CN102105433A - 6-nitro acetophenone compounds, preparation methods and uses thereof - Google Patents

6-nitro acetophenone compounds, preparation methods and uses thereof Download PDF

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CN102105433A
CN102105433A CN2009801291868A CN200980129186A CN102105433A CN 102105433 A CN102105433 A CN 102105433A CN 2009801291868 A CN2009801291868 A CN 2009801291868A CN 200980129186 A CN200980129186 A CN 200980129186A CN 102105433 A CN102105433 A CN 102105433A
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compound
yue
definition
nitro
alkyl
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CN102105433B (en
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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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    • 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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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

6-Nitro acetophenone compounds of Formula (I), wherein the substituents are defined as the specification, preparation methods, uses in the preparation of 3-substituent-4-hydroxyquinoline and 3-substituent-4-chloroquinoline compounds, and the intermediates thereof.

Description

6- nitro-acetophenone classes compound, preparation method and the usage
6- nitro-acetophenone classes compound, preparation method and the usage technical field
The present invention relates to available for 6- nitro-acetophenone class compounds for preparing 3- substitution -4- oxinoid compounds and 3- substitution -4- chlorinated quinoline compounds and its production and use, and its intermediate.More specifically, being related to 6- nitro-acetophenone class compounds shown in structural formula following article Formulas I and preparation method thereof and its is used to prepare 3- substitution -4- oxinoid compounds（Compound shown in formula A）With 3- substitution -4- chlorinated quinoline compounds（Formula A, shown compound）Purposes.Background technology
A A'
3-substitution-4- oxinoid compounds（Formula A) and 3- substitution -4- chlorinated quinoline compounds（Formula A') it is important medicine intermediate, it is the important intermediate for preparing the substituted quinoline derivatives of 3,4- bis-.For example, 3,4- bis- substituted quinoline derivatives are irreversible small molecule tyrosine kinase inhibitors（ Journal of Medicinal Chemistry, 46 (1):49-63), with active anticancer, part of compounds therein such as EKB-569 and HKI-272 (Journal of Medicinal Chemistry, 48 (4):1107-1131) etc. to treatment colorectal cancer, breast cancer and non-small cell lung cancer effectively, clinical investigation phase is come into, it is more likely that the anti-cancer agent with preferable market prospects can be turned into.Also Bosutinib (SKI-606) (Journal of Medicinal Chemistry, 2001,44 (23), 3965-3977), is also the anti-cancer agent clinically got a good chance of.
Η Κ Ι -272 Bosutinib (SKI606) are when the X in formula A is ester group, and the different substituted quinoline derivatives of 3,4- bis- are in antimalarial, coccidiosis（US3542781) or treatment type ii diabetes（WO2005073229) aspect also has extensive use.Therefore, optimization 3- substitution -4- oxinoid compounds and the synthesis technique of 3- substitution -4- chlorinated quinoline compounds, just have important practical value.
The crucial synthesis step of such compound is the formation of quinoline female ring, and needs to use hot conditions the synthesis of quinoline female ring more.For example when X is cyano group, the preparation method of formula A compounds is that formula C compounds are heated into 240 °C -260 °C in high boiling solvent reacts 10-20 hours（Reaction equation I) (WO03093241, WO2005065181, CN101012225)0Reaction condition used is more harsh, and yield is low, only 40 50 %, and high boiling solvent such as road oil generation（Dowtherm) inevitably volatilization is adversely affected to the health of working environment and operating personnel at high temperature, is had pollution to environment, is not suitable for large-scale industrial production.Therefore, mild condition, high income are found, cost is low, environmental pollution is small, just become particularly urgent suitable for the preparation method of industrialized production.
C A
Reaction equation I
The content of the invention
The present inventor is directed to finding the preparation method of mild condition, easy to operate, high income, low cost, safety and environmental protection, the 3- substitution -4- oxinoid compounds for being adapted to large-scale commercial production and 3- substitution -4- chlorinated quinoline compounds.Thus the 6- nitro-acetophenone class compounds shown in structural formula following article Formulas I have been invented, and it is easy, in high yield using the 6- nitro-acetophenone classes compound shown in Formulas I 3- substitution -4- oxinoid compounds and 3- substitution -4- chlorinated quinoline compounds are synthesized.
It is an object of the present invention to provide 6- nitro-acetophenone class compounds.
It is a further object to provide the preparation method of above-mentioned 6- nitro-acetophenones class compound.The a further object of the present invention is to provide the purposes of above-mentioned 6- nitro-acetophenones class compound.
It is yet another object of the invention to provide the intermediate that above-mentioned preparation method is related to.
The present invention provides the 6- nitro-acetophenone class compounds as shown in following formula I： In Formulas I,
X is cyano group, trifluoro Yue bases, nitro ,-NHCOR3、 -NHCOOR3、 -CONR3R3,-N=CHR3Or-C02R3, wherein R3And R3, the alkyl of 1 C of C 10 replaced for hydrogen, C1 C10 alkyl, the alkenyls of 1 C of C 10, aryl or aryl with being same to each other or different to each other；
Z be-NH -, -0- or-N -;
Ri and Ri, betrays base with being same to each other or different to each other for the betray C1 C10 alkoxies of base or aryl substitution of C1 C10 alkanoyls, C1 C10 alkoxies of Yue acyl groups, the alkyl of 1 C of C 10, the alkenyls of 1 C of C 10, aryl, the C1 C10 alkyl of aryl substitution, C1 C10 alkanoyls, aroyl, aryl substitution；
R2For C1 C10 alkyl, C1 C10 alkenyls or aryl, the alkyl is unnecessarily by halogen, alkoxy, aryl or heterocyclic radical containing 120 or N（Such as pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, homopiperazine base）Substitution, wherein the heterocyclic radical is unnecessarily replaced by C1 C10 alkyl or C1 C10 alkoxies；
And when it is Yue bases that Z, which is -0-, Ri, R2It is not Yue bases.
