CN101602687A - 6-nitro-acetophenone compounds, Preparation Method And The Use - Google Patents

6-nitro-acetophenone compounds, Preparation Method And The Use Download PDF

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CN101602687A
CN101602687A CNA200810038964XA CN200810038964A CN101602687A CN 101602687 A CN101602687 A CN 101602687A CN A200810038964X A CNA200810038964X A CN A200810038964XA CN 200810038964 A CN200810038964 A CN 200810038964A CN 101602687 A CN101602687 A CN 101602687A
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compound
formula
definition
reaction
nitro
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茆勇军
李剑峰
谢凯
李海泓
张容霞
段宏亮
郭洪利
沈敬山
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Priority to CNA200810038964XA priority Critical patent/CN101602687A/en
Priority to PCT/CN2009/000653 priority patent/WO2009149622A1/en
Priority to CN200980129186.8A priority patent/CN102105433B/en
Publication of CN101602687A publication Critical patent/CN101602687A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C07C211/46—Aniline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
    • C07C211/50—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton with at least two amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/51—Phenylenediamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring

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Abstract

The present invention relates to 6-nitro-acetophenone compounds shown in the formula I and preparation method thereof, and be used to prepare the purposes of 3-replacement-4-hydroxyquinoline compounds and 3-replacement-4-chloro quinolines, and the intermediate of formula I compound.Among the formula I, X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3Or-CO 2R 3, R wherein 3And R 3' be C1～C10 alkyl that hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replace identical or differently; Z is-NH-or-O-or formula II; R 1And R 1' be C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or aryl that C1～C10 alkyl, C1～C10 alkyloyl, aroyl, aryl that formyl radical, C1～C10 alkyl, C1～C10 alkenyl, aryl, aryl replace replace replace identical or differently; R 2Be C1～C10 alkyl, C1～C10 alkenyl or aryl, described alkyl must not replaced by halogen, alkoxyl group, aryl or the heterocyclic radical that contains 1～2 O or N, and wherein said heterocyclic radical must not replaced by C1～C10 alkyl or C1～C10 alkoxyl group; And when Z is-O-, R 1During for methyl, R 2It is not methyl.

Description

6-nitro-acetophenone compounds, Preparation Method And The Use
Technical field
The present invention relates to can be used for 6-nitro-acetophenone compounds for preparing 3-replacement-4-hydroxyquinoline compounds and 3-replacement-4-chloro quinolines and its production and use, and its intermediate.More specifically, relate to structural formula 6-nitro-acetophenone compounds shown in hereinafter formula I and preparation method thereof and be used to prepare the purposes of 3-replacement-4-hydroxyquinoline compounds (compound shown in the formula A) and 3-replacement-4-chloro quinolines (formula A ' shown in compound) with it.
Background technology
3-replacement-4-hydroxyquinoline compounds (formula A) and 3-replacement-4-chloro quinolines (formula A ') be important medicine intermediate, be preparation 3, the important intermediate of 4-two substituted quinoline derivatives.For example, 3,4-two substituted quinoline derivatives are irreversible small molecules tyrosine kinase inhibitor (Journal of Medicinal Chemistry, 46 (1): 49-63), has antitumour activity, part of compounds wherein such as EKB-569 and HKI-272 (Journal of Medicinal Chemistry, 48 (4): 1107-1131) grade is effective to treatment large bowel cancer, mammary cancer and nonsmall-cell lung cancer, entered the clinical study stage, probably can become anti-cancer agent with better market outlook.Also have Bosutinib (SKI606) (Journal of Medicinal Chemistry, 2001,44 (23), 3965-3977), also be the anti-cancer agent that gets a good chance of clinically.
Figure S200810038964XD00021
HKI-272 Bosutinib(SKI606)
When the X among the formula A was ester group, different 3,4-two substituted quinoline derivatives also had widespread use aspect antimalarial, coccidiosis (US3542781) or the treatment type ii diabetes (WO2005073229).Therefore, optimize the synthesis technique of 3-replacement-4-hydroxyquinoline compounds and 3-replacement-4-chloro quinolines, just have important practical value.
The crucial synthesis step of this compounds is the formation of the female ring of quinoline, and the synthetic many of the female ring of quinoline need use hot conditions.For example when X is cyano group, the preparation method of formula A compound is, with formula C compound in high boiling solvent, be heated to 240 ℃-260 ℃ reactions 10-20 hour (reaction formula I) (WO03093241, WO2005065181, CN101012225).Used reaction conditions is comparatively harsh, and yield is low, only is 40～50%, and high boiling solvent such as road oil generation (Dowtherm) at high temperature inevitably volatilization Working environment and operator's health is had disadvantageous effect, environment there is pollution, is not suitable for large-scale commercial production.Therefore, searching mild condition, yield height, preparation method that cost is low, environmental pollution is little, that be suitable for suitability for industrialized production just become particularly urgent.
Figure S200810038964XD00022
Reaction formula I
Summary of the invention
The inventor be devoted to seek mild condition, easy and simple to handle, yield is high, cost is low, safety and environmental protection, the 3-replacement-4-hydroxyquinoline compounds that is fit to large-scale commercial applications production and the preparation method of 3-replacement-4-chloro quinolines.Invented the 6-nitro-acetophenone compounds of structural formula shown in hereinafter formula I thus, and the 6-nitro-acetophenone compounds shown in the formula of the employing I is easy, synthesized 3-replacement-4-hydroxyquinoline compounds and 3-replacement-4-chloro quinolines with high yield.
An object of the present invention is to provide 6-nitro-acetophenone compounds.
Another object of the present invention provides the preparation method of above-mentioned 6-nitro-acetophenone compounds.
An also purpose of the present invention provides the purposes of above-mentioned 6-nitro-acetophenone compounds.
Another purpose of the present invention provides the intermediate that above-mentioned preparation method relates to.
The invention provides as shown in the formula the 6-nitro-acetophenone compounds shown in the I:
Among the formula I,
X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3Or-CO 2R 3, R wherein 3And R 3' be C1～C10 alkyl that hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replace with being same to each other or different to each other;
Z is-NH-,-O-or
Figure S200810038964XD00032
R 1And R 1' be C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or aryl that C1～C10 alkyl, C1～C10 alkyloyl, aroyl, aryl that formyl radical, C1～C10 alkyl, C1～C10 alkenyl, aryl, aryl replace replace replace with being same to each other or different to each other;
R 2Be C1～C10 alkyl, C1～C10 alkenyl or aryl, described alkyl is necessarily replaced by halogen, alkoxyl group, aryl or the heterocyclic radical (for example pyrrolidyl, piperidyl, morpholinyl, piperazinyl, high piperazinyl) that contains 1～2 O or N, and wherein said heterocyclic radical is necessarily replaced by C1～C10 alkyl or C1～C10 alkoxyl group;
And when Z is-O-, R 1During for methyl, R 2It is not methyl.
In the preferred embodiment of the invention, among the formula I,
X be cyano group, trifluoromethyl ,-NHCOR 3,-NHCOOR 3,-N=CHR 3, C1～C10 carbalkoxy or carboxyl;
Z is-NH-or-O-;
R 1Be C1～C5 alkyl, ethanoyl, propionyl, benzoyl, tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz) or trityl;
R 2For methyl, ethyl, propyl group, benzyl ,-(CH 2) n-Cl ,-(CH 2) n-Br,
Figure S200810038964XD00041
Or
Figure S200810038964XD00042
The integer of n=1～5 wherein, Alkyl is C1～C5 alkyl.
In further preferred embodiment of the present invention, among the formula I,
X is cyano group (CN), ethoxycarbonyl (COOC 2H 5), methoxycarbonyl (COOCH 3);
Z is-NH-or-O-;
R 1Be ethanoyl, benzoyl, benzyl or methyl;
R 2For ethyl ,-(CH 2) 3-Cl ,-(CH 2) 3-Br,
Figure S200810038964XD00043
Or
Figure S200810038964XD00044
Further in the embodiment preferred, formula I is in the present invention:
3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone
3 '-benzoylamino-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone
3 '-benzamido group-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone
3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-ethoxy carbonyl methyl phenyl ketone
3 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--6 '-nitro-2-cyano-acetophenone.
The present invention relates to the preparation method of the 6-nitro-acetophenone compounds shown in the formula I, it is characterized in that this method comprises:
(1) when X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3Or-CO 2R 3, R wherein 3And R 3' when being the C1 that replaces of hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl～C10 alkyl, V obtains Compound I through decarboxylic reaction by compound with being same to each other or different to each other, its reaction formula is:
Figure S200810038964XD00051
Wherein,
Z is-NH-,-O-or
Figure S200810038964XD00052
R 1And R 1' be C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or aryl that C1～C10 alkyl, C1～C10 alkyloyl, aroyl, aryl that formyl radical, C1～C10 alkyl, C1～C10 alkenyl, aryl, aryl replace replace replace with being same to each other or different to each other;
R 2Be C1～C10 alkyl, C1～C10 alkenyl or aryl, described alkyl is necessarily by halogen, alkoxyl group, aryl or contain 1～2 O or N heterocyclic radical (for example pyrrolidyl, piperidyl, morpholinyl, piperazinyl, high piperazinyl) replaces, and wherein said heterocyclic radical is necessarily replaced by C1～C10 alkyl or C1～C10 alkoxyl group;
R 4C1～C10 alkyl for hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replacement;
And when Z is-O-, R 1During for methyl, R 2It is not methyl.
