (56mg, It is 1.0mmol) raw material, TLC tracking reaction to terminal, obtains light yellow solid 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid alkynes Propyl ester (Ia-4):Ia-4 mass be 78mg, yield 48.7%；mp:146-148℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3223, 2950,1739,1647,1602,1412,1332,1154,768；1H NMR(CDCl3,500MHz)δ:8.30(dd,J1= 1.5Hz,J2=8.0Hz, 1H, Ar-H1), 8.09 (d, J=8.0Hz, 1H, Ar-H8), 7.65 (dd, J1=1.5Hz, J2= 7.5Hz, 1H, Ar-H3), 7.35 (t, J=7.5Hz, 1H, Ar-H2), 7.20 (d, J=8.0Hz, 1H, Ar-H7), 4.74 (d, J =2.5Hz, 2H, OCH2),4.05(s,2H,Ar-CH2),2.46(s,6H,2×Ar-CH3), 2.44 (t, J=2.5Hz, 1H, CH)；EI-MS m/z (%):320(M+,100),305(23),281(17),253(63),238(20),237(99),209 (44),165(31)；Elemental analysis (C20H16O4):Measured value:C,74.81；H, 5.06%；Calculated value:C,74.99；H, 5.03%.
(5) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-phenylmethyl acetate (Ia-5)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-phenylmethyl acetate with (1), with benzyl alcohol (108mg, It is 1.0mmol) raw material, TLC tracking reaction to terminal, obtains white solid 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid benzene first Ester (Ia-5):Ia-5 mass be 152mg, yield 81.7%；mp:118-120℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:1735, 1652,1604,1411,1333,1172,765；Hydrogen is composed1H NMR(CDCl3,500MHz)δ:8.29(dd,J1=2.0Hz, J2= 8.0Hz, 1H, Ar-H1), 8.08 (d, J=8.0Hz, 1H, Ar-H8), 7.64 (dd, J1=1.5Hz, J2=7.5Hz, 1H, Ar- ), H3 7.34 (t, J=7.8Hz, 1H, Ar-H2), 7.23-7.21 (m, 5H, Ar'), 7.19 (d, J=8.5Hz, 1H, Ar-H7), 5.15(s,2H,OCH2),4.03(s,2H,Ar-CH2),2.41(s,3H,Ar-CH3),2.26(s,3H,Ar-CH3)；EI-MS m/ Z (%):372(M+,56),282(24),281(100),253(54),237(100),209(36),165(26),91(28)；Member Element analysis (C24H20O4):Measured value:C,77.37；H, 5.43%；Calculated value:C,77.40；H, 5.41%.
(6) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid-(4- chlorobenzenes first) ester (Ia-6)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid-(4- chlorobenzenes first) ester is with (1), with to chlorobenzene first Alcohol (143mg, 1.0mmol) is raw material, and TLC tracking reaction to terminal, obtains white solid 2- (5,6- dimethylxanthene ketone -4- Base)-acetic acid-(4- chlorobenzenes first) ester (Ia-6):Ia-6 mass be 54mg, yield 26.6%；mp:125-127℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:1742,1648,1604,1412,1330,1169,769；Hydrogen is composed1H NMR(CDCl3,500MHz)δ:8.30 (dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.09 (d, J=8.0Hz, 1H, Ar-H8), 7.63 (dd, J1=1.5Hz, J2=7.0Hz, 1H, Ar-H3), 7.35 (t, J=7.5Hz, 1H, Ar-H2), 7.21 (d, J=8.0Hz, 1H, Ar-H7), 7.15- 7.11(m,4H,Ar'),5.09(s,2H,OCH2),4.02(s,2H,Ar-CH2),2.42(s,3H,Ar-CH3),2.19(s,3H, Ar-CH3)；EI-MS m/z (%):406/408(M+,29/11),282(24),281(100),253(39),238(16),237 (71),209(22),165(16)；EI- high resolution mass spectrums (C24H19 35ClO4):Measured value M+406.0981 (calculated values 406.0972)。
Embodiment 2
Reaction equation B：
(7) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-N- propyl acetamides (Ib-1)
By 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid (141mg, 0.5mmol), n-propylamine (36mg, 0.6mmol), Amidation process reagent dicyclohexylcarbodiimide (DCC, 124mg, 0.6mmol) and 1- hydroxy benzo triazoles (HOBt, 81mg, 0.6mmol) and heated in n,N-Dimethylformamide (DMF, 20mL) solvent, TLC tracking reaction to terminal, is reacted Time for 4~for 24 hours；Reaction solution is cooled to room temperature overnight precipitation dicyclohexylurea (DCU) (DCU), filters out and mother liquor is poured into ice after DCU White solid is precipitated in water, filters up to crude product, then white solid 2- (5,6- dimethylxanthenes are recrystallized to obtain with absolute ethyl alcohol Ketone -4- bases)-N- propyl acetamides (Ib-1):Ib-1 mass be 105mg, yield 64.9%；mp:187-188℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3292,2962,1653,1602,1413,1332,1212,763；Hydrogen is composed1H NMR(CDCl3,500MHz) δ:8.31 (d, J=8.0Hz, 1H, Ar-H1), 8.10 (d, J=8.0Hz, 1H, Ar-H8), 7.69 (d, J=6.0Hz, 1H, Ar- ), H3 7.38 (t, J=7.0Hz, 1H, Ar-H2), 7.23 (d, J=8.0Hz, 1H, Ar-H7), 5.53 (br, 1H, NH), 3.95 (s,2H,Ar-CH2),3.23-3.19(m,2H,NHCH2 ),2.47(s,6H,2×Ar-CH3),1.47-1.43(m,2H,CH2 CH3), 0.80 (t, J=7.3Hz, 3H, CH2 CH3 )；EI-MS m/z (%):323(M+,29),239(18),238(100), 237(11),223(18),209(11),195(11),165(9)；Elemental analysis (C20H21NO3):Measured value:C,74.39；H, 6.61；N, 4.29%；Calculated value:C,74.28；H,6.55；N, 4.33%.
(8) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-N- butyl acetamide (Ib-2)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-N- butyl acetamides with (7), with n-butylamine (44mg, It is 0.6mmol) raw material, TLC tracking reaction to terminal, obtains white solid 2- (5,6- dimethylxanthene ketone -4- bases)-N- butyl second Amide (Ib-2):Ib-2 mass be 56mg, yield 33.2%；mp:201-204℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3293, 2929,1654,1601,1412,1335,1210,761；Hydrogen is composed1H NMR(CDCl3,500MHz)δ:8.31(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.11 (d, J=8.0Hz, 1H, Ar-H8), 7.68 (dd, J1=1.3Hz, J2=7.3Hz, 1H, ), Ar-H3 7.39 (t, J=7.5Hz, 1H, Ar-H2), 7.24 (d, J=8.0Hz, 1H, Ar-H7), 5.47 (br, 1H, NH), 3.94(s,2H,Ar-CH2),3.26-3.22(m,2H,NHCH2 ),2.48(s,6H,2×Ar-CH3),1.42-1.36(m,2H,CH2 CH2CH3),1.22-1.15(m,2H,CH2 CH2 CH3), 0.79 (t, J=7.3Hz, 3H, CH2 CH3 )；EI-MS m/z (%): 337(M+,29),239(18),238(100),237(12),223(14),209(10),195(9)；Elemental analysis (C21H23NO3): Measured value:C,74.82；H,7.04；N, 4.12%；Calculated value:C,74.75；H,6.87；N, 4.15%.