In a preferred embodiment of the present invention, in Formulas I,
X is cyano group, trifluoro Yue bases ,-NHCOR3、 -NHCOOR3、 -N=CHR3、 C1-C10 Alkoxy carbonyl group or carboxyl；
Z is-NH- or -0-；
For 15 alkyl, acetyl group, propiono, benzene Yue acyl groups, tertbutyloxycarbonyl, benzyl, benzyloxycarbonyl group or triphen Yue bases；
/ ~ \
-†CH2i-N N-Alkyl
R2For Yue bases, ethyl, propyl group, benzyl ,-(CH2)n-Cl、 -(CH2)n-Br、 ^
-†CH2i-( N-Alkyl
Or " ^, whereinn=l 5 integer, Alkyl is C1 C5 alkyl.In further preferred embodiment of the present invention, in Formulas I,
X is that cyano group (- CN), ethoxy are betrayed base (- COOC2H5), Yue oxygen carbonyls（ -COOCH3 );
Z is-NH- or -0-；
For acetyl group, benzene Yue acyl groups, benzyl or Yue bases；
R2For ethyl ,-(CH2)3-C1 、 -(CH2)3-Br 、 Or
-†CH2j^ ~ ^N-CH3In the embodiment of the present invention still more preferably, Formulas I is：
3,-acetamido -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones；
3,-benzene Yue amide groups -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones；
3,-benzamido group -4,-ethyoxyl -6,-nitro -2- ^ acetophenones；
3,-acetamido -4,-ethyoxyl -6,-nitro -2- ethyoxyls are betrayed benzoylformaldoxime；
3,-Yue epoxide -4,-(the small piperazinyl of 4- Yue bases) propoxyl group -6,-nitro -2- cyano-acetophenones.
The present invention relates to the preparation method of the 6- nitro-acetophenone class compounds shown in Formulas I, it is characterised in that this method includes：
(1) when X is cyano group, trifluoro Yue bases, Xiao Ji ,-NHCOR3、-NHCOOR3、-CONR3R3, -N=CHR3Or-C02R3, wherein R3And R3, when being hydrogen, C1 C10 alkyl, C1 C10 alkenyls, aryl or the C1 C10 alkyl of aryl substitution with being same to each other or different to each other, compound I is obtained through decarboxylic reaction by compound V；Its reaction equation is：
Z be-NH -, -0- or-N -;
Ri and Ri, betrays base with being same to each other or different to each other for the betray C1 C10 alkoxies of base or aryl substitution of C1 C10 alkanoyls, C1 C10 alkoxies of Yue acyl groups, the alkyl of 1 C of C 10, the alkenyls of 1 C of C 10, aryl, the C1 C10 alkyl of aryl substitution, C1 C10 alkanoyls, aroyl, aryl substitution；
R2For C1 C10 alkyl, C1 C10 alkenyls or aryl, the alkyl is unnecessarily by halogen, alkoxy, aryl or containing 120 or N heterocyclic radicals（Such as pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, homopiperazine base）Substitution, wherein the heterocyclic radical is unnecessarily replaced by C1 C10 alkyl or C1 C10 alkoxies；
R4The C1 C10 alkyl replaced for hydrogen, C1 C10 alkyl, C1 C10 alkenyls, aryl or aryl；
And when it is Yue bases that Z, which is -0-, Ri, R2It is not Yue bases.
Wherein, compound V can be bought by market；Or replace -6- nitrobenzene Yue acid to be prepared for raw material with reference to the method for embodiment 15 or embodiment 23 with 3,4- bis-.3,4- bis- replaces -6- nitrobenzene Yue acid to be bought by market or by 3,4- disubstituted benzenes Yue acid Yue esters are prepared after nitrification, hydrolysis ester group, also it can be obtained with 3- amino -4- substitution -6- nitrobenzene Yue acid through amination, or replace -4- hydroxyls -6- nitros-benzene Yue acid with 3- Yue esters are acidified and obtain.
Or (2) when X=cyano group, compound D is obtained by compound B nitrifications, compound D bromos obtain compound II, and compound II obtains compound I through cyano group substitution reaction；Its reaction equation is：
BD II I wherein Z, 1^ sums are defined as above；
Or
(3) when X=cyano group, compound III is obtained by compound B brominations, compound III nitrifications obtain compound II, and compound II obtains compound I through cyano group substitution reaction；Its reaction equation is：
Wherein Z, 1^ sum is defined as above；
Or
(4) when X=cyano group, compound III is obtained by compound B bromos, compound III obtains compound IV through cyano group substitution reaction, and compound IV nitrifications obtain compound I；Its reaction equation is： Wherein Z sums are defined as above；
In above-mentioned reaction, in the preparation of compound of formula I, the reaction such as the decarboxylation, bromo, nitrification, substitution is all popular response in the art.Compound B can be bought by market, or the method by raw material of parahydroxyacet-ophenone with reference to embodiment one is synthesized, or the method by raw material of 3-Yue epoxides-4-hydroxyacetophenone with reference to embodiment 35 is synthesized.
The invention further relates to the purposes of the 6- nitro-acetophenone class compounds shown in Formulas I, it is characterised in that 6- nitro-acetophenone class compounds shown in Formulas I can be prepared as follows compound shown in formula A,
X is cyano group, trifluoro Yue bases, nitro ,-NHCOR3、 -NHCOOR3, -CONR3R3,-N=CHR3Or C02R3, wherein R3And R3, the C1 C10 alkyl replaced for hydrogen, C1 C10 alkyl, C1 C10 alkenyls, aryl or aryl with being same to each other or different to each other；
Z be-NH -, -0- or-N -;
Ri and Ri, betrays base with being same to each other or different to each other for the betray C1 C10 alkoxies of base or aryl substitution of C1 C10 alkanoyls, C1 C10 alkoxies of Yue acyl groups, the alkyl of 1 C of C 10, the alkenyls of 1 C of C 10, aryl, the C1 C10 alkyl of aryl substitution, C1 C10 alkanoyls, aroyl, aryl substitution；
R2For C1 C10 alkyl, C1 C10 alkenyls or aryl, the alkyl is unnecessarily replaced by halogen, alkoxy, aryl or heterocyclic radical containing 1 ~ 20 or N, such as pyrrolidines, piperidines, morpholine, piperazine, homopiperazine, wherein the heterocycle unnecessarily can be replaced by C1 C10 alkyl or C1 C10 alkoxies；
(1) compound I and compound E carries out condensation reaction and obtains compound shown in Formula IV,
E
Wherein, Y is-N (R5)2Or-OR5, R5、 R6And R7In the C1 C10 alkyl replaced selected from C1 C10 alkyl, C1 C10 alkenyls, aryl and aryl identical or differently.
Compound VI obtains compound shown in Formula VII under the reducing conditions, and compound cyclization shown in Formula VII obtains compound shown in formula A；Or compound VII can directly carry out ring-closure reaction without isolation Obtain compound shown in formula A；Its reaction equation is：
Or
(2) compound I obtains compound VIII or compound VIII acid-addition salts under the reducing conditions, compound VIII (or its acid-addition salts）Condensation reaction is carried out with compound E and obtains compound VII and/or compound IX, and compound VII and/or compound IX cyclizations obtain compound shown in formula A；Or compound VII and compound IX can directly carry out ring-closure reaction and obtain compound shown in formula A without isolation；Its reaction equation is：
；Or
(3) compound I obtains compound VIII, compound VIII fragrant amino and acid anhydrides under the reducing conditions（（R8)2Or halides 0)（Such as R8C1、 R8Br) react, obtain compound X, compound X and compound E progress condensation reaction and obtain compound XI, compound XI obtains compound XII through cyclization, and compound XII Deprotections obtain compound A；Its reaction equation is：
Wherein R8The C1 C10 alkoxy carbonyls that can replace for C1 C10 alkanoyls, C1 C10 alkoxy carbonyls or the aryl of general protection group, i.e. Yue acyl groups, C1 C10 alkanoyls, aroyl, aryl substitution.It can be completed by compound X prepare compounds A reaction with one kettle way, intermediate X I and XII can be without isolation.