Wherein, compound V can be bought by market; Or with 3, to be raw material prepare with reference to the method for embodiment 15 or embodiment 23 4-two replacement-6-nitrobenzoic acids.3,4-two replacement-6-nitrobenzoic acids can be by the market purchase or by 3,4-disubstituted benzenes methyl-formiate prepares behind nitrated, hydrolysis ester group, and also available 3-amino-4-replacement-6-nitrobenzoic acid obtains through amination, or obtains through etherificate with 3-replacement-4-hydroxyl-6-nitro-methyl benzoate.
Perhaps
(2) when X=cyano group, by the nitrated Compound D that obtains of compd B, the Compound D bromo obtains Compound I I, and Compound I I obtains Compound I through the cyano group substitution reaction, and its reaction formula is:
Figure S200810038964XD00061
Wherein Z, R 1, R 2Definition the same;
Perhaps
(3) when X=cyano group, obtain compound III by the compd B bromination, the nitrated Compound I I that obtains of compound III, Compound I I obtains Compound I through the cyano group substitution reaction, and its reaction formula is:
Wherein Z, R 1, R 2Definition the same;
Perhaps
(4) when X=cyano group, obtain compound III by the compd B bromo, compound III obtains compound IV through the cyano group substitution reaction, and compound IV is nitrated to obtain compound shown in the Compound I, and its reaction formula is:
Figure S200810038964XD00063
Wherein Z, R 1, R 2Definition the same;
In above-mentioned reaction, in the preparation of formula I compound, reaction such as described decarboxylation, bromo, nitrated, cyano group replacement all is the popular response in the present technique field.Compd B can be bought by market, or is that raw material is synthetic with reference to the method for embodiment one with the parahydroxyacet-ophenone, is that raw material is synthetic with reference to the method for embodiment 35 with 3-methoxyl group-4-hydroxy acetophenone perhaps.
The invention still further relates to the purposes of the 6-nitro-acetophenone compounds shown in the formula I, it is characterized in that, the 6-nitro-acetophenone compounds shown in the formula I is compound shown in the preparation formula A as follows
Figure S200810038964XD00071
Wherein,
X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3, or CO 2R 3, R wherein 3And R 3' be C1～C10 alkyl that hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replace with being same to each other or different to each other;
Z is-NH-,-O-or
R 1And R 1' be C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or aryl that C1～C10 alkyl, C1～C10 alkyloyl, aroyl, aryl that formyl radical, C1～C10 alkyl, C1～C10 alkenyl, aryl, aryl replace replace replace with being same to each other or different to each other;
R 2Be C1～C10 alkyl, C1～C10 alkenyl or aryl, described alkyl is necessarily replaced by halogen, alkoxyl group, aryl or the heterocyclic radical that contains 1～2 O or N, for example tetramethyleneimine, piperidines, morpholine, piperazine, high piperazine, wherein said heterocycle can necessarily be replaced by C1～C10 alkyl or C1～C10 alkoxyl group;
(1) Compound I and compd E carry out condensation reaction and obtain compound shown in the formula VI,
Wherein, Y is-N (R 5) 2Or-OR 5, R 5, R 6And R 7Be selected from the C1～C10 alkyl of C1～C10 alkyl, C1～C10 alkenyl, aryl and aryl replacement identical or differently.Compound VI obtains compound shown in the formula VII under reductive condition, the cyclization of compound shown in the formula VII obtains compound shown in the formula A, and compound VI I can directly carry out ring-closure reaction without separating, and its reaction formula is:
Figure S200810038964XD00081
Perhaps
(2) Compound I obtains the acid salt of compound VIII or compound VIII under reductive condition, compound VIII (or its acid salt) is carried out condensation reaction with compd E and is obtained compound VI I and/or Compound I X, compound VI I and/or Compound I X cyclization obtain compound shown in the formula A, and compound VI I can directly carry out ring-closure reaction without separating with Compound I X, and its reaction formula is:
Figure S200810038964XD00082
Or
Figure S200810038964XD00083
Perhaps
(3) Compound I obtains compound VIII under reductive condition, amino and the acid anhydrides ((R of the virtue of compound VIII 8) 2O) or halides (R for example 8C1, R 8Br) reaction obtains compounds X, and compounds X and compd E carry out condensation reaction and obtain compounds X I, and compounds X I obtains compounds X II through cyclization, and compounds X II takes off R 8Protecting group obtains compd A, and its reaction formula is:
Figure S200810038964XD00091
R wherein 8Can be general amino protecting group, i.e. C1～C10 the alkoxy carbonyl of the C1～C10 alkyloyl of formyl radical, C1～C10 alkyloyl, aroyl, aryl replacement, C1～C10 alkoxy carbonyl or aryl replacement.The reaction that is prepared compd A by compounds X can be finished with one kettle way, and intermediate X I and XII can be without separating.
In the above-mentioned method for preparing compd A, the condition that described and E carry out condensation reaction can be directly substrate to be mixed with E under the situation that does not add catalyzer, reacts under normal temperature or heating condition.Reductive condition can be: under the hydrogenation catalyst existence condition, feed hydrogen and react, hydrogenation catalyst can be palladium carbon, active nickel or PtO 2Also can be: add reductive agent, for example add iron powder, zinc powder or tin protochloride.Preparing compd A by compound VI can be that reduction and ring-closure reaction one go on foot and finish under the condition that reductive agent exists, and need not separation of intermediates VII; Preparing compd A by compound VIII can be that compound VIII is mixed with E, and condensation and one step of ring-closure reaction finish under normal temperature or heating condition, need not separation of intermediates VII and/or IX.Compounds X is by compound VIII and contains R 8Substituent acid anhydrides or halides are carried out conventional acidylate or halogenating reaction and are obtained.The preferred N of compd E, N-diformamide dimethylacetal (DMF-DMA), trimethyl orthoformate or triethyl orthoformate.
The invention still further relates to another purposes of the 6-nitro-acetophenone compounds shown in the formula I, it is characterized in that, the 6-nitro-acetophenone compounds shown in the formula I is compound shown in the preparation formula A ' as follows
Figure S200810038964XD00101
Wherein, R 1, R 2, X and Z definition cotype A compound.
(1) Compound I and compd E carry out condensation reaction and obtain compound shown in the formula VI,
Figure S200810038964XD00102
Wherein, Y is-N (R 5) 2Or-OR 5, R 5, R 6And R 7Be selected from the C1～C10 alkyl of C1～C10 alkyl, C1～C10 alkenyl, aryl and aryl replacement identical or differently.Compound VI obtains formula A ' compound through reduction, cyclization, chloro, wherein midbody compound VII, compd A can be without separation.Its reaction formula is:
Figure S200810038964XD00103
Perhaps
(2) Compound I obtains compound VIII under reductive condition, compound VIII and compd E carry out condensation reaction and obtain compound VI I and/or Compound I X, compound VI I and/or Compound I X obtain compound shown in the formula A ' through cyclization, chloro, and midbody compound VII/ Compound I X and compd A are without separating compound shown in the direct preparation formula A ', and its reaction formula is:
Or
Figure S200810038964XD00105
The above-mentioned compd A for preparing ' method in, described reduction, cyclization, carry out the preparation method of the condition of condensation reaction with above-mentioned formula A with E.Described chlorination can adopt chlorinating agent to react, and for example adopts chlorinating agents such as phosphorus oxychloride, phosphorus pentachloride to react.
The present invention also provides the compound of Formula Il～XI:
Wherein, X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3Or-CO 2R 3, R wherein 3And R 3' be C1～C10 alkyl that hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replace with being same to each other or different to each other; Z is-NH-,-O-or
Figure S200810038964XD00112
R 1And R 1' be C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or aryl that C1～C10 alkyl, C1～C10 alkyloyl, aroyl, aryl that formyl radical, C1～C10 alkyl, C1～C10 alkenyl, aryl, aryl replace replace replace with being same to each other or different to each other; R 2Be C1～C10 alkyl, C1～C10 alkenyl or aryl, described alkyl is necessarily replaced by halogen, alkoxyl group, aryl or the heterocyclic radical that contains 1～2 O or N, for example pyrrolidyl, piperidyl, morpholinyl, piperazinyl, high piperazinyl, wherein said heterocyclic radical can necessarily be replaced by C1～C10 alkyl or C1～C10 alkoxyl group; And when Z is-O-, R 1During for methyl, R 2It is not methyl; Y is-N (R 5) 2Or-OR 5, R 5Be selected from the C1～C10 alkyl of C1～C10 alkyl, C1～C10 alkenyl, aryl and aryl replacement; R 8Can be general amino protecting group, i.e. C1～C10 the alkoxy carbonyl of the C1～C10 alkyloyl of formyl radical, C1～C10 alkyloyl, aroyl, aryl replacement, C1～C10 alkoxy carbonyl or aryl replacement.