(9) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-phenyl acetanilide,Phenacetylaniline (Ib-3)
The preparation method of 2- (5,6- dimethylxanthene ketone -4- bases)-phenyl acetanilide,Phenacetylaniline with (7), with aniline (56mg, It is 0.6mmol) raw material, TLC tracking reaction to terminal, obtains white solid 2- (5,6- dimethylxanthene ketone -4- bases)-N- phenyl second Amide (Ib-3):Ib-3 mass be 143mg, yield 80.0%；mp:227-231℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3282, 1657,1602,1443,1413,1327,765；Hydrogen is composed1HNMR(DMSO-d6,500MHz)δ:10.42(s,1H,NH),8.11 (dd,J1=2.0Hz, J2=8.0Hz, 1H, Ar-H1), 7.93 (d, J=8.0Hz, 1H, Ar-H8), 7.83 (dd, J1=1.5Hz, J2=7.0Hz, 1H, Ar-H3), 7.62 (dd, J1=1.0Hz, J2=8.5Hz, 2H, Ar-H2'and Ar-H6'), 7.44 (t, J =7.8Hz, 1H, Ar-H2), 7.33-7.28 (m, 1H+2H, Ar-H7+Ar-H3'and Ar-H5'), 7.06 (t, J=8.0Hz, 1H,Ar-H4'),4.13(s,2H,Ar-CH2),2.39(s,3H,Ar-CH3),2.35(s,3H,Ar-CH3)；EI-MS m/z (%):357(M+,43),264(21),239(18),238(100),227(28),209(28),208(16),165(26)；Element Analyze (C23H19NO3):Measured value:C,77.21；H,5.44；N, 3.87%；Calculated value:C,77.29；H,5.36；N, 3.92%.
(10) preparation of N- (4- chlorphenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-4)
The preparation method of N- (4- chlorphenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is with (7), with to chlorobenzene Amine (77mg, 0.6mmol) is raw material, and TLC tracking reaction to terminal, obtains white solid N- (4- chlorphenyls) -2- (5,6- dimethyl Xanthone -4- bases)-acetamide (Ib-4):Ib-4 mass be 86mg, yield 43.9%；mp:>260℃；INFRARED SPECTRUM IR νmax (KBr)/cm-1:3275,1655,1597,1492,1399,1334,1230,1091,762；Hydrogen is composed1H NMR(CDCl3, 500MHz)δ:8.28(dd,J1=1.3Hz, J2=8.0Hz, 1H, Ar-H1), 8.08 (d, J=8.0Hz, 1H, Ar-H8), 7.72 (d, J=7.0Hz, 1H, Ar-H3), 7.43-7.36 (m, 1H+2H, Ar-H2+Ar-H2'and Ar-H6'), 7.26-7.24 (m, 2H, Ar-H3'and Ar-H5'), 7.21 (d, J=8.0Hz, 1H, Ar-H7), 4.07 (s, 2H, Ar-CH2),2.43(s,3H, Ar-CH3),2.42(s,3H,Ar-CH3)；EI-MSm/z (%):391/393(M+,48/16),265(25),264(86),238 (100),237(89),209(51),208(33),194(19)；Elemental analysis (C23H18ClNO3):Measured value:C,70.43；H, 4.63；N, 3.59%；Calculated value:C,70.50；H,4.63；N, 3.57%.
(11) preparation of N- (3- chlorphenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-5)
The preparation method of N- (3- chlorphenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is with (7), with a chlorobenzene Amine (77mg, 0.6mmol) is raw material, and TLC tracking reaction to terminal, obtains white solid N- (3- chlorphenyls) -2- (5,6- dimethyl Xanthone -4- bases)-acetamide (Ib-5):Ib-5 mass be 109mg, yield 55.7%；mp:>260℃；INFRARED SPECTRUM IR νmax (KBr)/cm-1:3280,1655,1595,1414,1334,1229,763；Hydrogen is composed1HNMR(CDCl3,500MHz)δ:8.27(dd, J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.08 (d, J=8.0Hz, 1H, Ar-H8), 7.71 (d, J=6.5Hz, 1H, Ar- ), H3 7.62 (s, 1H, Ar-H2'), 7.46 (br, 1H, NH), 7.36 (t, J=7.8Hz, 1H, Ar-H2), 7.29 (t, J= 7.5Hz, 1H, Ar-H5'), 7.22-7.19 (m, 1H+1H, Ar-H7+Ar-H6'), 7.07 (d, J=8.0Hz, 1H, Ar-H4'), 4.07(s,2H,Ar-CH2),2.43(s,3H,Ar-CH3),2.41(s,3H,Ar-CH3)；EI-MS m/z (%):391/393(M+,45/14),265(21),264(98),238(100),237(71),209(40),208(23),165(30)；Elemental analysis (C23H18ClNO3):Measured value:C,77.27；H,5.54；N, 3.46%；Calculated value:C,70.50；H,4.63；N, 3.57%.
(12) preparation of N- (3,4- dichlorophenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-6)
The preparation method of N- (3,4- dichlorophenyls) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is with (7), with 3, 4- dichloroanilines (97mg, 0.6mmol) are raw material, and TLC tracking reaction to terminal, obtains beige solid N- (3,4- dichloro-benzenes Base) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-6):Ib-6 mass be 125mg, yield 58.6%；mp:216- 220℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3322,3232,2928,1652,1601,1477,1412,1384,1332,1229, 764；Hydrogen is composed1H NMR(CDCl3,400MHz)δ:8.28(dd,J1=1.6Hz, J2=8.0Hz, 1H, Ar-H1), 8.08 (d, J= 8.4Hz, 1H, Ar-H8), 7.76 (s, 1H, Ar'), 7.64 (d, J=6.8Hz, 1H, Ar-H3), 7.39-7.32 (m*,1H+2H+ 1H, Ar-H2+Ar'+NH), 7.20 (d, J=8.4Hz, 1H, Ar-H7), 4.00 (s, 2H, Ar-CH2),2.45(s,3H,Ar- CH3),2.44(s,3H,Ar-CH3)*overlap；EI-MS m/z (%):425(M+,16),282(48),264(65),251 (28),237(100),223(9),209(18),165(34)；Elemental analysis (C23H17Cl2NO3):Measured value:C,64.92；H, 3.59；N, 3.35%；Calculated value:C,64.80；H,4.02；N, 3.29%.
(13) preparation of N- (the chloro- 4- fluorophenyls of 3-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-7)
The preparation method of N- (the chloro- 4- fluorophenyls of 3-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is same (7), with The chloro- 4- fluoroanilines (87mg, 0.6mmol) of 3- are raw material, and TLC tracking reaction to terminal, obtains white solid N- (the chloro- 4- fluorobenzene of 3- Base) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-7):Ib-7 mass be 81mg, yield 39.6%；mp:>260 ℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3244,1655,1603,1501,1384,1230,765；Hydrogen is composed1H NMR(CDCl3, 500MHz)δ:8.26(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.08 (d, J=8.0Hz, 1H, Ar-H8), 7.71- 7.67 (m, 1H+1H, Ar-H3+Ar'), 7.44 (br, 1H, NH), 7.37 (t, J=7.5Hz, 1H, Ar-H2), 7.28-7.25 (m, 1H, Ar'), 7.21 (d, J=8.0Hz, 1H, Ar-H7), 7.05 (t, J=8.8Hz, 1H, Ar'), 4.07 (s, 2H, Ar-CH2), 2.44(s,3H,Ar-CH3),2.41(s,3H,Ar-CH3)；EI-MS m/z (%):409/411(M+,35/11),265(27), 264(100),238(59),237(75),209(37),208(27),165(29)；Elemental analysis (C23H17ClFNO3):Measured value: C,67.16；H,4.14；N, 3.36%；Calculated value:C,67.40；H,4.18；N, 3.42%.
(14) N- (3- trifluoromethyl -4- nitrobenzophenones) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-8) Preparation
The preparation method of N- (3- trifluoromethyl -4- nitrobenzophenones) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide With (7), with m-trifluoromethyl paranitroanilinum (124mg, 0.6mmol) for raw material, TLC tracking reaction to terminal, obtains yellow and consolidates Body N- (3- trifluoromethyl -4- nitrobenzophenones) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-8):Ib-8 mass is 68mg, yield 28.9%；mp:110-113℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3483,3373,2928,1626,1609, 1492,1329,1262,1149,1039；Hydrogen is composed1H NMR(CDCl3,400MHz)δ:8.28(dd,J1=1.6Hz, J2= 8.0Hz,1H,Ar-H1),8.09(s,1H,Ar'),8.07(d*, J=8.0Hz, 1H+1H, Ar-H8+NH), 8.04-8.03 (m, 2H, Ar'), 7.66 (d, J=6.4Hz, 1H, Ar-H3), 7.35 (t, J=7.8Hz, 1H, Ar-H2), 7.19 (d, J=8.4Hz, 1H,Ar-H7),4.03(s,2H,Ar-CH2),2.43(s,3H,Ar-CH3),2.42(s,3H,Ar-CH3)*overlap；EI-MS M/z (%):470(M+,10),440(3),367(7),282(51),264(13),237(100),208(11),165(20)；EI- High resolution mass spectrum (C24H17F3N2O5):Measured value M+(470.1103 calculated value 470.1090).