In above-mentioned prepare compound A method, the condition that condensation reaction is carried out with E can directly mix substrate with E in the case where being not added with catalyst, be reacted under normal temperature or heating condition.Described reducing condition can be：Under hydrogenation catalyst existence condition, it is passed through hydrogen and is reacted, hydrogenation catalyst can be palladium carbon, active nickel or Pt02;Can also be：Reducing agent is added, for example, adds iron powder, zinc powder or stannous chloride.Can be that reduction and the step of ring-closure reaction one are completed under conditions of reducing agent presence by compound VI prepare compounds A, without separation of intermediates VII；Can mix compound VIII with E by compound VIII prepare compounds A, condensation and the step of ring-closure reaction one are completed under normal temperature or heating condition, without separation of intermediates VII and/or IX.Compound X is with containing R by compound VIII8The acid anhydrides of substituent carries out the acylation of routine for thing or obtained for reaction.The sour three Yue esters of the Yue acetals (DMF-DMA) of bis- Yue acid amides of compound E preferred N, N- two, original Yue or original Yue triethylenetetraminehexaacetic acid esters.
In above-mentioned prepare compound A method, reducing condition preferably is：Under hydrogenation catalyst existence condition, it is passed through hydrogen and is reacted, hydrogenation catalyst is palladium carbon, solvent for use is acetic acid；Or reducing condition is：Reducing agent is added, reducing agent is iron powder or zinc powder, further adds calcium chloride or ice Acetic acid, solvent for use is alcohol or alcohol-water mixed solvent.
The invention further relates to another purposes of the 6- nitro-acetophenone class compounds shown in Formulas I, it is characterised in that the 6- nitro-acetophenone class compounds shown in Formulas I can be prepared as follows formula A, shown compound, Wherein, R2, X and Z definition with formula A compounds.
(1) compound I and compound E carries out condensation reaction and obtains compound shown in Formula IV,
O 6
Y people OR7
E
Wherein, Y is-N (R5)2Or-OR5, R5、 R6And R7In the C1 C10 alkyl replaced selected from C1 C10 alkyl, C1 C10 alkenyls, aryl and aryl identical or differently.
Compound VI obtains formula A, compound through reduction, cyclization, chloro；Or wherein intermediate
' compound；Its reaction equation is：
Or
(2) compound I obtains compound VIII under the reducing conditions, compound VIII and compound E carries out condensation reaction and obtains compound VII and/or compound IX, compound VII and/or compound IX obtains formula A, shown compound through cyclization, chloro；Or midbody compound VII/ compounds IX and compound A direct formula A, shown compound without isolation；Its reaction equation is：
In above-mentioned prepare compound A' method, the reduction, cyclization and E carry out preparation method of the condition with above-mentioned formula A of condensation reaction.The chlorination can be reacted using chlorinating agent, be reacted for example with chlorinating agents such as POCl3, phosphorus pentachlorides.
Invention also provides following formula Π Χ Ι compounds：
Wherein, X is cyano group, trifluoro Yue bases, nitro ,-NHCOR3、 -NHCOOR3、 -CONR3R3,-N=CHR3Or-C02R3, wherein R3And R3, the C1 C10 alkyl replaced for hydrogen, C1 C10 alkyl, C1 C10 alkenyls, aryl or aryl with being same to each other or different to each other；Z be-NH -, -0- or -;！^ and！^, betrays base with being same to each other or different to each other for the betray C1 C10 alkoxies of base or aryl substitution of C1 C10 alkanoyls, C1 C10 alkoxies of Yue acyl groups, C1 C10 alkyl, C1 C10 alkenyls, aryl, the C1 C10 alkyl of aryl substitution, C1 C10 alkanoyls, aroyl, aryl substitution； R2For C1 C10 alkyl, C1 C10 alkenyls or aryl, the alkyl is unnecessarily replaced by halogen, alkoxy, aryl or heterocyclic radical containing 1 ~ 20 or N, such as pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, homopiperazine base, wherein the heterocyclic radical unnecessarily can be replaced by C1 C10 alkyl or C1 C10 alkoxies；And when Z is -0-, is Yue bases, R2It is not Yue bases；Y is-N (R5)2Or-OR5, R5In the C1 C10 alkyl replaced selected from C1 C10 alkyl, C1 C10 alkenyls, aryl and aryl； R8The C1 C10 alkoxy carbonyls that can replace for C1 C10 alkanoyls, C1 C10 alkoxy carbonyls or the aryl of general amino protecting group, i.e. Yue acyl groups, C1 C10 alkanoyls, aroyl, aryl substitution.