In the above compound, R 1Be preferably C1～C5 alkyl, ethanoyl, propionyl, benzoyl, tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz) or trityl; R 2Be preferably methyl, ethyl, propyl group, benzyl ,-(CH 2) n-Cl ,-(CH 2) n-Br or
Figure S200810038964XD00121
N=1～5 wherein, Alkyl is C1～C5 alkyl; X be preferably cyano group, trifluoromethyl ,-NHCOOR 3,-NHCOOR 3,-N=CHR 3, C1～C10 carbalkoxy or carboxyl; Z is preferably-NH-or-O-; Y is preferred-N (CH 3) 2,-OCH 3, OC 2H 5R 8Preferred ethanoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz).
Above compound is more preferably:
Formula II compound is preferred:
3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone;
3 '-benzoylamino-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone;
3 '-benzamido group-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone;
3 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--6 '-nitro-2-bromoacetophenone;
The formula III compound is preferred:
3 '-acetamido-4 '-oxyethyl group-2-bromoacetophenone;
3 '-benzoylamino-4 '-oxyethyl group-2-bromoacetophenone;
3 '-benzamido group-4 '-oxyethyl group-2-bromoacetophenone;
3 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--2-bromoacetophenone;
Formula IV compound is preferred:
3 '-acetamido-4 '-oxyethyl group-2-cyano-acetophenone;
3 '-benzoylamino-4 '-oxyethyl group-2-cyano-acetophenone;
3 '-benzamido group-4 '-oxyethyl group-2-cyano-acetophenone;
3 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--2-cyano-acetophenone;
Formula V compound is preferred:
3-(5-acetamido-4-oxyethyl group-2-nitrophenyl)-2-cyano group-3-carbonyl-ethyl propionate;
2-(5-acetylaminohydroxyphenylarsonic acid 4-oxyethyl group-2-nitro benzoyl) diethyl malonate;
Formula VI compound is preferred:
N-(5-(2-cyano group-3-(dimethyl amido) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide;
N-(5-(2-cyano group-3-(methoxyl group) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide;
N-(5-(2-ethoxy carbonyl-3-(dimethyl amido) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide;
Formula VIII compound is preferred:
3 '-acetamido-4 '-oxyethyl group-6 '-amino-2-cyano-acetophenone;
3 '-benzoylamino-4 '-oxyethyl group-6 '-amino-2-cyano-acetophenone;
3 '-benzamido group-4 '-oxyethyl group-6 '-amino-2-cyano-acetophenone;
3 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--6 '-amino-2-cyano-acetophenone.
The technique effect that the present invention realizes is as follows:
(1) in the present invention, prepare the method for compd A and A ',, can avoid using hot conditions, avoid using high boiling solvent, environmental protection and safety with respect to the literature method of the preparation of existing quinoline ring with Compound I.Especially, yield reaches more than 80% when X=cyano group or ester group, obviously is better than existing method.
(2) Compound I can by industrial raw material easily, high productivity obtains.
(3) Fan Ying transformation efficiency height is easy and simple to handle, and the reaction conditions gentleness.The multistep intermediate does not need separation and purification, can be directly used in the next step, has greatly improved yield, has simplified operation.Can realize suitability for industrialized production.
(4) preparing with Compound I in the method for compd A or A ', preferred method (2), its reaction conditions gentleness, intermediate is stable, easier purifying, yield is higher, and cost reduces greatly.The impurity that the reaction of preparation target compound A or A ' produces is few, the easy purifying of product, and easy and simple to handle, total recovery is higher, easier realization suitability for industrialized production.
In a word, by the present invention, realized the brand-new synthetic route of 3-replacement-4-hydroxyquinoline compounds and 3-replacement-4-chloroquinoline compounds, mild condition is operated simple and easy, safe and effective.
Embodiment
Further specify the present invention by following examples, following examples only are used for preferred implementation of the present invention more specifically is described, are not used in technical scheme of the present invention is limited.The technical scheme of the invention described above is the technical scheme that can realize the object of the invention.Be temperature that following examples adopt and reagent, all available relevant temperature mentioned above and reagent substitute to realize purpose of the present invention.
In the following preparation example, nucleus magnetic resonance is by Bruker AMX-400 type and INVOA-600 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; Mass spectrum is measured by MAT-711 type and MAT-95 type mass spectrograph; Column chromatography silica gel 200-300 order, Haiyang Chemical Plant, Qingdao produces; The HSGF-254 type thin-layer chromatography precoated plate that the TLC silica-gel plate is produced for the chemical plant, Yantai; The sherwood oil boiling range is 60-90 ℃; Adopt ultraviolet lamp, the colour developing of iodine cylinder.If do not particularly point out working method, described concentrated finger steams with the solvent that Rotary Evaporators will prepare in the compound solution in the preparation example; Described drying refers to will prepare the compound oven dry with the DHG-9240A thermostatic drying chamber at 60 ℃.
Embodiment one 3-acetamido-4-phenetole ethyl ketone (compd B, R 1=ethanoyl, R 2=ethyl, Z=-NH-) synthetic
(1) preparation of 3-nitro-4-hydroxy acetophenone
In the ice bath, (136.2g 1.0mol) joins in the vitriol oil (1000ml), stirs 10min, and (96.0g 0.95mol), stirs 2h, and (7.1g 0.07mol), stirs 1h, and reaction finishes to add saltpetre again to add saltpetre with parahydroxyacet-ophenone.Reaction solution is poured in the 3000ml trash ice, is separated out a large amount of solids, suction filtration, washing, drying, the 3-nitro-4-hydroxy acetophenone 171.2g of pale yellow powder, yield 94.5%.
(2) preparation of 3-amino-4-hydroxy methyl phenyl ketone
Under the normal temperature, (171.2g 0.945mol) is dissolved among the THF (1500ml), adds Raney Ni 20g, normal pressure hydrogenation reaction 24h, reaction end with 3-nitro-4-hydroxy acetophenone.Filter, concentrate, drying gets tawny solid 3-amino-4-hydroxy methyl phenyl ketone 132.8g, yield 93.0%.
(3) preparation of 3-acetamido-4-hydroxy acetophenone
With 3-amino-4-hydroxy methyl phenyl ketone (121.0g 0.8mol) is dissolved in the glacial acetic acid (1000ml), 60 ℃ of stirrings, drip diacetyl oxide (115.0ml, 1.2mol), 1h adds, restir 30min, reaction finishes.Reaction solution is poured in the 2000ml frozen water, is separated out a large amount of solids, stir to place 2h, suction filtration, washing, drying, the 3-acetamido-4-hydroxy acetophenone 134.8g of tawny powder, yield 87.2%.