(15) preparation of N- (the chloro- pyridine -2- bases of 5-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-9)
The preparation method of N- (the chloro- pyridine -2- bases of 5-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is same (7), with The chloro- 2-aminopyridine of 5- (77mg, 0.6mmol) is raw material, and TLC tracking reaction to terminal, obtains beige solid N- (the chloro- pyrroles of 5- Pyridine -2- bases) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-9):Ib-9 mass be 60mg, yield 34.7%；mp: 179-182℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3254,2927,1654,1601,1493,1413,1333,1228,763；Hydrogen Spectrum1H NMR(CDCl3,400MHz)δ:8.27(dd,J1=1.6Hz, J2=8.0Hz, 1H, Ar-H1), 8.23 (d, J=8.8Hz, 1H, Ar'), 8.12 (d, J=2.0Hz, 1H, Ar'), 8.02 (d, J=8.4Hz, 1H, Ar-H8), 7.81 (br, 1H, NH), 7.68-7.64(m*, 1H+1H, Ar-H3+Ar'), 7.33 (t, J=7.6Hz, 1H, Ar-H2), 7.13 (d, J=8.4Hz, 1H, Ar-H7),4.03(s,2H,Ar-CH2),2.43(s,3H,Ar-CH3),2.42(s,3H,Ar-CH3)*overlap；EI-MS m/z (%):392(M+,3),309(3),296(20),282(60),264(12),237(100),209(15),165(26)；EI- high Resolution Mass Spectrometry (C22H17 35ClN2O3):Measured value M+(392.0926 calculated value 392.0928).
(16) preparation of N- (the bromo- pyridine -2- bases of 5-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-10)
The preparation method of N- (the bromo- pyridine -2- bases of 5-) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is same (7), with The bromo- 2-aminopyridine of 5- (104mg, 0.6mmol) is raw material, and TLC tracking reaction to terminal, obtains brown solid N- (the bromo- pyrroles of 5- Pyridine -2- bases) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-10):Ib-10 mass be 36mg, yield 16.5%； mp:172-175℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3324,2927,1654,1601,1493,1412,1332,1228, 763；Hydrogen is composed1H NMR(CDCl3,400MHz)δ:8.25 (d, J=2.0Hz, 1H, Ar'), 8.22 (dd, J1=1.6Hz, J2= 8.0Hz, 1H, Ar-H1), 8.18 (d, J=8.8Hz, 1H, Ar'), 8.00 (d, J=8.0Hz, 1H, Ar-H8), 7.82 (br, 1H, NH),7.77(dd,J1=2.0Hz, J2=8.8Hz, 1H, Ar'), 7.64 (d, J=6.4Hz, 1H, Ar-H3), 7.30 (t, J= 7.6Hz, 1H, Ar-H2), 7.11 (d, J=8.0Hz, 1H, Ar-H7), 4.00 (s, 2H, Ar-CH2),2.41(s,3H,Ar-CH3), 2.40(s,3H,Ar-CH3)；EI-MSm/z (%):436/438(M+,2/2),296(13),282(3),264(4),237(29), 224(6),209(3),165(5)；EI- high resolution mass spectrums (C22H17 79BrN2O3):Measured value M+436.0429 (calculated values 436.0423)。
(17) N- (4- hydroxy 3-methoxybenzenes base) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-11) It prepares
The preparation method of N- (4- hydroxy 3-methoxybenzenes base) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide is same (7), with chinese cymbidium amine (92mg, 0.6mmol) for raw material, TLC tracking reaction to terminal, obtains white solid N- (4- hydroxyl -3- methoxies Base phenyl) -2- (5,6- dimethylxanthene ketone -4- bases)-acetamide (Ib-11):Ib-11 mass be 109mg, yield 52.0%； mp:244-247℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3507,3283,2925,1653,1631,1601,1515,1276, 1209,763；Hydrogen is composed1H NMR(CDCl3,500MHz)δ:8.31(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.10 (d, J=8.5Hz, 1H, Ar-H8), 7.69 (d, J=6.5Hz, 1H, Ar-H3), 7.38 (t, J=7.5Hz, 1H, Ar-H2), 7.23 (d, J=8.0Hz, 1H, Ar-H7), 6.68 (d, J=8.5Hz, 1H, Ar'), 6.61 (d, J=7.5Hz, 1H, Ar'), 6.58 (s, 1H, Ar'), 5.77 (br, 1H, OH), 5.49 (s, 1H, NH), 4.33 (d, J=6.0Hz, 2H,CH2 NH),3.97(s, 2H,Ar-CH2),3.62(s,3H,OCH3),2.44(s,3H,Ar-CH3),2.31(s,3H,Ar-CH3)；EI-MS m/z (%): 417(M+,57),281(20),238(97),209(14),165(19),152(17),137(100),122(19)；EI- high-resolution Mass spectrum (C25H23NO5):Measured value M+(417.1568 calculated value 417.1576).
(18) preparation of 2- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl acetate (Ib-12)
The preparation method of 2- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl acetate is with (7), with glycine Ethyl ester (62mg, 0.6mmol) be raw material, TLC tracking reaction to terminal, obtain white solid 2- (2- (5,6- dimethylxanthene ketone- 4- yls) acetamido) ethyl acetate (Ib-12):Ib-12 mass be 177mg, yield 96.5%；mp:132-134℃；INFRARED SPECTRUM IRνmax(KBr)/cm-1:3297,2928,1750,1654,1601,1412,1213,763；Hydrogen is composed1H NMR(CDCl3, 500MHz)δ:8.15(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 7.98 (d, J=8.0Hz, 1H, Ar-H8), 7.67 (dd,J1=1.5Hz, J2=7.5Hz, 1H, Ar-H3), 7.28 (t, J=7.5Hz, 1H, Ar-H2), 7.14 (d, J=8.5Hz, 1H, Ar-H7), 6.49 (br, 1H, NH), 4.15 (q, J=7.0Hz, 2H, OCH2 CH3), 4.04 (d, J=6.0Hz, 2H, NHCH2 ),3.94(s,2H,Ar-CH2),2.40(s,3H,Ar-CH3),2.38(s,3H,Ar-CH3), 1.22 (t, J=7.0Hz, 3H,CH2 CH3 )；EI-MS m/z (%):367(M+,35),296(11),264(29),238(94),224(35),209(7),195 (6),165(14)；EI- high resolution mass spectrums (C21H21NO5):Measured value M+(367.1416 calculated value 367.1420).