In above compound, Ri is preferably C1 C5 alkyl, acetyl group, propiono, benzene Yue acyl groups, tertbutyloxycarbonyl, benzyl, benzyloxycarbonyl group or triphen Yue bases； R2Preferably Yue bases, ethyl, propyl group,
-+CH2- 1-N N-Alkyl Nian CH2" bases of N-Alkyl thousand ,-(CH2)n-Cl、 -(CH2) n-Br, ^ or ' " ^, wherein n=l 5, Alkyl be C1 C5 alkyl；X is preferably cyano group, trifluoro Yue bases ,-NHCOOR3、 -NHCOOR3、 -N=CHR3, C1 C10 alkoxy carbonyl groups or carboxyl；Z is preferably-NH- or -0-； Y It is preferred that-N (C)2、 -OC¾、 OC2H5; R8Base, benzyloxycarbonyl group it is preferred that acetyl group, tertiary fourth oxygen are betrayed.Above compound is more preferably：
Formula II compound is preferred：
3,-acetamido -4,-ethyoxyl -6,-Xiao Ji -2- bromoacetophenones；
3,-benzene Yue amide groups -4,-ethyoxyl -6,-nitro -2- bromoacetophenones；
3,-benzamido group -4,-ethyoxyl -6,-nitro -2- bromoacetophenones；
3 ,-Yue epoxide-4 ,-(- 1-piperazinyl of 4- Yue bases) propoxyl group-6 ,-nitro-2- bromoacetophenones；
Formula III compound is preferred：
3,-acetamido -4,-ethyoxyl -2- bromoacetophenones；
3,-benzene Yue amide groups -4,-ethyoxyl -2- bromoacetophenones；
3,-benzamido group -4,-ethyoxyl -2- bromoacetophenones；
3,-Yue epoxide -4,-(4- Yue base -1- piperazinyls) propoxyl group -2- bromoacetophenones；
Formula IV compound is preferred：
3,-acetamido -4,-ethyoxyl -2- cyano-acetophenones；
3,-benzene Yue amide groups -4,-ethyoxyl -2- cyano-acetophenones；
3,-benzamido group -4,-ethyoxyl -2- cyano-acetophenones；
3 '-Yue epoxide-4 ,-(- 1-piperazinyl of 4- Yue bases) propoxyl group-2- cyano-acetophenones；
Formula V compound is preferred：
3- (5- acetamido -4- ethyoxyl -2- nitrobenzophenones) carbonyl-ethyl propionate；
2- (5- acetylaminohydroxyphenylarsonic acids4- ethyoxyl-2- nitrobenzene Yue acyl groups) diethyl malonate；
Formula IV compound is preferred：
N-(5-(2- cyano group-3- (two Yue bases amidos) acryloyl group)-2- ethyoxyl-4- nitrobenzophenone）Acetamide；
N- (5- (2- cyano group -3- (Yue epoxides) acryloyl group) -2- ethyoxyl -4- nitrobenzophenones）Acetamide；
N- (5- (2- ethoxy carbonyls -3- (two Yue base amidos）Acryloyl group) -2- ethyoxyl -4- nitrobenzophenones) acetamide； Formula VIII compound is preferred：
3,-acetamido -4,-ethyoxyl -6,-amino -2- cyano-acetophenones；
3,-benzene Yue amide groups -4,-ethyoxyl -6,-amino -2- cyano-acetophenones；
3,-benzamido group -4,-ethyoxyl -6,-amino -2- cyano-acetophenones；
3 ,-Yue epoxide-4 ,-(- 1-piperazinyl of 4- Yue bases) propoxyl group-6 ,-amino-2- cyano-acetophenones.The technique effect that the present invention is realized is as follows：
(1) in the present invention, with compound I prepare compound A and A, method, relative to the literature method of the preparation of existing quinoline ring, can avoid using hot conditions, it is to avoid use high boiling solvent, environmental protection and safety.Particularly, X=cyano group or yield reaches more than 80% during ester group, hence it is evident that better than existing method.
(2) compound I very convenient, high productivity can be obtained by the raw material of industry.
(3) high conversion rate of reaction, easy to operate, and reaction condition is gentle.More intermediate is not required to isolate and purify, and can be directly used for the next step, drastically increases yield, simplifies operation.Industrialized production can be realized.
(4) with compound I prepare compound A or A, method in, method for optimizing（2), its reaction condition is gentle, and intermediate is stable, and more easy purification, yield is higher, and cost is substantially reduced.Prepare object A or A, reaction produce impurity it is few, product is easily purified, easy to operate, and total recovery is higher, is more easy to realize industrialized production.
In a word, by the present invention, the brand-new synthetic route of 3- substitution -4- oxinoid compounds and 3- substitution -4- chloroquinoline class compounds is realized, mild condition, operation is simple, safely and effectively.Embodiment
The present invention is further illustrated by the examples that follow, following examples are only used for being more particularly described the preferred embodiment of the present invention, are not used in and technical scheme is defined.The technical scheme of the invention described above is the technical scheme of achievable the object of the invention.I.e. following examples use temperature And reagent, it can use relevant temperature described above and reagent to substitute to realize the purpose of the present invention.In following preparation examples, nuclear magnetic resonance is by Bmker AMX-400 types and INVOA-600 type nmr determinations, and TMS is internal standard, and chemical shift unit is ppm;Mass spectrum is determined by MAT-711 types and the general instrument of MAT-95 type matter i；Column chromatography silica gel 200-300 mesh, Haiyang Chemical Plant, Qingdao's production；TLC silica gel plates are the HSGF-254 type thin-layer chromatography prefabricated boards that Yantai chemical plant is produced；Petroleum ether boiling range is 60-90 °C;Using uviol lamp, the colour developing of iodine cylinder.If unspecified operating method in preparation example, the concentration, which refers to, is steamed the solvent in prepare compound solution with Rotary Evaporators；The drying, which refers to, is dried prepare compound at 60 °C with DHG-9240A thermostatic drying chambers.
3- acetamido -4- ethoxy the ethyl ketones of embodiment one（Compound B, acetyl group, R2=ethyl, Z=- NH-) synthesis
(1) preparation of 3- nitros -4-hydroxyacetophenone
In ice bath, by parahydroxyacet-ophenone（136.2g, l .Omol) it is added to dense stone υ acid（In 1000ml), 10min is stirred, potassium nitrate is added（103.0g, 1.02mol), 2h is stirred, reaction terminates.Reaction solution is poured into 3000ml trash ices, a large amount of solids are separated out, suction filtration is washed, dries, obtain 3- nitros -4-hydroxyacetophenone 171.2g of pale yellow powder, yield 94.5%.
The preparation of (2) 3-amino-4-hydroxy acetophenones
Under normal temperature, by 3- nitros -4-hydroxyacetophenone（171.2g, 0.945mol) it is dissolved in THF
In (1500ml), power mouth enters Raney Ni 20g, and normal pressure hydrogenation reaction 24h, reaction terminates.Filtering, is concentrated, and is dried, is obtained the 3- amino-4-hydroxy acetophenone 132.8g of Tan solid, yield 93.0%.