(4) preparation of 3-acetamido-4-phenetole ethyl ketone
With 3-acetamido-4-hydroxy acetophenone (96.6g, 0.5mol) and salt of wormwood (138.2g 1.0mol) is dissolved among the DMF (500ml), and 60 ℃ are stirred 10min, dripping bromine ethane (60ml, 0.75mol), 1h adds, restir 30min, reaction finishes.Reaction solution is poured in the 2000ml frozen water, with ethyl acetate extraction (600ml * 4), the washing organic layer, drying, concentrate 3-acetamido-4-phenetole ethyl ketone (compd B, the R of beige powder 1=ethanoyl, R 2=ethyl, Z=-NH-) 100.9g, yield 91.2%. 1HNMR(300MHz，CDCl 3)δ1.49(t，3H)，2.22(s，3H)，2.56(s，3H)，4.19(q，2H)，6.90(d，1H)，7.74(m，2H)，8.96(s，1H)。ESI-MS(m/z)222(M+1)，244(M+23)，260(M+39)。
Embodiment two 3-acetamido-4-oxyethyl group-6-nitro-acetophenone (Compound D, R 1=ethanoyl, R 2=ethyl, Z=-NH-) synthetic
With compd B (R 1=ethanoyl, R 2=ethyl, Z=-NH-) (88.5g 0.4mol) is dissolved in the Nitromethane 99Min. (1000ml), and (17.7ml, 0.4mol), in 40 ℃ of stirring 12h, (15.5ml 0.35mol), stirs 10h, and reaction finishes to add nitrosonitric acid to add nitrosonitric acid.Reaction solution is poured in the saturated sodium bicarbonate solution (1000ml), stir separatory, washing organic layer, dry, filter, add 10g gac, backflow 20min in the filtrate, the heat filter, concentrate red oil, 40 ℃ of constant pressure and dries get incarnadine solid 3-acetamido-4-oxyethyl group-6-nitro-acetophenone (Compound D, R 1=ethanoyl, R 2=ethyl, Z=-NH-) 86.5g, yield 81.2%. 1HNMR(300MHz，CDCl 3)δ1.52(t，3H)，2.24(s，3H)，2.52(s，3H)，4.22(q，2H)，7.53(s，1H)，7.98(s，1H)，8.52(s，1H)。ESI-MS(m/z)265(M-1)。
Embodiment 33 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone (Compound I I, R 1=ethanoyl, R 2=ethyl, Z=-NH-) synthetic
With Compound D (R 1=ethanoyl, R 2=ethyl, Z=-NH-) (79.9g 0.3mol) is dissolved in the methylene dichloride (1000ml), adds liquid bromine (14.6ml, 0.285mol), stirring at normal temperature 12h, reaction solution is become faint yellow by incarnadine, add liquid bromine (1.1ml, 0.021mol), stir 2h, reaction finishes.Concentrate 3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone (Compound I I, the R of incarnadine oily matter 1=ethanoyl, R 2=ethyl, Z=-NH-) 110.0g can be directly used in next step reaction. 1HNMR(300MHz，CDCl 3)δ1.55(t，3H)，2.24(s，3H)，4.27(q，2H)，4.30(s，2H)，7.64(s，1H)，8.01(s，1H)，8.58(s，1H)。ESI-MS(m/z)346(M+1)，368(M+23)。
Embodiment 43 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With Compound I I (R 1=ethanoyl, R 2=ethyl, and Z=-NH-) (110.0g 0.3mol) is dissolved among ethanol (600ml) and the DMSO (200ml), the ice bath cooling, and (1h adds for 29.4g, water 0.6mol) (300ml) solution, and reaction solution is chocolate, normal-temperature reaction 6h, reaction end to drip sodium cyanide.Reaction solution is poured in the 2000ml water, and transferring the pH value of solution value with 1M hydrochloric acid is 5, separates out a large amount of solids, suction filtration, washing, drying, 3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, the R of lark powder 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 68.3g, yield 78.2%. 1HNMR(300MHz，CDCl 3)δ1.56(t，3H)，2.28(s，3H)，3.85(s，2H)，4.28(q，2H)，7.64(s，1H)，8.02(s，1H)，8.58(s，1H)。ESI-MS(m/z)290(M-1)。
Embodiment five N-(5-(2-cyano group-3-(dimethyl amido) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide (compound VI, R 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-N (CH 3) 2, Z=-NH-) synthetic
With Compound I (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (58.3g 0.2mol) is dissolved in the glycol dimethyl ether (600ml), add N, and N-diformamide dimethylacetal (DMF-DMA) (29.2ml, 0.22mol), stirring at room is separated out pale yellow powder gradually in the reaction solution, the 1h afterreaction finishes.Suction filtration, washing, drying, N-(5-(2-cyano group-3-(dimethyl amido) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide (compound VI, the R of pale yellow powder 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-N (CH 3) 2, Z=-NH-) 93.0g, yield 91.0%. 1HNMR(300MHz，DMSO)δ1.43(t，3H)，2.17(s，3H)，3.27(s，3H)，3.31(s，3H)，4.28(q，2H)，7.73(s，1H)，8.26(s，1H)，9.52(s，1H)。ESI-MS(m/z)345(M-1)。
Embodiment six 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound VI (R 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-N (CH 3) 2, Z=-NH-) (34.6g 0.1mol) is dissolved in DMF (300ml), adds Raney Ni 6g, normal pressure hydrogenation reaction 3h, and reaction finishes.Filter, filtrate is concentrated into half volume, and solid is separated out in water (600ml) dilution again, and room temperature is placed and spent the night, suction filtration, washing, drying, 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R of pale yellow powder 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 16.6g, yield 61%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment seven 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound VI (R 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-N (CH 3) 2Z=-NH-) (5.0g, 0.0144mol) be dissolved in DMF (60ml) and ethanol (10ml), add calcium chloride (7.2g, water 0.0648mol) (10ml) solution, add reduced iron powder (3.6g, 0.0648mol), 75 ℃ of reactions, the 6h afterreaction finishes, add gac (0.5g), in 75 ℃ of decolouring 20min.Suction filtration, filtrate are concentrated into half volume, and filtrate is poured in the trash ice (100g), place 1h, separate out the khaki color solid, suction filtration, washing, dry khaki color solid 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 3.1g, yield 79%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment eight N-(5-(2-cyano group-3-(methoxyl group) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide (compound VI, R 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-OCH 3, Z=-NH-) synthetic
With Compound I (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (58.3g 0.2mol) is dissolved in the glycol dimethyl ether (600ml), adds trimethyl orthoformate (compd E, Y=OCH 3) (63.6g, 0.6mol), logical nitrogen protection, reflux, 5-6h reacts end.Steam solvent and get pale brown look solid, use recrystallization from ethyl acetate/petroleum ether, get N-(5-(2-cyano group-3-(methoxyl group) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide (compound VI, the R of pale yellow powder 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-OCH 3, Z=-NH-) 50.2g, yield 81%. 1HNMR(300MHz，DMSO)δ1.46(t，3H)，2.18(s，3H)，4.12(s，3H)，4.31(q，2H)，7.81(s，1H)，8.13(s，1H)，8.30(s，1H)，9.64(s，1H)。ESI-MS(m/z)334(M+1)。
Embodiment nine 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound VI (R 1=ethanoyl, R 2=ethyl, X=cyano group, Y=-OCH 3, Z=-NH-) (30.5g 0.1mol) is dissolved in DMF (300ml), adds Raney Ni 6g, normal pressure hydrogenation reaction 4h, and reaction finishes.Filter, filtrate is concentrated into half volume, and white solid is separated out in water (600ml) dilution again, and room temperature is placed and spent the night, suction filtration, washing, drying, 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R of pale yellow powder 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 20.5g, yield 76%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment 10 '-acetamido-4 '-oxyethyl group-2-bromoacetophenone (compound III, R 1=ethanoyl, R 2=ethyl, Z=-NH-) synthetic
With compd B (R 1=ethanoyl, R 2=ethyl, Z=-NH-) (66.4g 0.3mol) is dissolved in the methylene dichloride (1000ml), and adding liquid bromine (14.6ml, 0.285mol), stirring at normal temperature 2h separates out gray solid in the reaction solution, and (1.1ml 0.021mol), stirs 1h, and reaction finishes to add the liquid bromine.Concentration of reaction solution is to 300mL, suction filtration, washing, drying, 3 '-acetamido-4 '-oxyethyl group-2-bromoacetophenone (compound III, the R of gray solid 1=ethanoyl, R 2=ethyl, Z=-NH-) 98.0g, productive rate 80%. 1HNMR(300MHz，CDCl 3)δ1.56(t，3H)，2.28(s，3H)，3.85(s，2H)，4.28(q，2H)，7.64(s，1H)，8.02(s，1H)，8.58(s，1H)。EI-MS(m/z)300(M +)，299(M-1)。
Embodiment 11 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone (Compound I I, R 1=ethanoyl, R 2=ethyl, Z=-NH-) synthetic
With compound III (R 1=ethanoyl, R 2=ethyl, Z=-NH-) (98.0g 0.3mol) is dissolved in the Nitromethane 99Min. (1000ml), and (15.1ml, 0.36mol), in 40 ℃ of stirring 5h, (13.3ml 0.3mol), stirs 2h, and reaction finishes to add nitrosonitric acid to add nitrosonitric acid.Reaction solution is poured in the saturated sodium bicarbonate solution (1000ml), stir, the washing organic layer, drying is filtered, add the 10g gac in the filtrate, backflow 20min, heat filter, concentrate brown oil, 40 ℃ of constant pressure and dries get 3 ' of brown solid-acetamido-4 '-oxyethyl group-6 '-nitro-2-bromoacetophenone (Compound I I, R 1=ethanoyl, R 2=ethyl, Z=-NH-) 86.1g, yield 83.2%. 1HNMR(300MHz，CDCl 3)δ1.55(t，3H)，2.24(s，3H)，4.27(q，2H)，4.30(s，2H)，7.64(s，1H)，8.01(s，1H)，8.58(s，1H)。ESI-MS(m/z)346(M+1)，368(M+23)。
Embodiment 12 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With Compound I I (R 1=ethanoyl, R 2=ethyl, and Z=-NH-) (110.0g 0.3mol) is dissolved among ethanol (600ml) and the DMSO (200ml), and solid is not molten entirely, the ice bath cooling, and (1h adds for 29.4g, water 0.6mol) (300ml) solution, normal-temperature reaction 6h, reaction end to drip sodium cyanide.Reaction solution is poured in the 2000ml water, and transferring the pH value of solution value with 1M hydrochloric acid is 5, separates out a large amount of solids, suction filtration, washing, drying, 3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, the R of pale yellow powder 1=ethanoyl, R2=ethyl, X=cyano group, Z=-NH-) 68.3g, yield 80%. 1HNMR(300MHz，CDCl 3)δ1.56(t，3H)，2.28(s，3H)，3.85(s，2H)，4.28(q，2H)，7.64(s，1H)，8.02(s，1H)，8.58(s，1H)。
Embodiment 13 '-acetamido-4 '-oxyethyl group-2-cyano-acetophenone (compound IV, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound III (R 1=ethanoyl, R 2=ethyl, Z=-NH-) (98.0g 0.3mol) is dissolved among ethanol (500ml) and the DMSO (300ml), and solid is not molten entirely, the ice bath cooling, (1h adds for 29.4g, water 0.6mol) (300ml) solution to drip sodium cyanide, solid in the reaction solution dissolves gradually, normal-temperature reaction 2h, and reaction finishes.Reaction solution is poured in the 2000ml water, and transferring the pH value of solution value with 1M hydrochloric acid is 5, separates out a large amount of solids, suction filtration, washing, drying, 3 '-acetamido-4 '-oxyethyl group-2-cyano-acetophenone (compound IV, the R of pale yellow powder 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 57.0g, yield 77.2%. 1HNMR(300MHz，DMSO)δ1.38(t，3H)，2.11(s，3H)，4.22(q，2H)，4.67(s，2H)，7.18(d，1H)，7.70(m，1H)，8.54(s，1H)，9.17(s，1H)。EI-MS(m/z)246(M +)。
Embodiment 14 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound IV (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (73.8g 0.3mol) is dissolved in the Nitromethane 99Min. (1000ml), and (15.1ml 0.36mol), stirs 2h, and (13.3ml 0.3mol), stirs 5h, and reaction finishes to add nitrosonitric acid to add nitrosonitric acid.Reaction solution is poured in the saturated sodium bicarbonate solution (1000ml), stir washing organic layer, drying, filter, add the 10g gac in the filtrate, backflow 20min, heat filter, concentrate, drying obtains 3 ' of brown solid-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 71g, productive rate 81%. 1HNMR(300MHz，CDCl 3)δ1.56(t，3H)，2.28(s，3H)，3.85(s，2H)，4.28(q，2H)，7.64(s，1H)，8.02(s，1H)，8.58(s，1H)。
Embodiment 15 3-(5-acetamido-4-oxyethyl group-2-nitrophenyl)-2-cyano group-3-carbonyl-ethyl propionate (compound V, R 1=ethanoyl, R 2=ethyl, R 4=ethyl, X=cyano group, Z=-NH-) synthetic
(133.7g 0.8mol) is dissolved in the glacial acetic acid (1000mL), and 60 ℃ of stirrings are not molten entirely, and (115.0mL, 1.2mol), 1h adds, and reacts and finishes, and separates out a large amount of solids to drip diacetyl oxide with 3-amido-4-methyl hydroxybenzoate.Reaction solution is poured in the 2000mL frozen water, is separated out a large amount of solids, stir to place 1h, suction filtration, washing, drying, the 3-acetamido-4-methyl hydroxybenzoate 154.3g of Off-white solid, yield 92.2%.