(19) preparation of 3- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl propionate (Ib-13)
The preparation method of 3- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl propionate is with (7), with β-the third ammonia Acetoacetic ester (70mg, 0.6mmol) is raw material, and TLC tracking reaction to terminal, obtains white solid 3- (2- (5,6- dimethylxanthenes Ketone -4- bases) acetamido) ethyl propionate (Ib-13):Ib-13 mass be 176mg, yield 92.4%；mp:120-123℃；It is red Outer spectrum IR νmax(KBr)/cm-1:3290,2927,1727,1662,1640,1414,1213,766；Hydrogen is composed1H NMR(CDCl3, 500MHz)δ:8.30(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.08 (d, J=8.0Hz, 1H, Ar-H8), 7.65 (dd,J1=1.5Hz, J2=7.5Hz, 1H, Ar-H3), 7.36 (t, J=7.5Hz, 1H, Ar-H2), 7.21 (d, J=8.5Hz, 1H,Ar-H7),6.16(br,1H,NH),3.90(s,2H,Ar-CH2), 3.82 (q, J=7.2Hz, 2H, OCH2 CH3),3.52- 3.45(m,2H,NHCH 2),2.453(s*,6H,2×Ar-CH3),2.449(t*, J=6.8Hz, 2H, NHCH2 CH2 ),1.07(t,J =7.3Hz, 3H, CH2 CH3 )*overlap；EI-MS m/z (%):381(M+,28),367(4),336(5),264(10),238 (100),223(5),209(5),195(4)；EI- high resolution mass spectrums (C22H23NO5):Measured value M+381.1566 (calculated values 381.1576)。
(20) preparation of 4- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl benzoate (Ib-14)
The preparation method of 4- (2- (5,6- dimethylxanthene ketone -4- bases) acetamido) ethyl benzoate is with (7), with to ammonia Yl benzoic acid ethyl ester (99mg, 0.6mmol) is raw material, and TLC tracking reaction to terminal, obtains white solid 4- (2- (5,6- dimethyl Xanthone -4- bases) acetamido) ethyl benzoate (Ib-14):Ib-14 mass be 170mg, yield 79.3%；mp:271-273 ℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3238,1716,1668,1654,1596,1530,1406,1268,1175,1099, 763；Hydrogen is composed1H NMR(CDCl3,500MHz)δ:8.29(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 8.09 (d, J= 8.0Hz, 1H, Ar-H8), 7.99 (d, J=8.5Hz, 2H, Ar'), 7.73 (dd, J1=1.5Hz, J2=7.5Hz, 1H, Ar-H3), 7.63 (br, 1H, NH), 7.57 (d, J=8.5Hz, 2H, Ar'), 7.39 (t, J=7.8Hz, 1H, Ar-H2), 7.22 (d, J= 7.5Hz, 1H, Ar-H7), 4.36 (q, J=7.0Hz, 2H, OCH2 CH3),4.11(s,2H,Ar-CH2),2.44(s,3H,Ar- CH3),2.42(s,3H,Ar-CH3), 1.38 (t, J=6.8Hz, 3H, CH2 CH3 )；EI-MS m/z (%):429(M+,86),384 (15),264(57),238(100),209(12),192(11),165(52),120(21)；ESI-MS:430.2[M+H]+, 452.2[M+Na]+；EI- high resolution mass spectrums (C26H23NO5):Measured value M+(429.1561 calculated value 429.1576).
Embodiment 3
Reaction equation C：
(21) preparation of 2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Ic)
By 2- (5,6- dimethylxanthene ketone -4- bases)-ethyl acetate (155mg, 0.5mmol) and 85% hydrazine hydrate (2.3mL) Hybrid Heating, back flow reaction in absolute ethyl alcohol (10mL) can continue to add hydrazine hydrate in right amount reacting fully, TLC To terminal, the reaction time is 2~10 hours for tracking reaction.It is filtered after cooling up to white solid 2- (5,6- dimethylxanthenes Ketone -4- bases)-acethydrazide (Ic):Ic mass be 140mg, yield 94.6%；mp:239-241℃；INFRARED SPECTRUM IR νmax(KBr)/ cm-1:3290,3063,2915,1654,1639,1618,1602,1413,1332,1228,758；Hydrogen is composed1H NMR(DMSO-d6, 500MHz)δ:9.34(s,1H,NHNH2),8.08(dd,J1=1.5Hz, J2=8.0Hz, 1H, Ar-H1), 7.93 (d, J= 8.0Hz, 1H, Ar-H8), 7.77 (d, J=6.5Hz, 1H, Ar-H3), 7.41 (t, J=7.5Hz, 1H, Ar-H2), 7.31 (d, J =8.0Hz, 1H, Ar-H7), 4.27 (s, 2H, NHNH 2),3.82(s,2H,Ar-CH2),2.450(s,3H,Ar-CH3),2.446 (s,3H,Ar-CH3)；EI-MS m/z (%):296(M+,53),265(72),237(100),209(10),194(6),178(6), 165(17),152(4)；Elemental analysis (C17H16N2O3):Measured value:C,68.83；H,5.38；N, 9.61%；Calculated value:C, 68.91；H,5.44；N, 9.45%.
(22) preparation of N'- (2- hydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-1)
By 2- obtained in above-mentioned (21) (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Ic (44mg, 0.15mmol) with Salicylide (20mg, 0.165mmol) heats in absolute ethyl alcohol (20mL), back flow reaction, and TLC tracking reaction to terminal, is reacted Time is 2~12 hours；It cools down after reaction, crude product is obtained by filtration, recrystallized with absolute ethyl alcohol after crude product is dried to obtain the final product White solid N'- (2- hydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-1):Id-1 mass is 59mg, yield 99.2%；mp:247-249℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3247,3031,1688,1639,1620, 1490,1414,1273,1226,752；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:12.03and 11.54(both s, total 1H,NH),11.10and 10.12(both s,total 1H,OH),8.47and 8.37(both s,total 1H, ), N=CH 8.11and 8.09 (both d, J=8.8Hz, total 1H, Ar-H1), 7.93 (d, J=8.0Hz, 1H, Ar- ), H8 7.84and 7.83 (both d, J=6.5Hz, total 1H, Ar-H3), 7.69and 7.54 (both d, J= 7.6Hz, total 1H, Ar'), 7.45and 7.43 (both t, J=7.6Hz, total 1H, Ar-H2), 7.30-7.23 (m*, 1H+1H, Ar-H7+Ar'), 6.91and 6.77 (both t, J=7.5Hz, total 2H, Ar'), 4.40and 4.03 (both s,total 2H,Ar-CH2),2.44,2.40,2.39and 2.33(all s,total 6H,2×Ar-CH3)* overlap；EI-MS m/z (%):400(M+,28),296(11),281(9),265(30),238(100),209(15),194 (9),165(28)；Elemental analysis (C24H20O2N4):Measured value:C,71.86；H,4.97；N, 7.11%；Calculated value:C,71.99； H,5.03；N, 7.00%.
(23) preparation of N'- (4- hydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-2)
The preparation method of N'- (4- hydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide is same (22), With parahydroxyben-zaldehyde (20mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains brown solid N'- (4- hydroxyls Benzene methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-2):Id-2 mass be 31mg, yield 52.1%； mp:259-262℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3360,2964,1676,1638,1604,1496,1413,1228, 762；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.59and 11.38(both s,total 1H,NH),9.90and 9.87 (both s, total 1H, OH), 8.16and 7.97 (both s, total 1H, N=CH), 8.10and 8.08 (both dd,J1=1.2Hz, J2=7.6Hz, total 1H, Ar-H1), 7.94 (d, J=8.0Hz, 1H, Ar-H8), 7.82 (d, J=7.2Hz, 1H, Ar-H3), 7.53and 7.52 (both d, J=8.4Hz, total 2H, Ar'), 7.43and 7.42 (both t, J=7.6Hz, total 1H, Ar-H2), 7.30 (d, J=8.0Hz, 1H, Ar-H7), 6.77 (both of 6.82and D, J=8.8Hz, total 2H, Ar'), 4.39and 3.98 (both s, total 2H, Ar-CH2),2.44,2.41, 2.40and 2.33(all s,total 6H,2×Ar-CH3)；EI-MS m/z (%):400(M+,26),281(14),265 (21),237(100),209(15),194(9),165(30),136(25)；EI- high resolution mass spectrums (C24H20N2O4):Measured value M+ (400.1425 calculated value 400.1423).