(3) preparation of 3- acetamidos -4-hydroxyacetophenone
By 3-amino-4-hydroxy acetophenone（121.0g, 0.8mol) it is dissolved in glacial acetic acid（In 1000ml), acetic anhydride is added dropwise in 60 °C of stirrings（115.0ml, 1.2mol), lh is added, and is stirred for 30min, and reaction terminates.Reaction solution is poured into 2000ml frozen water, a large amount of solids are separated out, 2h is placed in stirring, and suction filtration is washed, dries, obtain 3- acetamidos -4-hydroxyacetophenone 134.8g of yellowish-brown powder, yield 87.2%. (4) preparation of 3- acetamidos -4- acetophenones
By 3- acetamidos -4-hydroxyacetophenone（96.6g, 0.5mol) and potassium carbonate（138.2g, l .Omol) it is dissolved in DMF (500ml), bromoethane (60ml, 0.75mol) is added dropwise, and lh is added, and is stirred for 30min, and reaction terminates in 60 °C of stirring lOmin.Reaction solution is poured into 2000ml frozen water, extracted with ethyl acetate（600mlx4), organic layer is washed, dries, is concentrated to give the 3- acetamido -4- acetophenones of grey-brown powder（Compound B, Ri=acetyl group, R2=ethyl, Z=- NH-) 100.9g, yield 91.2%. 1HNMR (300MHz, CDC13) 51.49 (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+l), 244(M+23), 260(M+39).3- acetamido -4- ethyoxyl -6- the nitro-acetophenones of embodiment two（Compound D, acetyl group, R2=ethyl, Z=- NH-) synthesis
By compound B (1^=acetyl group, R2=ethyl, Z=- NH-) (88.5g, 0.4mol) be dissolved in nitro Yue alkane（In 1000ml), fuming nitric aicd is added（17.7ml, 0.4mol), in 40 ° of 〇 stirring 12h, add fuming nitric aicd（15.5ml, 0.35mol), 10h is stirred, reaction terminates.Reaction solution is poured into saturated sodium bicarbonate solution（In 1000ml), stirring, point liquid washes organic layer, dry, filtering, 10g activated carbons are added in filtrate, flow back 20min, heat filter, is concentrated to give red oil, 40 °C of constant pressure and dries obtain the 3- acetamido -4- ethyoxyl -6- nitro-acetophenones of light red solid（Compound D, acetyl group, R2=ethyl, Z=- NH-) 86.5g, yield 81.2%. 1HNMR (300MHz, CDC13)51.52 (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-l).Embodiment 33,-acetamido -4,-ethyoxyl -6,-nitro -2- bromoacetophenones（Compound II, acetyl group, R2=ethyl, Z=- NH-) synthesis
By compound D (Ri=acetyl group, R2=ethyl, Z=- NH-) (79.9g, 0.3mol) be dissolved in Dichloro Yue alkane（In 1000ml), bromine is added（15.7ml, 0.306mol), stirring at normal temperature 12h, reaction solution is changed into faint yellow from pale red, and reaction terminates.It is concentrated to give the 3 of pale red grease,-acetamido -4,-ethyoxyl -6,-nitro -2- bromoacetophenones（Compound II, R corpse acetyl group, R2=ethyl, Z=- NH-) HO.Og, it can be directly used for next step reaction.1HNMR (300MHz, CDC13) 51.55 (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+l), 368(M+23)0Example IV 3,-acetamido -4,-ethyoxyl -6,-nitro-acetophenone（Compound I, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
By compound II (1^=acetyl group, R2=ethyl, Z=- NH-) (HO.Og, 0.3mol) be dissolved in ethanol（600ml) and in DMSO (200ml), Cymag is added dropwise in ice bath cooling（29.4g, 0.6mol) water（300ml) solution, lh is added, and reaction solution is in dark brown, and normal-temperature reaction 6h, reaction terminates.Reaction solution is poured into 2000ml water, adjusts solution ph to be 5 with 1M hydrochloric acid, a large amount of solids are separated out, suction filtration is washed, dries, obtain the 3 of lark powder,-acetamido -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones（Compound I, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 68.3g, yield 78.2%. 1HNMR (300MHz, CDC13) 51.56 (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-l)oThe N- of embodiment five (5- (2- L bases -3- (dimethyl amido) acryloyl group) -2- ethyoxyl -4- nitrobenzophenones) acetamide（Compound VI, acetyl group, R2=ethyl, X=l^, Y=- N (CH3)2, Z=- NH-) synthesis
By compound I (R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) (58.3g, 0.2mol) be dissolved in the Yue ethers of ethylene glycol two（In 600ml), N is added, the Yue acetals (DMF-DMA) (29.2ml, 0.22mol) of bis- Yue acid amides of N- two are stirred at room temperature, gradually separated out in reaction solution anti-after pale yellow powder, lh It should terminate.Suction filtration, is washed, and is dried, is obtained N- (5- (2- cyano group -3- (two Yue bases amidos) acryloyl group) -2- ethyoxyl -4- nitrobenzophenones of pale yellow powder）Acetamide（Compound VI, R corpse acetyl group, R2=ethyl, X=cyano group, Y=- N (C)2, Z=- NH-) and 93.0g, yield 91.0%. ifiNMR (300MHz:DMSO) 51.43 (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-l).Base -4- hydroxyls the quinolines of six 6- acetamido -7- ethyoxyls -3- of embodiment 1 drench（Compound A, acetyl group, R2=ethyl, X=FU- Z=- NH-) synthesis
By compound VI (1^=acetyl group, R2=ethyl, X=cyano group, Y=- N (CH3)2, Z=- NH-) and (34.6g, O. lmol) be dissolved in DMF (300ml), and power mouth enters Raney Ni 6g, and normal pressure hydrogenation reaction 3h, reaction terminates.Filtering, filtrate is concentrated into half volume, then uses water（600ml) dilute, separate out solid, left at room temperature over night, suction filtration is washed, dries, obtain the 6- acetamido -7- ethyoxyl -3- cyano group -4- oxyquinolines of pale yellow powder（Compound A, R acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 16.6g, the % of yield 61.IHNMR pOOMHz'DMSO^l ^S (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-l).Base -4- hydroxyls the quinolines of seven 6- acetamido -7- ethyoxyls -3- of embodiment 1 drench（Compound A, acetyl group, R2=ethyl, X=FU- Z=- NH-) synthesis
By compound VI (R corpse acetyl group, R2=ethyl, X=cyano group, Y=- N (C)2, Z=- NH-) and (5.0g, 0.0144mol) be dissolved in DMF (60ml) and ethanol（10ml), the water of calcium chloride (7.2 g, 0.0648mol) is added（10ml) solution, adds to react after reduced iron powder (3.6g, 0.0648mol), 75 °C of reactions, 6h and terminates, add activated carbon（0.5g), in 75 °C of decolouring 20min.Suction filtration, filtrate is concentrated into half volume, and filtrate pours into trash ice（100 g) in, place lh, separate out khaki solid, suction filtration, washing, dry khaki solid 6- acetamido -7- ethyoxyl -3- cyano group -4- hydroxyls Base quinoline（Compound A, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 3.1g, yield 79%.1HNMR (300MHz, DMSO) 51.45 (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-l).The N- of embodiment eight (5- (2- L bases -3- (methacryloyl) -2- second -4- nitrobenzophenones）Acetamide（Compound VI, second StJ^, R2=ethyl, X=FU-> Y=-OCH3, Z=- NH-) synthesis