With 3-acetamido-4-methyl hydroxybenzoate (104.6g, 0.5mol) and salt of wormwood (138.2g 1.0mol) is dissolved among the DMF (500mL), and 60 ℃ are stirred 10min, not molten entirely, and dripping bromine ethane (60.0mL, 0.75mol), 1h adds, and reaction finishes, and separates out a large amount of solids.Reaction solution is poured in the 2000mL frozen water, separated out a large amount of solids, suction filtration, washing, drying gets pale pink solid 3-acetamido-4-ethoxy-benzoic acid methyl ester 112.0g, yield 94.5%. 1H-NMR(300MHz，CDCl 3)δ1.47(t，3H)，2.21(s，3H)，3.87(s，3H)，4.15(q，2H)，6.87(d，1H)，7.70(s，1H)，7.77(dd，1H)，8.97(d，1H)。ESI-MS(m/z)238(M+1)，260(M+23)。
(95.0g 0.4mol) is dissolved in the Nitromethane 99Min. (1500mL), and (50.0mL 1.2mol), stirs 3h, the reaction end in 30 ℃ to add nitrosonitric acid with 3-acetamido-4-ethoxy-benzoic acid methyl ester under the normal temperature.(80.0g 0.75mol) in the aqueous solution (1200mL), stirs, and separatory is washed organic layer, and drying steams 3-acetamido-4-oxyethyl group-6-nitrobenzoic acid methyl esters 104.0g that solvent gets light red brown solid, yield 92.0% to pour reaction solution into yellow soda ash. 1H-NMR(300MHz，CDCl 3)δ1.52(t，3H)，2.25(s，3H)，3.88(s，3H)，4.22(q，2H)，7.44(s，1H)，7.90(s，1H)，8.74(s，1H)。ESI-MS(m/z)283(M+1)，305(M+23)。
(85.0g, (500mL, 1.3mol), back flow reaction 4h reacts and finishes 0.3mol) to be dissolved in THF (500mL) and 10% aqueous sodium hydroxide solution with 3-acetamido-4-oxyethyl group-6-nitrobenzoic acid methyl esters.Be cooled to room temperature, the reaction solution layering, the upper strata is faint yellow, and lower floor is a chocolate, separatory, lower floor is 4-5 with the glacial acetic acid adjust pH, ethyl acetate extraction (200mL * 5 time), washing organic layer, drying, steam solvent and get the 3-amido-4-oxyethyl group-6-nitrobenzoic acid methyl esters 63.8g of brown blocks of solid, yield 94%.Be directly used in next step reaction. 1H-NMR(300MHz，DMSO)δ1.37(t，3H)，4.13(q，2H)，6.40(s，1H)，6.68(s，1H)，7.44(s，1H)，13.20(bs，1H)。ESI-MS(m/z)227(M+1)。
With 3-amido-4-oxyethyl group-6-nitrobenzoic acid methyl esters (63.8g 0.282mol) is dissolved in the glacial acetic acid (600mL), 60 ℃ of stirrings, drip diacetyl oxide (29.0mL, 0.3mol), 1h adds, reaction finishes.Reaction solution is poured in the frozen water (1000mL), separated out a large amount of grey powder, place 1h, suction filtration, washing, drying gets lark solid 3-acetamido-4-oxyethyl group-6-nitrobenzoic acid 63.0g,, yield 83%. 1H-NMR(300MHz，DMSO)δ1.40(t，3H)，2.17(s，3H)，4.26(q，2H)，7.60(s，1H)，8.56(s，1H)，9.46(s，1H)，13.50(bs，1H)。。ESI-MS(m/z)267(M-1)。
(54.0g 0.2mol) is dissolved in the methylene dichloride (300ml), and is not molten entirely with 3-acetamido-4-oxyethyl group-6-nitrobenzoic acid, the adding sulfur oxychloride (58.0ml, 0.8mol), back flow reaction, prolong upper ends Calcium Chloride Powder Anhydrous drying tube, the 2h afterreaction finishes, the reaction solution clarification.Concentrate the 3-acetamido-4-oxyethyl group-6-nitrobenzoyl chloride that obtains brown solid.
With sodium Metal 99.5 (9.2g, 0.4mol) be dissolved in ethanol (150ml), treat sodium complete molten after back flow reaction 10min again, question response liquid is cooled to 50 ℃-60 ℃, and the dropping ethyl cyanacetate (47.0ml, 0.44mol), 10min adds, generate a large amount of white powders in the reaction solution, back flow reaction 30min again, then cryosel is bathed and is cooled to-8 ℃.Drip the anhydrous THF solution (150ml) of 3-acetamido-4-oxyethyl group-6-nitrobenzoyl chloride in reaction solution, 1h adds, and keeps temperature of reaction below 0 ℃, dropwises reaction and promptly finishes.In reaction solution, drip frozen water (100ml), keep reacting liquid temperature below 10 ℃, (the accent reacting liquid pH value is 1-2 for 10ml, frozen water 0.15mol) (1000ml) solution to add the vitriol oil again in reaction solution, separate out a large amount of solids, stir and place 1h, suction filtration, washing, dry tawny solid 3-(5-acetamido-4-oxyethyl group-2-nitrophenyl)-2-cyano group-3-carbonyl-ethyl propionate (compound V, the R that get 1=ethanoyl, R 2=ethyl, R 4=ethyl, X=cyano group, Z=-NH-) 68.0g, yield 93.5%. 1HNMR(300MHz，DMSO)δ0.96(t，3H)，1.43(t，3H)，2.20(s，3H)，3.86(q，2H)，4.28(q，2H)，7.79(s，1H)，8.14(s，1H)，9.51(s，1H)。ESI-Ms(m/z)362(M-1)。
Embodiment 16 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound V (R 1=ethanoyl, R 2=ethyl, R 4=ethyl, X=cyano group, Z=-NH-) (36.3g 0.1mol) is dissolved in 90%DMSO/ water (160ml), in 110 ℃ of reaction 30min.Yellow powder is separated out in reaction solution cooling back water (800ml) dilution, and transferring pH value of solution with 1N sulfuric acid is 1-2, suction filtration, and washing, drying obtains 3 ' of faint yellow solid-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 25.8g, yield 88.6%. 1HNMR(300MHz，CDCl 3)δ1.56(t，3H)，2.28(s，3H)，3.85(s，2H)，4.28(q，2H)，7.64(s，1H)，8.02(s，1H)，8.58(s，1H)。
Embodiment 17 '-benzoylamino-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=benzoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With 3-amino-4-hydroxy methyl phenyl ketone is raw material; according to the step 3 of embodiment one, 4 and the operation of embodiment two to four; prepare title compound through benzoylation, ethylization, nitrated, bromo, cyano groupization; get title compound 3 '-benzoylamino-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, the R of yellow powder 1=benzoyl, R 2=ethyl, X=cyano group, Z=-NH-), total recovery 56%.ESI-MS(m/z)352(M-1)。
Embodiment 18 '-benzamido group-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, R 1=benzyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With 3-benzamido group-4-phenetole ethyl ketone is raw material, and the operation according to embodiment two to four is equipped with title compound with legal system, gets title compound 3 '-benzamido group-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone (Compound I, the R of yellow powder 1=benzyl, R 2=ethyl, X=cyano group, Z=-NH-).ESI-MS(m/z)338(M-1)。
Embodiment 19 '-acetamido-4 '-oxyethyl group-6 '-amino-2-cyano-acetophenone (compound VIII, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Compound I (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (29.1g, 0.1mol), iron powder (28g 0.5mol) mixes with 400ml tetrahydrofuran (THF), 50ml ethanol, 20ml water, add dilute hydrochloric acid and transfer pH=4-5, backflow 2h, reaction finishes.Filter, solvent evaporated gets brown solid, gets khaki color solid compound VIII (R with tetrahydrofuran (THF)/ethyl acetate (each 200ml) recrystallization 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 21.5g, yield 81%. 1HN(300MHz，DMSO)δ1.36(t，3H)，1.99(s，3H)，3.27(s，2H)，4.00(q，2H)，6.33(s，1H)，7.28(s，1H)，7.76(s，1H)，8.88(s，1H)。EI-MS(m/z)261(M +)。