(24) system of N'- (3- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-3) It is standby
The preparation method of N'- (3- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide is same (22), with m-methoxybenzaldehyde (22mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains light yellow solid N'- (3- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-3):Id-3 mass be 50mg, yield 81.2%；mp:240-241℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3182,3077,2966,1667,1599,1409,1269, 764；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.81and 11.62(both s,total 1H,NH),8.25and 8.05 (both s, total 1H, N=CH), 8.10and 8.09 (both dd, J1=1.2Hz, J2=7.6Hz, total 1H, ), Ar-H1 7.93 (d, J=8.0Hz, 1H, Ar-H8), 7.84 (d, J=6.8Hz, 1H, Ar-H3), 7.43 (both of 7.44and T, J=7.2Hz, total 1H, Ar-H2), 7.38-7.26 (m*,1H+3H,Ar-H7+Ar'),7.01-6.97(m,1H,Ar'), 4.44and 4.02(both s,total 2H,Ar-CH2),3.79and 3.77(both s,total 3H,CH3O),2.41, 2.40and 2.33(all s,total 6H,2×Ar-CH3)*overlap；EI-MS m/z (%):414(M+,36),281 (28),265(29),237(100),209(11),194(6),165(16),150(14)；Elemental analysis (C25H22O2N4):It measures Value:C,72.56；H,5.27；N, 6.81%；Calculated value:C,72.45；H,5.35；N, 6.76%.
(25) system of N'- (4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-4) It is standby
The preparation method of N'- (4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide is same (22), with P-methoxybenzal-dehyde (22mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains white solid N'- (4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-4):Id-4 mass be 53mg, yield 86.1%；mp:>260℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3075,2968,1669,1648,1384,1246,1173,764； Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:8.21and 8.02 (both s, total 1H, N=CH), 8.11and 8.09 (both dd,J1=2.0Hz, J2=8.0Hz, total 1H, Ar-H1), 7.94 (d, J=8.4Hz, 1H, Ar-H8), 7.83 (d, J=8.0Hz, 1H, Ar-H3), 7.65and 7.64 (both d, J=8.8Hz, total 2H, Ar'), 7.44and 7.43 (both t, J=7.6Hz, total 1H, Ar-H2), 7.31 (d, J=8.8Hz, 1H, Ar-H7), 7.01-6.94 (both d, J =8.8Hz, total 2H, Ar'), 4.42and 4.00 (both s, total 2H, Ar-CH2),3.80and 3.79(both s,total 3H,CH3O),2.41,2.40and 2.34(all s,total 6H,2×Ar-CH3)；EI-MS m/z (%):414 (M+,26),281(21),264(18),237(100),209(13),165(25),150(50),134(19)；Elemental analysis (C25H22N2O4):Measured value:C,72.27；H,5.46；N, 6.82%；Calculated value:C,72.45；H,5.35；N, 6.76%.
(26) N'- (5- chlorine-2-hydroxyl benzene methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-5) It prepares
The preparation method of N'- (5- chlorine-2-hydroxyl benzene methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide is same (22), with 5- chloro-salicylic aldehydes (26mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains light yellow solid N'- (5- Chlorine-2-hydroxyl benzene methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-5):Id-5 mass be 51mg, yield 79.0%；mp:257-260℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3188,2959,1673,1630,1410,1341,1230, 763；Hydrogen is composed1HNMR(DMSO-d6,400MHz)δ:12.12and 11.62(both s,total 1H,NH),11.14and 10.42 (both s, total 1H, OH), 8.44and 8.31 (both s, total 1H, N=CH), 8.10and 8.08 (both dd,J1=2.0Hz, J2=8.2Hz, total 1H, Ar-H1), 7.92and 7.91 (both d, J=8.0Hz, Total 1H, Ar-H8), 7.83and 7.81 (both d, J=6.8Hz, total 1H, Ar-H3), 7.69and 7.64 (both d, J=2.6Hz, total 1H, Ar'), 7.44and 7.42 (both t, J=8.0Hz, total 1H, Ar-H2), 7.31-7.23(m*,1H+1H,Ar-H7+Ar'),6.93-6.90(m,1H,Ar'),4.40and4.02(both s,total 2H,Ar-CH2),2.39,2.38,2.36and 2.31(all s,total 6H,2×Ar-CH3)*overlap；EI-MS m/z (%):434/436(M+,14/5),368(20),296(28),265(51),237(100),209(13),194(10),165 (21)；Elemental analysis (C24H19ClN2O4):Measured value:C,66.23；H,4.36；N, 6.41%；Calculated value:C,66.29；H, 4.40；N, 6.44%.
(27) N'- (3,4,5- trimethoxy-benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id- 6) preparation
The preparation side of N'- (3,4,5- trimethoxy-benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Method is with (22), and with 3,4,5-Trimethoxybenzaldehyde (32mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains white Color solid N'- (3,4,5- trimethoxy-benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-6):Id-6 Quality is 66mg, yield 93.7%；mp:>260℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3199,3014,2941,1660, 1577,1416,1329,1234,1129,762；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:8.20and 8.00(both s, Total 1H, N=CH), 8.12and 8.10 (both d, J=8.0Hz, total 1H, Ar-H1), 7.94 (d, J=8.4Hz, 1H, Ar-H8), 7.85and 7.83 (both d, J=6.8Hz, total 1H, Ar-H3), 7.45and 7.44 (both t, J =8.0Hz, total 1H, Ar-H2), 7.31 (d, J=8.4Hz, 1H, Ar-H7), 7.03and 7.02 (both s, total 2H,Ar'),4.45and 4.02(both s,total 2H,Ar-CH2),3.81,3.79and 3.69(all s,total 9H,3×OCH3),2.42,2.41,2.34and 2.33(all s,total 6H,2×Ar-CH3)；EI-MS m/z (%):474 (M+,89),368(32),265(17),237(100),209(26),193(92),178(29),165(24)；Elemental analysis (C27H26N2O6):Measured value:C,68.56；H,5.47；N, 6.11%；Calculated value:C,68.34；H,5.52；N, 5.90%.
(28) N'- (3,4- dihydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-7) It prepares
The preparation method of N'- (3,4- dihydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide is same (22), with 3,4- 4-dihydroxy benzaldehydes (23mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains light yellow solid N'- (3,4- dihydroxy benzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-7):Id-7 mass is 43mg, yield 69.5%；mp:>260℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3480,3246,2965,1666,1601,1444, 1284,762；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.56and 11.34(both s,total 1H,NH),9.41, 9.38,9.26and 9.19(all s,total 2H,2×OH),8.11-8.06(m*,total 1H,Ar-H1),8.08and 7.91 (both s, total 1H, N=CH), 7.91 (d, J=8.0Hz, 1H, Ar-H8), 7.83and 7.81 (both d, J= 7.2Hz, total 1H, Ar-H3), 7.43and 7.42 (both t, J=7.6Hz, total 1H, Ar-H2), 7.27 (d, J= 7.6Hz, 1H, Ar-H7), 7.22and 7.20 (both d, J=2.0Hz, total1H, Ar'), 6.92 (both of 6.94and dd,J1=2.0Hz, J2=8.0Hz, total 1H, Ar'), 6.78and 6.76 (both d, J=8.0Hz, 1H, Ar'), 4.38and 3.96(both s,total 2H,Ar-CH2),2.39,2.38and 2.30(all s,total 6H,2×Ar- CH3)*overlap；EI-MS m/z (%):416(M+,16),368(5),282(8),265(20),237(60),209(10), 165(19),152(18)；EI- high resolution mass spectrums (C24H20N2O5):Measured value M+(416.1384 calculated value 416.1372).