By compound I (Ri=acetyl group, R2=ethyl, X=L＆, Z=- NH-) (58.3g, 0.2mol) be suspended in the Yue ethers of ethylene glycol two（In 600ml), the sour three Yue esters of original Yue are added（Compound E, Y=OCH3) (63.6g, 0.6mol), lead to nitrogen protection, be heated to reflux, 5-6h reactions terminate.Steam solvent and obtain yellow-brown solid, with recrystallization from ethyl acetate/petroleum ether, obtain pale yellow powder N- (5- (2- cyano group-3- (Yue epoxides) acryloyl group)-2- ethyoxyl-4- nitrobenzophenone）Acetamide（Compound VI, Ri=acetyl group, R2=ethyl, X=cyano group, Y=- OCH3, Z=- NH-) and 50.2g, yield 81%.1HNMR (300MHz, DMSO) 51.46 (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+l).Base -4- hydroxyls the quinolines of nine 6- acetamido -7- ethyoxyls -3- of embodiment 1 drench（Compound A, acetyl group, R2=ethyl, X=FU- Z=- NH-) synthesis
By compound VI (R corpse acetyl group, R2=ethyl, X=cyano group, Y=- OCH3, Z=- NH-) and (30.5g, O. lmol) be dissolved in DMF (300ml), and power mouth enters Raney Ni 6g, and normal pressure hydrogenation reaction 4h, reaction terminates.Filtering, filtrate is concentrated into half volume, then uses water（600ml) dilute, separate out white solid, left at room temperature over night, suction filtration is washed, dries, obtain the 6- acetamido -7- ethyoxyl -3- cyano group -4- oxyquinolines of pale yellow powder（Compound A, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 20.5g, yield 76%.IfiNMR (300MHz, DMSO) 51.45 (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-l).Embodiment 10,-acetamido -4,-ethyoxyl -2- bromoacetophenones（Compound III, acetyl group, R2=ethyl, Z=- NH-) synthesis
By compound B (1^=acetyl group, R2=ethyl, Z=- NH-) (66.4g, 0.3mol) be dissolved in dichloro Yue alkane（In 1000ml), bromine is added（15.7ml, 0.306mol), stirring at normal temperature 2h separates out gray solid in reaction solution, reaction terminates.Concentration of reaction solution is to 300 mL, and suction filtration, washing, drying obtain the 3 of gray solid,-acetamido -4,-ethyoxyl -2- bromoacetophenones（Compound III, Acetyl group, R2=ethyl, Z=- NH-) 98.0g, yield 80%. ifiNMR (300MHz,
CDC13) 51.56 (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-l ).Embodiment 11,-acetamido -4,-ethyoxyl -6,-nitro -2- bromoacetophenones（Compound II, acetyl group, R2=ethyl, Z=- NH-) synthesis
By compound III (Ri=acetyl group, R2=ethyl, Z=- NH-) (98.0g, 0.3mol) be dissolved in nitro Yue alkane（In 1000ml), fuming nitric aicd is added（15.1ml, 0.36mol), 5h is stirred in 40 °C, fuming nitric aicd is added（13.3ml, 0.3mol), 2h is stirred, reaction terminates.Reaction solution is poured into saturated sodium bicarbonate solution（In 1000ml), organic layer is washed in stirring, is dried, filtering, 10g activated carbons are added in filtrate, flow back 20min, heat filter is concentrated to give brown oil, 40 °C of constant pressure and dries obtain the 3 of brown solid,-acetamido -4,-ethyoxyl -6,-nitro -2- bromoacetophenones（Compound II, R corpse acetyl group, R2=ethyl, Z=- NH-) 86. lg, yield 83.2%. 1HNMR (300MHz, CDC13) 51.55 (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+l), 368(M+23). Embodiment 12,-acetamido -4,-ethyoxyl -6, the benzoylformaldoximes of-nitro -2- 1（Compound I, Ri=acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
By compound II (R corpse acetyl group, R2=ethyl, Z=- NH-) (HO.Og, 0.3mol) be dissolved in ethanol（600ml) and in DMSO (200ml), solid is incomplete molten, and Cymag is added dropwise in ice bath cooling（29.4g, 0.6mol) water（300ml) solution, lh is added, and normal-temperature reaction 6h, reaction terminates.Reaction solution is poured into 2000ml water, adjusts solution ph to be 5 with 1M hydrochloric acid, a large amount of solids are separated out, suction filtration is washed, dries, obtain the 3 of pale yellow powder,-acetamido -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones（Compound I, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 68.3g, yield 80% 1HNMR (300MHz, CDC13) 51.56 (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,-acetophenone（Compound IV, acetyl group, R2=ethyl, X=FU- Z=- NH-) synthesis
By compound III (1^=acetyl group, R2=ethyl, Z=- NH-) (98.0g, 0.3mol) be dissolved in ethanol（500ml) and in DMSO (300ml), solid is incomplete molten, and Cymag is added dropwise in ice bath cooling（29.4g, 0.6mol) water（300ml) solution, lh is added, and the solid in reaction solution gradually dissolves, and normal-temperature reaction 2h, reaction terminates.Reaction solution is poured into 2000ml water, adjusts solution ph to be 5 with 1M hydrochloric acid, a large amount of solids are separated out, suction filtration is washed, dries, obtain the 3 of pale yellow powder,-acetamido -4,-ethyoxyl -2- cyano-acetophenones（Compound IV, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 57.0g, yield 77.2%.1HNMR (300MHz, DMSO) 51.38 (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,-ethyoxyl -6,-nitro -2-H benzoylformaldoximes（Compound I, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis By compound IV (R corpse acetyl group, R2=ethyl, X=L＆, Z=- NH- X 73.8g, 0.3mol) it is dissolved in nitro Yue alkane（In 1000ml), fuming nitric aicd is added（15.1ml, 0.36mol), 2h is stirred, fuming nitric aicd is added（13.3ml, 0.3mol), 5h is stirred, reaction terminates.Reaction solution is poured into saturated sodium bicarbonate solution（In 1000ml), organic layer is washed in stirring, is dried, filtering, 10g activated carbons are added in filtrate, flow back 20min, heat filter is concentrated, dried, obtain the 3 of brown solid,-acetamido -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones（Compound I, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 71g, yield 81%.1HNMR (300MHz, CDC13) 51.56 (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).The 3- of embodiment 15 (5- acetamido -4- second -2- nitrobenzophenones) -2-H^-3-^- ethyl propionates（Compound V, acetyl group, R2=ethyl, R4=ethyl, X=H^, Z=- NH-) synthesis
By 3- amido -4- hydroxy benzenes Yue acid Yue esters（133.7 g, 0.8 mol) it is dissolved in glacial acetic acid（1000 mL) in, 60 °C of stirrings are incomplete molten, and acetic anhydride is added dropwise（115.0 mL, 1.2 mol), lh power mouthful is complete, and reaction terminates, and separates out a large amount of solids.Reaction solution is poured into 2000 mL frozen water, a large amount of solids are separated out, lh is placed in stirring, and suction filtration is washed, dries, obtain the g of 3- acetamido -4- hydroxy benzenes Yue acid Yue esters 154.3 of Off-white solid, yield 92.2%.