Embodiment 20 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Under the ice bath, compound VIII (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (26.1g, 0.1mol) be dissolved in glycol dimethyl ether (250mL), add N, and N-diformamide dimethylacetal (DMF-DMA) (16.0ml, 0.12mol), reaction 4h, separate out the khaki color powder in the reaction solution, suction filtration, washing, dry khaki color solid 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 22.5g, yield 83.0%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment 21 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Under the ice bath, and compound VIII HCl (be the hydrochloride of VIII, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (29.7g 0.1mol) mixes with glycol dimethyl ether, and ice bath drips N, and N-diformamide dimethylacetal (DMF-DMA) (13.3ml, 0.1mol), reaction 4h, reaction finishes.Reaction solution is concentrated into half volume, and filtrate is poured in the trash ice (100g), places 1h, separates out the khaki color solid, suction filtration, washing, dry khaki color solid 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 23.5g, yield 80%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment 22 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Compound VIII (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (26.1g 0.1mol) is dissolved in glycol dimethyl ether (250ml), and (20.0ml, 0.12mol), back flow reaction 3h reacts and finishes to add triethyl orthoformate.Separate out the khaki color powder in the reaction solution, suction filtration, washing, dry khaki color solid 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 20.5g, yield 76%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment 23 2-(5-acetylaminohydroxyphenylarsonic acid 4-oxyethyl group-2-nitro benzoyl) diethyl malonate (compound V, R 1=ethyl, R 2=ethyl, X=ethoxy carbonyl, R 4=ethyl, Z=-NH-) synthetic
Under the normal temperature, with 3-acetamido-4-oxyethyl group-6-nitrobenzoic acid (5.3g 0.02mol) is dissolved in the methylene dichloride (60ml), and is not molten entirely, add sulfur oxychloride (7.2ml, 0.1mol), back flow reaction, the 1h afterreaction finishes, the reaction solution clarification.Solvent evaporated gets brown solid, adds anhydrous THF solution (30ml), and evaporate to dryness gets 3-acetamido-4-oxyethyl group-6-nitrobenzoyl chloride, can be directly used in next step reaction.
Under the normal temperature, with sodium Metal 99.5 (1.0g, 0.043mol) be dissolved in ethanol (30ml), treat sodium complete molten after back flow reaction 10min again, question response liquid is cooled to 50 ℃-60 ℃, drip diethyl malonate (7.0ml, 0.046mol), 3min adds, again back flow reaction 30min, the solution clarification then is cooled to-10 ℃.Drip the anhydrous THF solution (30ml) of 3-acetamido-4-oxyethyl group-6-nitrobenzoyl chloride in reaction solution, 20min adds, and keeps temperature of reaction below 0 ℃, dropwises reaction and promptly finishes.In reaction solution, drip frozen water (20ml); keep reacting liquid temperature below 0 ℃; transferring reacting liquid pH value with dilute sulphuric acid again is 1-2; stir and place; separate out solid, suction filtration, washing; dry tawny solid 2-(5-acetylaminohydroxyphenylarsonic acid 4-oxyethyl group-2-nitro benzoyl) diethyl malonate (compound V, the R of getting 1=ethyl, R 2=ethyl, X=ethoxy carbonyl, R 4=ethyl, Z=-NH-) 6.4g, yield 78.0%. 1H-NMR(300MHz，CDCl 3)δ0.98(t，3H)，1.36(t，3H)，1.53(t，3H)，2.23(s，3H)，3.94(q，2H)，4.24(q，2H)，4.37(q，2H)，7.67(s，1H)，7.91(s，1H)，8.53(s，1H)，14.1(s，1H)。EI-MS(m/z)410(M +)。
Embodiment 24 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-ethoxy carbonyl methyl phenyl ketone (Compound I, R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) synthetic
With compound V (R 1=ethyl, R 2=ethyl, X=ethoxy carbonyl, R 4=ethyl, Z=-NH-) (3.1g 0.0076mol) is dissolved in 90%DMSO/ water (20ml), in 110 ℃ of reaction 30min.Reaction solution cooling back water (150ml) dilution; separate out yellow powder, transferring reacting liquid pH value with dilute sulphuric acid is 2-3, stirs and places; separate out solid; suction filtration, washing, dry Compound I (the R1=ethanoyl that gets faint yellow solid; the R2=ethyl; the X=ethoxy carbonyl, Z=-NH-) 2.3g, yield 91.0%. 1H-NMR(300MHz，CDCl 3)δ1.25(t，3H)，1.53(t，3H)，2.25(s，3H)，3.83(s，2H)，4.17(q，2H)，4.24(q，2H)，7.59(s，1H)，7.95(s，1H)，8.59(s，1H)。EI-MS(m/z)338(M +)。
Embodiment 25 N-(5-(2-ethoxy carbonyl-3-(dimethyl amido) acryl)-2-oxyethyl group-4-nitrophenyl) ethanamide (compound VI, R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Y=-N (CH 3) 2, Z=-NH-) synthetic
With Compound I (R 1=ethanoyl, R 2=ethyl, the X=ethoxy carbonyl, Z=-NH-) (0.8g 0.00236mol) is dissolved in glycol dimethyl ether (20ml), adds N, and N-diformamide dimethylacetal (DMF-DMA) (0.93ml, 0.007mol), back flow reaction 6-8h, reaction finishes.Solvent evaporated gets faint yellow solid compound VI (R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Y=-N (CH 3) 2, Z=-NH-) 0.95g can be directly used in next step reaction. 1H-NMR(300MHz，CDCl 3)δ0.91(t，3H)，1.45(t，3H)，2.17(s，3H)，3.04(s，3H)，3.32(s，3H)，3.87(q，2H)，4.16(q，2H)，7.53(s，1H)，7.92(s，1H)，7.98(s，1H)，9.39(s，1H)。EI-MS(m/z)393(M +)。
Embodiment 26 compound VIII (R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) synthetic
With Compound I (R 1=ethanoyl, R 2=ethyl, the X=ethoxy carbonyl, Z=-NH-) (0.8g 0.00236mol) is dissolved in THF (20ml), adds Raney Ni (0.2g), room temperature hydrogenation 12h, and reaction finishes.Filter, evaporate to dryness filtrate gets tawny solid compound VIII (R 1=ethanoyl, R 2=ethyl, X=ethoxycarbonyl, Z=-NH-) 0.67g, yield 91.5%. 1H-NMR(300MHz，CDCl 3)δ1.22(t，3H)，1.48(t，3H)，2.20(s，3H)，3.95(s，2H)，4.18(q，2H)，4.24(q，2H)，6.05(s，1H)，6.31(s，1H)，7.45(s，1H)，8.63(s，1H)。ESI-MS(m/z)331(M+23)。
Embodiment 27 6-acetamido-7-oxyethyl group-3-aminocarboxyl-4-hydroxyquinoline (compd A, R 1=ethanoyl, R2=ethyl, X=ethoxy carbonyl, Z=-NH-) synthetic
With compound VI (R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Y=-N (CH 3) 2, Z=-NH-) (0.4g 1mmol) is dissolved in DMF (3mL), adds Raney Ni 0.1g, normal pressure hydrogenation reaction 4h, and reaction finishes.Filter, filtrate is concentrated into half volume, and white solid is separated out in water (4mL) dilution again, suction filtration, washing, drying, 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R of pale yellow powder 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) 0.20g, yield 62%. 1H-NMR(300MHz，DMSO)δ1.26(t，3H)，1.47(t，3H)，2.18(s，3H)，4.20(q，4H)，7.07(s，1H)，7.36(s，1H)，8.68(s，1H)，9.13(s，1H)，12.04(s，1H)。EI-MS(m/z)318(M +)。
Embodiment 28 6-acetamido-7-oxyethyl group-3-aminocarboxyl-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) synthetic
Normal temperature, compound VIII (R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) (0.31g, 1mmol) be dissolved in glycol dimethyl ether (4mL), add N, and N-diformamide dimethylacetal (DMF-DMA) (0.16mL, 1.2mol), reaction 2h, separate out the khaki color powder in the reaction solution, suction filtration, washing, dry khaki color solid 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) 0.22g, yield 69%.