(29) N'- (4- hydroxy 3-methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id- 8) preparation
The preparation side of N'- (4- hydroxy 3-methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Method is with (22), and with vanillic aldehyde (25mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains white solid N'- (4- hydroxyls Base -3- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-8):Id-8 mass is 49mg, is received Rate 76.7%；mp:230-232℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3440,3041,1650,1601,1512,1413, 1384,1273,763；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.63and 11.40(both s,total 1H,NH), 9.52and 9.49 (both s, total 1H, OH), 8.15and 7.96 (both s, total 1H, N=CH), 8.09and 8.08(both dd,J1=1.6Hz, J2=8.0Hz, total 1H, Ar-H1), 7.92and 7.91 (both d, J=8.0Hz, total 1H,Ar-H8),7.82and 7.81(both dd,J1=2.0Hz, J2=6.8Hz, total 1H, Ar-H3), 7.43and 7.42 (both t, J=7.6Hz, total 1H, Ar-H2), 7.29-7.26 (m*,1H+1H,Ar-H7+Ar'), 7.10and 7.08(both dd,J1=1.6Hz, J2=8.4Hz, total 1H, Ar'), 6.83and 6.80 (both d, J= 8.4Hz,total 1H,Ar'),4.40and 3.97(both s,total 2H,Ar-CH2),3.79and 3.78(both s, total 3H,OCH3),2.39,2.38and 2.31(all s,total 6H,2×Ar-CH3)*overlap；EI-MS m/z (%):430(M+,35),282(17),265(13),237(100),209(14),194(9),165(43),149(22)；Element Analyze (C25H22N2O5):Measured value:C,69.91；H,5.19；N, 6.58%；Calculated value:C,69.76；H,5.15；N, 6.51%.
(30) N'- (4- hydroxy-3-methoxy -2- nitrobenzoyls alkenyl) -2- (5,6- dimethylxanthene ketone -4- bases)-second The preparation of hydrazides (Id-9)
N'- (4- hydroxy-3-methoxy -2- nitrobenzoyls alkenyl) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Preparation method with (22), with 2- nitro vanillins (33mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains shallow Yellow solid N'- (4- hydroxy-3-methoxy -2- nitrobenzoyls alkenyl) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-9):Id-9 mass be 68mg, yield 96.3%；mp:>260℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3184,2949, 1684,1634,1603,1528,1307,1229,756；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.62and 10.98 (both s, total 1H, NH), 9.73 (s, 1H, OH), 8.13and 7.91 (both s, total 1H, N=CH), 8.10 (dd,J1=1.6Hz, J2=8.4Hz, 1H, Ar-H1), 7.94 (d, J=8.4Hz, 1H, Ar-H8), 7.80 (d, J=7.2Hz, total 1H,Ar-H3),7.45-7.38(m*, 1H+1H, Ar-H2+Ar'), 7.31 (d, J=8.0Hz, 1H, Ar-H7), 7.10 (d, J=9.2Hz, 1H, Ar'), 4.24and 3.98 (boths, total 2H, Ar-CH2),3.85and 3.83(both s, total 3H,OCH3),2.45,2.41,2.33and 2.31(all s,total6H,2×Ar-CH3)*overlap；EI-MS M/z (%):475(M+,12),281(4),265(19),237(100),209(11),194(7),178(6),165(21)；Element Analyze (C25H21N3O7):Measured value:C,63.32；H,4.46；N, 8.62%；Calculated value:C,63.15；H,4.45；N, 8.84%.
(31) N'- (3- hydroxyl -4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id- 10) preparation
The preparation side of N'- (3- hydroxyl -4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Method is with (22), and with isovanillin (25mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains light yellow solid N'- (3- hydroxyl -4- methoxybenzenes methene) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-10):Id-10 mass is 37mg, yield 57.9%；mp:259-262℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3289,3080,2952,1673,1644, 1602,1412,1276,1213,764；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.62and 11.42(both s, total 1H,NH),9.26and 9.21(both s,total 1H,OH),8.12and 7.95(both s,total 1H,N =CH), 8.08 (dd, J1=1.6Hz, J2=8.0Hz, 1H, Ar-H1), 7.91 (d, J=8.0Hz, 1H, Ar-H8), 7.83and 7.81 (both d, J=7.6Hz, total 1H, Ar-H3), 7.43and 7.42 (both t, J=8.0Hz, total 1H, Ar-H2),7.27-7.22(m*,1H+1H,Ar-H7+Ar'),7.06and7.04(both dd,J1=2.0Hz, J2=8.4Hz, Total 1H, Ar'), 6.96and 6.94 (both d, J=8.0Hz, total 1H, Ar'), 4.40and 3.97 (both s, total 2H,Ar-CH2),3.81and 3.80(both s,total 3H,OCH3),2.42,2.39,2.37and 2.30(all s,total 6H,2×Ar-CH3)*overlap；EI-MS m/z (%):430(M+,31),282(23),265(15),237 (100),209(13),194(8),165(41),149(20)；EI- high resolution mass spectrums (C25H22N2O5):Measured value M+430.1541 (calculated value 430.1529).
(32) N'- (benzo [d] [1,3] dioxolane -5- methenes) -2- (5,6- dimethylxanthene ketone -4- bases)-acetyl The preparation of hydrazine (Id-11)
N'- (benzo [d] [1,3] dioxolane -5- methenes) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Preparation method is with (22), and with heliotropin (25mg, 0.165mmol) for raw material, TLC tracking reaction to terminal, obtains white solid N'- (benzo [d] [1,3] dioxolane -5- methenes) -2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (Id-11): Id-11 mass be 58mg, yield 91.2%；mp:250-253℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3204,3040,2908, 1670,1654,1451,1260,1036,760；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:11.71and 11.48(both S, total 1H, NH), 8.18and 7.98 (both s, total 1H, N=CH), 8.10and 8.08 (both d, J= 8.0Hz, total 1H, Ar-H1), 7.92 (d, J=8.4Hz, 1H, Ar-H8), 7.82 (d, J=6.8Hz, 1H, Ar-H3), 7.44and 7.42 (both t, J=7.2Hz, total 1H, Ar-H2), 7.33-7.26 (m*,1H+1H,Ar-H7+Ar'), 7.15and 7.13 (both d, J=8.0Hz, total 1H, Ar'), 6.98and 6.94 (both d, J=8.0Hz, total 1H,Ar'),6.07and 6.06(both s,total 2H,OCH2O),4.40and3.98(both s,total 2H,Ar- CH2),2.40,2.38and 2.31(all s,total 6H,2×Ar-CH3)*overlap；EI-MSm/z (%):428(M+, 55),281(17),264(20),237(100),209(11),194(6),164(42),147(17)；Elemental analysis (C25H20N2O5):Measured value:C,69.87；H,4.66；N, 6.62%；Calculated value:C,70.08；H,4.71；N, 6.54%.
Embodiment 4
Reaction equation D：
(33) preparation of 4- pi-allyls -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) thiosemicarbazides (Ie-1)
By 2- obtained in above-mentioned (21) (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Ic (59mg, 0.2mmol) and Allyl isothiocyanate (20mg, 0.2mmol) is heated to reflux in absolute ethyl alcohol (10mL), and TLC tracking reaction to terminal, is reacted Time is 6~12 hours；It cools down after reaction, solid is obtained by filtration, recrystallize white solid with absolute ethyl alcohol after drying Body 4- pi-allyls -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) thiosemicarbazides (Ie-1):Ie-1 mass is 19mg, is received Rate 24.1%；mp:167-170℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3250,3068,2973,1698,1644,1601, 1542,1494,1414,1336,1215,763；Hydrogen is composed1H NMR(DMSO-d6,500MHz)δ:10.11(brs,1H,C(O)NHNH),9.39(s,1H,C(O)NHNH),8.13(brs,1H,C(S)NH),8.10(dd,J1=2.0Hz, J2=8.0Hz, 1H, ), Ar-H1 7.94 (d, J=8.0Hz, 1H, Ar-H8), 7.81 (d, J=7.0Hz, 1H, Ar-H3), 7.43 (t, J=7.5Hz, 1H, Ar-H2), 7.32 (d, J=8.5Hz, 1H, Ar-H7), 5.87-5.79 (m, 1H, CH2 CH=CH2),5.14(dd,J1= 1.5Hz,J2=17.5Hz, 1H ,=CHH,cis),5.06(dd,J1=1.0Hz, J2=10.0Hz, 1H ,=CHH,trans), 4.13-4.09(brs,2H,CH2 CH=CH2),3.97(s,1H,Ar-CHH),3.96(s,1H,Ar-CHH),2.48(s,3H,Ar- CH3),2.46(s,3H,Ar-CH3)；EI-MS m/z (%):384([M-C+H]+,3),368(3),353(2),339(1),296 (14),265(21),256(15),237(36)；ESI- high resolution mass spectrums (C21H21N3O3S-H):Measured value [M-H]-394.1229 (calculated value 394.1225).