By 3- acetamido -4- hydroxy benzenes Yue acid Yue esters (104.6 g, 0.5 mol) and potassium carbonate (138.2 g, l.Omol) be dissolved in DMF (500 mL), 60 °C stirring 10min, it is incomplete molten, bromoethane is added dropwise（60.0 mL, 0.75 mol), l h power.Complete, reaction terminates, and separates out a large amount of solids.Reaction solution is poured into 2000 mL frozen water, a large amount of solids are separated out, suction filtration is washed, dries, obtain the g of 3- acetamido -4- ethoxybenzenes Yue acid Yue esters 112.0 of pale pink solid, yield 94.5%. 1H-NMR (300MHz, CDC13) 51.47 (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+l), 260(M+23) o
By 3- acetamido -4- ethoxybenzenes Yue acid Yue esters under normal temperature（95.0 g, 0.4 mol) it is dissolved in nitro Yue alkane（1500 mL) in, add fuming nitric aicd（50.0 mL, 1.2 mol), 3 h are stirred in 30 °C, reaction terminates.Reaction solution is poured into sodium carbonate（80.0 g, 0.75 mol) aqueous solution（1200 mL) in, stirring, point liquid washes organic layer, dries, steams the g of 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acid Yue esters 104.0 that solvent obtains light red brown solid, yield 92.0%. 1H-NMR (300MHz, CDC13) 51.52 (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+l), 305(M+23)oBy 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acid Yue esters（85.0 g, 0.3 mol) it is dissolved in THF
(500 mL) and 10% sodium hydrate aqueous solution（500 mL, 1.3 mol), the h of back flow reaction 4, reaction terminates.Room temperature is cooled to, reaction liquid layer, upper strata is faint yellow, and lower floor is dark brown, point liquid, lower floor adjusts pH value to be 4-5 with glacial acetic acid, ethyl acetate is extracted（200 mLx5 times）, organic layer is washed, dries, steams the 3- amido -4- ethyoxyl -6- nitrobenzene Yue acid Yue ester 63.8g that solvent obtains brown blocks of solid, yield 94%.It is directly used in next step reaction.1H-NMR (300MHz, DMSO) 51.37 (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+l).
By 3- amido -4- ethyoxyl -6- nitrobenzene Yue acid Yue esters（63.8g, 0.282 mol) it is dissolved in glacial acetic acid
In (600 mL), acetic anhydride is added dropwise in 60 °C of stirrings（29.0 mL, 0.3 mol), l h power mouthful is complete, and reaction terminates.Reaction solution is poured into frozen water（1000 mL) in, a large amount of grey powder are separated out, 1 h is placed, suction filtration is washed, dries, obtain the 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acid 63.0g of pale yellow solid, yield 83%.1H-NMR (300MHz, DMSO) 51.40 (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-l).
By 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acid（54.0g, 0.2mol) it is dissolved in dichloro Yue alkane (300ml), it is incomplete molten, thionyl chloride (58.0ml, 0.8mol) is added, back flow reaction is cold React and terminate after solidifying pipe upper ends anhydrous calcium chloride drying tube, 2h, reaction solution clarification.It is concentrated to give the 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acyl chlorides of brown solid.
By metallic sodium（9.2g, 0.4mol) it is dissolved in ethanol（150ml), after sodium it is complete it is molten after back flow reaction 10min again, question response liquid is cooled to 50 °C -60 °C, cyan-acetic ester is added dropwise（47.0ml, 0.44mol), lOmin is added, and a large amount of white powders, then back flow reaction 30min are generated in reaction solution, and then ice salt bath is cooled to -8 °C.The anhydrous THF solution of 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acyl chlorides is added dropwise into reaction solution（150ml), lh is added, and is kept below 0 °C of reaction temperature, and completion of dropping reaction terminates.Frozen water is added dropwise into reaction solution（100ml), reacting liquid temperature is kept below 10 °C, then adds into reaction solution dense stone gram acid（10ml, 0.15mol) frozen water（1000ml) solution, it is 1-2 to adjust reacting liquid pH value, separates out a large amount of solids, lh is placed in stirring, suction filtration, washing, 3- (5- acetamido-4- ethyoxyl-2- nitrobenzophenones)-2- cyano group-3- carbonyls-ethyl propionate of dry Tan solid（Compound V, Ri=acetyl group, R2=ethyl, R4=ethyl, X=cyano group, Z=- NH-) 68.0g, the 1HNMR (300MHz of yield 93.5%, DMSO) 50.96 (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-l) embodiment 16,-acetamido -4,-ethyoxyl -6,-nitro -2-H benzoylformaldoximes（Compound I, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
By compound V (Ri=acetyl group, R2=ethyl, R4=ethyl, X=cyano group, Z=- NH- X 36.3g, O. lmol) it is dissolved in 96% DMSO/ water（160ml), 30 min are reacted in 110 °C.Water is used after reaction solution cooling（800ml) dilute, separate out yellow powder, it is 1-2 that pH value of solution is adjusted with IN grams of acid, suction filtration is washed, dries, obtain the 3 of faint yellow solid,-acetamido -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones（Compound I, R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 25.8g, yield 88.6%. 1HNMR (300MHz, CDC13) 51.56 (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,-benzamido -4,-ethyoxyl -6,-nitro-acetophenone（Compound I, benzoyl, R2=ethyl, X=FU^, Z=- NH-) synthesis
Using 3- amino-4-hydroxies acetophenone as raw material; according to the step 3 of embodiment one, 4 and embodiment two to four operation; through benzene Yue acylations, ethylization, nitrification, bromo, cyanalation prepare title compound; obtain the title compound 3 of yellow powder;-benzene Yue amide groups -4;-ethyoxyl -6,-nitro -2- ^ acetophenones（Compound I, benzene Yue acyl groups, R2=ethyl, X=cyano group, Z=- NH-), the % of total recovery 56.ESI-MS (m/z) 352 (M-1) embodiment 18,-benzamido group -4,-ethyoxyl -6,-nitro-acetophenone（Compound I, Ri=benzyl, R2=ethyl, X=H^, Z=- NH-) synthesis
Using 3- benzamido group -4- acetophenones as raw material, according to the operation of embodiment two to four, title compound is prepared with method, the title compound 3 of yellow powder,-benzamido group -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones is obtained（Compound I, Ri=benzyl, R2=ethyl, X=cyano group, Z=- NH-). ESI-MS (m/z) 338(M-1)0Embodiment 19,-acetamido -4,-ethyoxyl -6,-^-2-H benzoylformaldoxime（Compound VIII, acetyl group, R2=ethyl, X=FU->Z=- NH-) synthesis