Embodiment 29 6-acetamido-7-oxyethyl group-3-cyano group-4-chloroquinoline (compd A ', R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
With compound VI (R 1=ethanoyl, R 2=ethyl, X=cyano group, Y=N (CH 3) 2, Z=-NH-) (15.5g 0.045mol) is dissolved in DMF (130ml), adds Raney Ni 6g, normal pressure hydrogenation reaction 5～6h, and the TLC detection reaction finishes.Filter, filtrate is concentrated into dried, and products therefrom is used diethylene glycol dimethyl ether (120ml) dissolving again, and (9.3ml 0.099mol), reacts down in 80 ℃ (outer temperature) to add phosphorus oxychloride.4hr to 4.5hr reaction finishes, and slowly pours into reaction solution in the 2 volume frozen water and stirs 1h, separates out yellow powder, suction filtration, and washing, with a small amount of glycol dimethyl ether washing, 40 ℃ are dry down again, get the compd A of yellow powder ' (R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) 9.12g, yield 70.6%. 1HNMR(300MHz，DMSO)δ1.49(t，3H)，2.25(s，3H)，4.38(q，2H)，7.58(s，1H)，8.98(s，1H)，9.09(s，1H)，9.51(s，1H)。ESI-Ms(m/z)289(M-1)。
Embodiment 30 6-acetamido-7-oxyethyl group-3-cyano group-4-chloroquinoline (compd A ', R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Compound VIII (R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) (11.75g 0.045mol) is dissolved in glycol dimethyl ether (250ml), and (20.0ml, 0.12mol), back flow reaction 3h reacts and finishes to add triethyl orthoformate.Be chilled to room temperature, add phosphorus oxychloride (11ml) again, in 80 ℃ (outside temperature) reaction down.4hr to 4.5hr reaction finishes, and slowly pours into reaction solution in the 2 volume frozen water and stirs 1h, separates out yellow powder, suction filtration, and washing, with a small amount of glycol dimethyl ether washing, 40 ℃ are dry down again, get the compd A of yellow powder ' (R 1=ethanoyl, R 2=ethyl, X=ethoxy carbonyl, Z=-NH-) 8.9g, yield 68.5%. 1HNMR(300MHz，DMSO)δ1.49(t，3H)，2.25(s，3H)，4.38(q，2H)，7.58(s，1H)，8.98(s，1H)，9.09(s，1H)，9.51(s，1H)。ESI-Ms(m/z)289(M-1)。
Embodiment hentriaconta-3 '-acetamido-4 '-oxyethyl group-6 '-amino-2-cyano-acetophenone (compounds X, R 1=ethanoyl, R 2=ethyl, X=cyano group, R 8=tertbutyloxycarbonyl, Z=-NH-) synthetic
(1g 0.0038mol) is dissolved in the 12mL pyridine, adds under the room temperature (BoC) with the title compound of embodiment 19 2O (0.83mL, 0.0046mol).Room temperature reaction 12hr, reaction solution add 20mL water, with dichloromethane extraction 3 times (10mL/ time), merge organic phase, the organic phase anhydrous sodium sulfate drying, and back solvent evaporated gets faint yellow solid 1.10g, yield 80%.
Embodiment 32 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Under the ice bath, compounds X (R 1=ethanoyl, R 2=ethyl, X=cyano group, R 8=tertbutyloxycarbonyl, Z=-NH-) (0.1mol) be dissolved in glycol dimethyl ether (250mL), add N, N-diformamide dimethylacetal (DMF-DMA) (16.0ml, 0.12mol), reaction 5h adds tosic acid (0.1mol), separates out the khaki color powder in the reaction solution, suction filtration, washing, dry khaki color solid 6-acetamido-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=ethanoyl, R 2=ethyl, X=cyano group, Z=-NH-) 22.5g, yield 83.0%. 1HNMR(300MHz，DMSO)δ1.45(t，3H)，2.14(s，3H)，4.20(q，2H)，7.05(s，1H)，8.60(s，1H)，8.70(s，1H)，9.21(s，1H)，12.58(s，1H)。ESI-Ms(m/z)270(M-1)。
Embodiment 33 6-benzoylamino-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=benzoyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Title compound with embodiment 17 is a raw material, according to the operation of embodiment 19～20, is equipped with the title compound of embodiment 33, total recovery 71% with legal system.ESI-MS(m/z)332(M-1)。
Embodiment 34 6-benzamido group-7-oxyethyl group-3-cyano group-4-hydroxyquinoline (compd A, R 1=benzyl, R 2=ethyl, X=cyano group, Z=-NH-) synthetic
Title compound with embodiment 18 is a raw material, according to the operation of embodiment 19～20, is equipped with the title compound of embodiment 34 with legal system, yellow solid, total recovery 69%.ESI-MS(m/z)318(M-1)。
Embodiment 35 3-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) propoxy-methyl phenyl ketone (compd B, R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, Z=-O-) synthetic
With 3-methoxyl group-4-(3-chlorine propoxy-) methyl phenyl ketone (compd B, R 1=methyl, R 2=3-chloropropyl, Z=-O-) (with 3-methoxyl group-4-hydroxy acetophenone is that raw material is according to document preparation (Journal ofMedicinal Chemistry, 1989,32 (1): 105-118)) mix with DMF, salt of wormwood, 60 ℃ were reacted 5 hours, aftertreatment gets the title compound of embodiment 35 with the step 4 of embodiment one.EI-MS(m/z)306(M +)。
Embodiment 36 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--6 '-nitro-2-cyano-acetophenone (Compound I, R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) synthetic
With reference to embodiment 2 synthetic operation to embodiment 4, be raw material with the title compound of embodiment 36, be equipped with the title compound of embodiment 36, three step total recoverys 69% with legal system.EI-MS(m/z)376(M +)。
Embodiment 37 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--6 '-amino-2-cyano-acetophenone (compound VIII, R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) synthetic
Compound I (R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group Z=-O-) adopts iron powder reducing, with reference to the preparation method of embodiment 19, gets the compound VIII (R of yellow solid 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-), yield 85%.EI-MS(m/z)346(M +)。
Embodiment 38 6-methoxyl group-7-(4-methyl isophthalic acid-piperazinyl) propoxy--3-cyano group-4-hydroxyquinoline (compd A, R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) synthetic
Under the ice bath, compound VIII (R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) (34.6g, 0.1mol) be dissolved in glycol dimethyl ether (250mL), add N, and N-diformamide dimethylacetal (DMF-DMA) (16.0ml, 0.12mol), reaction 4h, separate out the khaki color powder in the reaction solution, suction filtration, washing, dry khaki color solid 6-methoxyl group-7-(4-methyl isophthalic acid-piperazinyl) propoxy--3-cyano group-4-hydroxyquinoline (compd A, the R that get 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) 29.5g, yield 82.8%.ESI-MS(m/z)357(M+1)。
Embodiment 39 6-methoxyl group-7-(4-methyl isophthalic acid-piperazinyl) propoxy--3-cyano group-4-chloroquinoline (compd A ', R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) synthetic
Compound VIII (R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) (15.6g 0.045mol) is dissolved in glycol dimethyl ether (250ml), and (20.0ml, 0.12mol), back flow reaction 3h reacts and finishes to add triethyl orthoformate.Be chilled to room temperature, add phosphorus oxychloride (11ml) again, in 80 ℃ (outside temperature) reaction down.4hr to 4.5hr reaction finishes, and slowly pours into reaction solution in the 2 volume frozen water and stirs 1h, separates out yellow powder, suction filtration, and washing, with a small amount of glycol dimethyl ether washing, 40 ℃ are dry down again, get the compd A of yellow powder ' (R 1=methyl, R 2=(4-methyl isophthalic acid-piperazinyl) propyl group, X=cyano group, Z=-O-) 11.5g, yield 68%.EI-MS(m/z)376(M +)。

Claims (23)

1, as shown in the formula the 6-nitro-acetophenone compounds shown in the I:
Wherein,
X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3Or-CO 2R 3, R wherein 3And R 3' be C1～C10 alkyl that hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replace with being same to each other or different to each other;
Z is-NH-,-O-or
Figure A2008100389640002C2
R 1And R 1' be C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or aryl that C1～C10 alkyl, C1～C10 alkyloyl, aroyl, aryl that formyl radical, C1～C10 alkyl, C1～C10 alkenyl, aryl, aryl replace replace replace with being same to each other or different to each other;
R 2Be C1～C10 alkyl, C1～C10 alkenyl or aryl, described alkyl is necessarily replaced by halogen, alkoxyl group, aryl or the heterocyclic radical that contains 1～2 O or N, and wherein said heterocyclic radical is necessarily replaced by C1～C10 alkyl or C1～C10 alkoxyl group;
And when Z is-O-, R 1During for methyl, R 2It is not methyl.
2, the 6-nitro-acetophenone compounds shown in the formula I according to claim 1, wherein,
X be cyano group, trifluoromethyl ,-NHCOR 3,-NHCOOR 3,-N=CHR 3, C1～C10 carbalkoxy or carboxyl;
Z is-NH-or-O-;
R 1Be C1～C5 alkyl, ethanoyl, propionyl, benzoyl, tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz) or trityl;
R 2For methyl, ethyl, propyl group, benzyl ,-(CH 2) n-Cl ,-(CH 2) n-Br,
Figure A2008100389640002C3
Or
Figure A2008100389640003C1
Wherein n is 1～5 integer, and Alkyl is C1～C5 alkyl.