(34) (R) -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) thiosemicarbazides (Ie-2) It prepares
(R) preparation method of -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) thiosemicarbazides is same (33), with (R)-isothiocyanic acid methyl benzyl ester (33mg, 0.2mmol) raw material, TLC tracking reaction to terminal, obtains white solid (R) -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) thiosemicarbazides (Ie-2):Ie-2 mass is 35mg, yield 38.3%；mp:229-232℃；+88.5°(c 0.1,EtOH)；INFRARED SPECTRUM IR νmax(KBr)/cm-1: 3242,3027,2974,1681,1647,1602,1537,1414,1216,760；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ: 10.13(br,1H,C(O)NHNH),9.37(s,1H,C(O)NHNH),8.08(dd,J1=1.6Hz, J2=8.0Hz, 1H, Ar- H1),8.06(brs,1H,C(S)NH), 7.92 (d, J=8.4Hz, 1H, Ar-H8), 7.82 (d, J=7.2Hz, 1H, Ar-H3), 7.41 (t, J=7.6Hz, 1H, Ar-H2), 7.32-7.28 (m, 1H+4H, Ar-H7+Ar'), 7.22 (t, J=6.8Hz, 1H, Ar'),5.64-5.60(m,1H,CHCH3),3.96(s,2H,Ar-CH2),2.44(s,3H,Ar-CH3),2.42(s,3H,Ar- CH3), 1.44 (d, J=7.2Hz, 3H, CHCH 3)；EI-MSm/z (%):459(M+,1),338(5),321(2),305(2),296 (77),265(100),237(100),209(17)；ESI- high resolution mass spectrums (C26H25N3O3S-H):Measured value [M-H]- (458.1546 calculated value 458.1538).
(35) (S) -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) thiosemicarbazides (Ie-3) It prepares
(S) preparation method of -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) thiosemicarbazides is same (33), with (S)-isothiocyanic acid methyl benzyl ester (33mg, 0.2mmol) for raw material, TLC tracking reaction to terminal, obtains white solid (S) -1- (2- (5,6- dimethylxanthene ketone -4- bases) acetyl) -4- (1- phenyl) thiosemicarbazides (Ie-3):Ie-3 mass is 38mg, yield 41.5%；mp:230-234℃；–81.1°(c 0.1,EtOH)；INFRARED SPECTRUM IR νmax(KBr)/cm-1: 3244,3027,2975,1682,1648,1602,1537,1414,1216,759；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ: 10.13(br,1H,C(O)NHNH),9.37(s,1H,C(O)NHNH),8.08(dd*,J1=1.6Hz, J2=8.0Hz, 1H+1H, Ar-H1+C(S)NH), 7.92 (d, J=8.0Hz, 1H, Ar-H8), 7.82 (d, J=6.8Hz, 1H, Ar-H3), 7.41 (t, J= 7.6Hz, 1H, Ar-H2), 7.32-7.27 (m, 1H+4H, Ar-H7+Ar'), 7.22 (t, J=6.8Hz, 1H, Ar'), 5.64- 5.60(m,1H,CHCH3),3.96(s,2H,Ar-CH2),2.44(s,3H,Ar-CH3),2.42(s,3H,Ar-CH3),1.44(d, J=7.2Hz, 3H, CHCH 3)*overlap；EI-MS m/z (%):382([M-C6H5]+,1),368(10),353(1),340 (1),296(49),265(70),237(100),209(11)；ESI- high resolution mass spectrums (C26H25N3O3S-H):Measured value [M-H]- (458.1543 calculated value 458.1538).
Embodiment 5
Reaction equation E：
(36) preparation of (E)-N'-3- hexenoyls-N-2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (If)
By 2- obtained in above-mentioned (21) (5,6- dimethylxanthene ketone -4- bases)-acethydrazide Ic (44.4mg, 0.15mmol), (E) -3- hexenoic acids (17mg, 0.15mmol), amidation process reagent dicyclohexylcarbodiimide (DCC, 37.1mg, 0.18mmol) and 1- hydroxy benzo triazoles (HOBt, 24.3mg, 0.18mmol) dimethylformamide (DMF, It 15mL) is heated in solvent, to terminal, the reaction time is 4~24 hours, and DCU is precipitated in reaction solution cool overnight for TLC tracking reaction； After filtering out DCU, mother liquor, which is poured into ice water, is precipitated solid；Crude product is filtered and recrystallizes to obtain beige solid with absolute ethyl alcohol (E)-N'-3- hexenoyls-N-2- (5,6- dimethylxanthene ketone -4- bases)-acethydrazide (If):If mass be 34.0mg, yield 57.8%；mp:172-176℃；INFRARED SPECTRUM IR νmax(KBr)/cm-1:3326,2963,1657,1602,1492,1413,1229, 763；Hydrogen is composed1H NMR(DMSO-d6,400MHz)δ:10.15 (br, 1H, NH), 9.85 (br, 1H, NH), 8.06 (d, J= 7.6Hz, 1H, Ar-H1), 7.90 (d, J=8.0Hz, 1H, Ar-H8), 7.81 (d, J=6.8Hz, 1H, Ar-H3), 7.39 (t, J =7.4Hz, 1H, Ar-H2), 7.27 (d, J=8.0Hz, 1H, Ar-H7), 5.60-5.51 (m, 1H,CH=CHCH2CH3),5.46- 5.38 (m, 1H, CH=CHCH2CH3),3.90(s,2H,Ar-CH2), 2.84 (d, J=6.4Hz, 2H, COCH2),2.44(s,3H, Ar-CH3),2.41(s,3H,Ar-CH3),1.98-1.93(m,2H,CH2 CH3), 0.90 (t, J=7.6Hz, 3H, CH2 CH3 )；EI- MS m/z (%):392(M+,21),296(27),265(63),237(100),209(13),194(8),178(8),165(26)； EI- high resolution mass spectrums (C23H24N2O4):Measured value M+(392.1742 calculated value 392.1736).
Embodiment 6
The derivative of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid tries the In-vitro Inhibitory Effect of different tumour cells It tests
1. preparation of samples
It is dissolved per 1mg samples with 20 μ L DMSO, 2 μ L is taken to be diluted with 1000 μ L culture solutions, make a concentration of 100 μ g/mL, then Concentration is extremely used with culture solution serial dilution.
2. culture medium is prepared and cell culture
The preparation of 2.1 culture mediums
Containing 800,000 units of Penicillin, 1.0g streptomysins, 10% inactivation calf serum in per 1000mL culture mediums.
The culture of 2.2 cells
By man―machine systems (people's carcinoma of endometrium Ishikawa, human lung cancer A549, human choriocarcinoma Bewo, human cervical cancer 1 Cancer HeLa and Siha, human breast carcinoma MCF-7, human leukemia HL-60, Human hepatocarcinoma cell line SMMC-7721, human lung cancer NCI-460, people's gastric gland Cancer BGC-823, purchased from Shanghai life science institute of the Chinese Academy of Sciences) it is inoculated in DMEM culture mediums, 37 DEG C are put, 5%CO2Incubator Middle culture is passed on for 3~5 days.
3. active anticancer is tested
Man―machine systems EDTA- pancreatin digestive juice is digested, and be diluted to 10 with culture medium6/ mL is added to 96 hole cells In culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, incline culture medium, addition culture The sample of the diluted various concentration of base, per 200 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2It is cultivated in incubator, 72h 10 μ L/ hole MTT (5mg/mL, purchased from Sigma) are added in cell culture well afterwards, put 37 DEG C of incubation 3h.150 μ L are added in per hole DMSO is vibrated with oscillator, and microplate reader colorimetric under 570nm wavelength is used after being completely dissolved.It is used without sample, contained with similarity condition The cell of the medium culture of same concentrations DMSO calculates institute's sample under various concentration to cancer cell in vitro strain as control Inhibiting rate (%) and sample to the half lethal concentration (IC of growth of cancer cells50)。
4. experimental result
Gained compound has carried out Anticancer Activity in vitro screening, and cancer cell line includes：People's carcinoma of endometrium Ishikawa, people Lung cancer A549, human choriocarcinoma Bewo, human cervical carcinoma HeLa and Siha, human breast carcinoma MCF-7, human leukemia HL-60, people liver Cancer BEL-7402, human lung cancer NCI-460, people sdenocarcinoma of stomach BGC-823, wherein active best compound Ib-4, Ib-5, Id-5 couple The IC of human lung cancer A549509.39 μM, 10.82 μM, 11.52 μM are respectively reached, compared with positive control sample CA-4, shows higher Inhibition tumor cell proliferation activity；Compound Ib-3 and Id-5 is to the IC of HL-60504.56 μM, 20.83 μM are respectively reached, Better than DDP.They are to the In-vitro Inhibitory Effect result (for the average value tested three times) of various cancer cells referring to table 1.
Part Vadimezan derivatives synthesized by table 1 are to the In-vitro Inhibitory Effect (IC of different cancer cells50μM)
a" nt " represents undetermined IC50Value；
b" compound Q " represents 2- (5,6- dimethylxanthene ketone -4- bases)-methyl acetate.
Embodiment 7
The internal inhibiting effect experiment of the derivative of 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid
Test sample：Compound Vadimezan, Ib-1, Ib-3 are suspended with PVP solution, and prepare corresponding control solvent. Experimental animal：ICR mouse, male, 18~22g, 39；It is provided by Zhejiang Province's Experimental Animal Center, raises and moved in clinical pharmacology Object laboratory, 25 DEG C of room temperature, drinking-water of freely ingesting.S180 knurl strains：Medical scientific institute of Zhejiang Province provides, every 7~9 days abdominal cavities Passage is primary.Modeling：S180 mouse-borne tumor animal ascites is taken, with normal saline dilution to 107/ mL, by every animal 2 × 106It connects Kind is in right oxter.Grouping：Animal is randomly divided into 4 groups, control group 11, remaining each 7.Dosage：According to preliminary result, Using compound Vadimezan 30mg/kg, remaining compound dosage is 200mg/kg, and negative control is using corresponding molten Agent；Administration route：Gavage；Administered volume：0.1mL/10g；Administration number of times：Gastric infusion, successive administration 6 from 2nd day after modeling My god, it is administered 6 times altogether.Observing time：It is observed continuously after modeling 7 days.Experiment in 7th day terminates, and puts to death animal, takes tumour, weigh, and claps According to.Statistical method：10.0 statistical packages of SPSS, one-way analysis of variance method.
The result shows that compound Ib-1, Ib-3 has certain internal inhibitory activity, wherein compound Ib-1 is in 200mg/kg 25.75% is reached to the internal inhibiting rate of mouse S180 transplantable tumors under dosage.
2 part of compounds of table is to the internal inhibiting effect of mouse S180 transplantable tumors
*p<0.05vs control；
**p<0.01vs control。

Claims (4)

1. a kind of method for the derivative for preparing 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid, selected from following chemical reaction：
(1) reaction equation A：
2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid with alcohol in toluene solvant is flowed back, is obtained through catalyst esterification Derivative I a is reacted to reflux temperature, and the reaction time is 2~10 hours；
The catalyst is in the concentrated sulfuric acid, p-methyl benzenesulfonic acid, dicyclohexylcarbodiimide, diphenylamines fluoroform sulphonate It is one or more of；
(2) reaction equation B：
2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid and arylamine or alkanamine in organic solvent are heated, tried through amidation process Derivative I b is obtained by the reaction in agent, and reaction temperature is 60~70 DEG C, and the reaction time is 4~24 hours；
The one kind of the organic solvent in dichloromethane, dimethylformamide, the amidation process reagent are selected from Dicyclohexylcarbodiimide, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide, 1- hydroxy benzo triazoles, 4- dimethylaminos One or more of pyridine；
(3) reaction equation C：
By 2- (5,6- dimethylxanthene ketone -4- bases)-ethyl acetate and hydrazine hydrate back flow reaction in absolute ethyl alcohol, derived Object Ic, that is, 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid hydrazides；Derivative I c again with aldehyde in ethanol solution through condensation reaction Derivative I d is obtained, reaction temperature is 80 DEG C, and the reaction time is 2~12 hours；
(4) reaction equation D：
Derivative I c made from reaction equation C and isothiocyanates back flow reaction in ethanol solution will be utilized, obtains derivative I e, Reaction temperature is 80 DEG C, and the reaction time is 6~12 hours；
(5) reaction equation E：
Derivative I c made from reaction equation C will be utilized to be heated with carboxylic acid in organic solvent, be obtained by the reaction through amidation process reagent Derivative I f, reaction temperature are 50~60 DEG C, and the reaction time is 4~24 hours；
The one kind of the organic solvent in dichloromethane, dimethylformamide, the amidation process reagent are selected from Dicyclohexylcarbodiimide, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide, 1- hydroxy benzo triazoles, 4- dimethylaminos One or more of pyridine；
R in above-mentioned reaction equation A, reaction equation B, reaction equation C, reaction equation D and reaction equation E1For CH3, ← HC=CH2、←C≡CH、 C3-6Cycloalkyl,R2For CH3、C3-6Cycloalkyl, halogenated pyridyl, COOR4、R3For C1-6Alkyl, C1-6Alkenyl, R4For H, C1-6Alkyl, C1-6Alkoxy, OH, NO2Or amino, R5、R6、R7、R8、R9For H, OH, C1-6 Alkyl or C3-6Cycloalkyl；
Wherein substituent group X, Y, Z H, halogen, COOR4、CF3、NO2、OH、C1-6Alkoxy, C1-6Alkyl, C3-6Cycloalkyl, Amino, CN, (CO) R5、NR6R7、C(O)NR8R9、(CH2)pR2、S(O)2NR6R7In one kind；
M is 7~17 natural number, and n is 1~17 natural number, and p is 1~17 natural number.
2. the method for the derivative according to claim 1 for preparing 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid, It is characterized in that, the catalyst in the reaction equation A is diphenylamines fluoroform sulphonate.
3. the method for the derivative according to claim 1 for preparing 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid, It is characterized in that, the organic solvent in the reaction equation B is dimethylformamide, and amidation process reagent is sub- for dicyclohexyl carbon two Amine and 1- hydroxy benzo triazoles.
4. the method for the derivative according to claim 1 for preparing 2- (5,6- dimethylxanthene ketone -4- bases)-acetic acid, It is characterized in that, the organic solvent in the reaction equation E is dimethylformamide, and amidation process reagent is sub- for dicyclohexyl carbon two Amine and 1- hydroxy benzo triazoles.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5281620A (en) * 1986-12-23 1994-01-25 Cancer Research Campaign Technology Limited Compounds having antitumor and antibacterial properties
CN101195609A (en) * 2007-09-28 2008-06-11 武汉远大制药集团有限公司 Method for producing 5,6-dimethyl xanthenone-4-acetic acid, derivant and pharmaceutical formulation produced with the method
CN101596187A (en) * 2001-09-03 2009-12-09 癌症研究科技有限公司 Anticancer combination

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2061518T3 (en) * 1986-12-23 1994-12-16 Warner Lambert Co COMPOUNDS THAT HAVE ANTITUMORAL AND ANTIBACTERIAL PROPERTIES.
FR2914640B1 (en) * 2007-04-04 2012-11-16 Centre Nat Rech Scient ISO CA-4 AND ANALOGUES: CYTOTOXIC POWERFUL, TUBULIN POLYMERIZATION INHIBITORS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5281620A (en) * 1986-12-23 1994-01-25 Cancer Research Campaign Technology Limited Compounds having antitumor and antibacterial properties
CN101596187A (en) * 2001-09-03 2009-12-09 癌症研究科技有限公司 Anticancer combination
CN101195609A (en) * 2007-09-28 2008-06-11 武汉远大制药集团有限公司 Method for producing 5,6-dimethyl xanthenone-4-acetic acid, derivant and pharmaceutical formulation produced with the method

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