3, the 6-nitro-acetophenone compounds shown in the formula I according to claim 2, wherein,
X is cyano group, ethoxycarbonyl or methoxycarbonyl;
Z is-NH-or-O-;
R 1Be ethanoyl, benzoyl, benzyl or methyl;
R 2For ethyl ,-(CH 2) 3-Cl ,-(CH 2) 3-Br,
Figure A2008100389640003C2
Or
Figure A2008100389640003C3
4, the 6-nitro-acetophenone compounds shown in the formula I according to claim 3, wherein, described compound is:
3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone,
3 '-benzoylamino-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone,
3 '-benzamido group-4 '-oxyethyl group-6 '-nitro-2-cyano-acetophenone,
3 '-acetamido-4 '-oxyethyl group-6 '-nitro-2-ethoxy carbonyl methyl phenyl ketone or
3 '-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl) propoxy--6 '-nitro-2-cyano-acetophenone.
5, the preparation method of the 6-nitro-acetophenone compounds shown in the described formula I of claim 1 is characterized in that, X be cyano group, trifluoromethyl, nitro ,-NHCOR 3,-NHCOOR 3,-CONR 3R 3' ,-N=CHR 3Or-CO 2R 3, R wherein 3And R 3' when being the C1 that replaces of hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl～C10 alkyl, V obtains Compound I through decarboxylic reaction by compound with being same to each other or different to each other, its reaction formula is:
Figure A2008100389640003C4
R wherein 1, R 2, Z definition with claim 1; R 4C1～C10 alkyl for hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or aryl replacement.
6, the preparation method of the 6-nitro-acetophenone compounds shown in the described formula I of claim 1 is characterized in that, when X was cyano group, its preparation method was:
(1) the nitrated Compound D that obtains of compd B, the Compound D bromo obtains Compound I I, and the substitution reaction of Compound I I cyano group obtains Compound I, and its reaction formula is:
Figure A2008100389640004C1
R wherein 1, R 2, Z definition with claim 1; Perhaps
(2) the compd B bromination obtains compound III, the nitrated Compound I I that obtains of compound III, and Compound I I obtains Compound I through the cyano group substitution reaction, and its reaction formula is:
Figure A2008100389640004C2
R wherein 1, R 2, Z definition with claim 1; Perhaps
(3) the compd B bromo obtains compound III, and compound III obtains compound IV through the cyano group substitution reaction, and compound IV is nitrated to obtain compound shown in the Compound I, and its reaction formula is:
Figure A2008100389640004C3
R wherein 1, R 2, Z definition with claim 1.
7, the purposes of 6-nitro-acetophenone compounds in compound shown in the preparation formula A shown in the described formula I of claim 1, wherein, compound shown in the preparation formula A as follows
Figure A2008100389640005C1
R wherein 1, R 2, Z and X definition identical with claim 1;
(1) Compound I and compd E carry out condensation reaction and obtain compound shown in the formula VI,
Figure A2008100389640005C2
Wherein, Y is-N (R 5) 2Or-OR 5, R 5, R 6And R 7Be selected from the C1～C10 alkyl of C1～C10 alkyl, C1～C10 alkenyl, aryl and aryl replacement identical or differently;
Compound VI obtains compound shown in the formula VII under reductive condition, the cyclization of compound shown in the formula VII obtains compound shown in the formula A, and compound VI I can directly carry out ring-closure reaction without separating, and its reaction formula is:
Perhaps
(2) Compound I obtains the acid salt of compound VIII or compound VIII under reductive condition, compound VIII or its sour additive salt and compd E carry out condensation reaction and obtain compound VI I and/or Compound I X, compound VI I and/or Compound I X cyclization obtain compound shown in the formula A, and compound VI I can directly carry out ring-closure reaction without separating with Compound I X, and its reaction formula is:
Figure A2008100389640005C4
Or
Figure A2008100389640006C1
Perhaps
(3) Compound I obtains compound VIII under reductive condition, the amino and acid anhydrides (R of the virtue of compound VIII 8) 2O or halides R 8Cl, R 8The Br reaction obtains compounds X, and compounds X and compd E carry out condensation reaction and obtain compounds X I, and compounds X I obtains compounds X II through cyclization, and compounds X II takes off R 8Protecting group obtains compd A, and its reaction formula is:
Figure A2008100389640006C2
R wherein 8C1～C10 alkoxy carbonyl that C1～C10 alkyloyl, C1～C10 alkoxy carbonyl or the aryl that replaces for formyl radical, C1～C10 alkyloyl, aroyl, aryl replaces; The reaction that is prepared compd A by compounds X can one pot be finished, and intermediate X I and XII can be without separating.
8, the purposes of 6-nitro-acetophenone compounds in compound shown in the preparation formula A ' shown in the described formula I of claim 1, wherein, compound shown in the preparation formula A ' as follows
Figure A2008100389640006C3
R wherein 1, R 2, Z and X definition identical with claim 1;
(1) Compound I and compd E carry out condensation reaction and obtain compound shown in the formula VI,
Figure A2008100389640007C1
Wherein, Y is-N (R 5) 2Or-OR 5, R 5, R 6And R 7Be selected from the C1～C10 alkyl of C1～C10 alkyl, C1～C10 alkenyl, aryl and aryl replacement identical or differently;
Compound VI obtains formula A ' compound through reduction, cyclization, chloro, wherein midbody compound VII, compd A can be without separation, its reaction formula is:
Figure A2008100389640007C2
Perhaps
(2) Compound I obtains compound VIII under reductive condition, compound VIII and compd E carry out condensation reaction and obtain compound VI I and/or Compound I X, compound VI I and/or Compound I X obtain compound shown in the formula A ' through cyclization, chloro, and midbody compound VII/ Compound I X and compd A are without separating compound shown in the direct preparation formula A ', and its reaction formula is:
Figure A2008100389640007C3
9, according to the purposes of the 6-nitro-acetophenone compounds shown in claim 7 or the 8 described formula I, it is characterized in that reductive condition is: under the hydrogenation catalyst existence condition, feed hydrogen and react, hydrogenation catalyst is palladium carbon, active nickel, PtO 2Perhaps reductive condition is: add reductive agent, reductive agent can be iron powder, zinc powder or tin protochloride.
10, the purposes of 6-nitro-acetophenone compounds in compound shown in the preparation formula A shown in the formula I according to claim 7 is characterized in that, X is a compound shown in the formula A of cyano group, as follows preparation
Figure A2008100389640008C1
Wherein, R wherein 1, R 2Definition identical with claim 1; The definition of Y is identical with claim 7.
11, according to the purposes of the 6-nitro-acetophenone compounds shown in claim 7 or the 8 described formula I, it is characterized in that, compd E described in its preparation method is N, N-diformamide dimethylacetal, trimethyl orthoformate or triethyl orthoformate are directly substrate to be mixed with E to react under normal temperature or heating condition with the reaction conditions of E.
According to the purposes of the 6-nitro-acetophenone compounds shown in claim 7 or the 8 described formula I, it is characterized in that 12, the reductive condition in its preparation method is to adopt iron powder as reductive agent.
13, as shown in the formula compound shown in the II:
Figure A2008100389640009C1
Wherein, R 1, R 2, the R among the definition of Z and the claim 1-3 in any claim 1, R 2, Z definition is identical.
14, compound shown in the following formula III:
Figure A2008100389640009C2
Wherein, R 1, R 2, the R among the definition of Z and the claim 1-3 in any claim 1, R 2, Z definition is identical.
15, as shown in the formula compound shown in the IV:
Figure A2008100389640009C3
Wherein, R 1, R 2, the R among the definition of Z and the claim 1-3 in any claim 1, R 2, Z definition is identical.
16, as shown in the formula compound shown in the V:
Figure A2008100389640009C4
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical; R 4Definition and claim 5 in definition identical.
17, as shown in the formula compound shown in the VI:
Figure A2008100389640010C1
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical; The definition of Y is identical with definition in the claim 7.
18, as shown in the formula compound shown in the VII:
Figure A2008100389640010C2
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical; The definition of Y is identical with definition in the claim 7.
19, as shown in the formula compound shown in the VIII:
Figure A2008100389640010C3
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical.
20, as shown in the formula compound shown in the IX:
Figure A2008100389640010C4
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical; The definition of Y is identical with definition in the claim 7.
21, as shown in the formula compound shown in the X:
Figure A2008100389640011C1
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical.R 8Definition and claim 7 in definition identical.
22, as shown in the formula compound shown in the XI:
Figure A2008100389640011C2
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical; Y, R 8Definition and claim 7 in definition identical.
23, as shown in the formula compound shown in the XII:
Figure A2008100389640011C3
R wherein 1, R 2, the R among the definition of X, Z and the claim 1-3 in any claim 1, R 2, X, Z the definition identical; R 8Definition and claim 7 in definition identical.
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