Compound I (Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) (29.1g, O.lmol), iron powder（28g, 0.5mol) mixed with 400ml tetrahydrofurans, 50ml ethanol, 20ml water, plus watery hydrochloric acid adjusts pH=4-5, flow back 2h, and reaction terminates.Filtering, solvent evaporated obtains brown solid, with tetrahydrofuran/ethyl acetate（1 :1,200ml) be beaten pale yellow solid compound VIII (R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 21.5g, yield 81%.1HNMR (300MHz, DMSO) 51.36 (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+)。 6- acetamido -7- ethyl -3-H^-4- the oxyquinolines of embodiment 20（Compound A, acetyl group, R2=ethyl, X=H^, Z=- NH-) synthesis
Room temperature, compound VIII (R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) (26.1g, O.lmol) be dissolved in the Yue ethers of ethylene glycol two（250 mL), add N, bis- Yue acid amides of N- two Yue acetals (DMF-DMA) (16.0ml, 0.12mol), react and lark powder, suction filtration are separated out in 4h, reaction solution, washing, dry pale yellow solid 6- acetamido -7- ethyoxyl -3- cyano group -4- oxyquinolines（Compound A, Ri=acetyl group, R2=ethyl, X=L＆, Z=- NH-) 22.5g, yield 83.0%.1HNMR (300MHz, DMSO) 51.45 (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-l).6- acetamido -7- ethyoxyl -3-4fU^-4- the oxyquinolines of embodiment 21（Compound A, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
Under ice bath, compound Vin'HCl (i.e. VIII hydrochloride, Ri=acetyl group, R2=ethyl, X=cyano group, Z=- NH-) (29.7g, O.lmol) mix with the Yue ethers of ethylene glycol two, ice bath, is added dropwise Ν, Ν-two Yue acid amides two Yue acetals (DMF-DMA) (13.3 ml, O.lmol), 4h is reacted, reaction terminates.Reaction solution is concentrated into half volume, filtrate pours into trash ice（In 100g), lh is placed, khaki solid, suction filtration, washing, dry khaki solid 6- acetamido -7- ethyoxyl -3- cyano group -4- oxyquinolines is separated out（Compound A, Ri=acetyl group, R2=ethyl, X=L＆, Z=- NH-) 23.5g, the ifiNMR of yield 80% (300MHz, DMSO) 51.45 (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-l).6- acetamido -7- ethyoxyl -3-4fU^-4- the oxyquinolines of embodiment 22（Compound A, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis Compound VIII (R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) (26.1g, O. lmol) be suspended in the Yue ethers of ethylene glycol two（250 ml), add original Yue triethylenetetraminehexaacetic acid esters（20.0ml, 0.12mol), back flow reaction 3h, reaction terminates.Separate out khaki powder in reaction solution, suction filtration, washing, the 6- acetamido -7- ethyoxyl -3- cyano group -4- oxyquinolines of dry khaki solid（Compound A, R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 20.5g, yield 76%.1HNMR (300MHz, DMSO) 51.45 (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-l).The 2- of embodiment 23 (5- acetyl atmosphere base -4- second Gas base -2- nitro benzoyls) diethyl malonate（Compound V, ethyl, R2=ethyl, X=ethyoxyl R4=ethyl, Z=- NH-) synthesis
Under normal temperature, by 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acid（5.3g, 0.02mol) it is suspended in dichloro Yue alkane（In 60ml), thionyl chloride is added（7.2ml, O.lmol), back flow reaction is reacted after lh and terminated, reaction solution clarification.Solvent evaporated obtains brown solid, adds anhydrous THF solution (30ml), is evaporated, obtains 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acyl chlorides, can be directly used for next step reaction.
Under normal temperature, by metallic sodium（1.0g, 0.043mol) it is dissolved in ethanol（30ml), after sodium it is complete it is molten after the Omin of back flow reaction 1 again, question response liquid is cooled to 50 °C -60 °C, diethyl malonate is added dropwise（7.0ml, 0.046mol), 3min is added, then the Omin of back flow reaction 3, solution clarification, is then cooled to -10 °C.The anhydrous THF solution (30ml) of 3- acetamido -4- ethyoxyl -6- nitrobenzene Yue acyl chlorides is added dropwise into reaction solution, 20min is added, keeps below 0 °C of reaction temperature, completion of dropping reaction terminates.Frozen water is added dropwise into reaction solution（20ml); reacting liquid temperature is kept below 0 °C; reacting liquid pH value is adjusted to be 1-2 with dilute sulfuric acid again; stirring is placed; separate out solid; suction filtration, washing, 2- (5- acetylaminohydroxyphenylarsonic acid 4- ethyoxyl -2- nitrobenzene Yue acyl groups) diethyl malonate of dry Tan solid（Compound V, Ri=ethyl, R2=ethyl, X=ethyoxyl is betrayed base, R4=ethyl, Z=- NH-) 6.4g, yield 78.0%。 'H-NMR (300MHz, CDC13) 5 0.98 (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,-ethyoxyl -6,-nitro -2- second Gas base carbonyl ethyl ketones（Compound I, acetyl group, R2=ethyl, X=ethoxy carbonyl, Z=- NH-) synthesis
By compound V (Ri=ethyl, R2=ethyl, X=ethyoxyl is betrayed base, R4=ethyl, Z=- NH-) (3.1g, 0.0076mol) be dissolved in 90% DMSO/ water（20ml), 30min is reacted in 110 °C.Water is used after reaction solution cooling（150ml) dilute; yellow powder is separated out, adjusts reaction solution pH values to be 2-3 with dilute sulfuric acid, stirring is placed; separate out solid; suction filtration, washing, the compound I (R1=acetyl group of dry faint yellow solid; R2=ethyl; X=ethyoxyl is betrayed base, Z=- NH-) 2.3g, yield 91.0%. 1H-NMR (300MHz, CDC13) 5 1.25 (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+).The N- of embodiment 25 (5- (2- ethoxy carbonyls -3- (diformazan Jfe yls) acryloyl group) -2- ethyoxyl -4- nitrobenzophenones) acetamide（Compound VI, acetyl group, R2=ethyl, X=ethyoxyl atmosphere base, Y=- N (CH3)2, Z=- NH-) synthesis
By compound I (Ri=acetyl group, R2=ethyl, X=ethyoxyl is betrayed base, Z=- NH-) (0.8g, 0.00236mol) be dissolved in the Yue ethers of ethylene glycol two（20ml), N, the Yue acetals of bis- Yue acid amides of N- two are added
(DMF-DMA) (0.93ml, 0.007mol), back flow reaction 6-8h, reaction terminates.Solvent evaporated obtains faint yellow solid compound VI (R corpse acetyl group, R2=ethyl, X=ethoxy carbonyl, Y=- N (CH3)2, Z=- NH-) and 0.95g, it can be directly used for next step reaction.1H-NMR (300MHz, CDC13) 5 0.91 (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 ten).26 compound of embodiment 111 (=acetyl group, R2=ethyl, X=ethoxy carbonyl, Z=- NH-) synthesis
By compound I (1^=acetyl group, R2=ethyl, X=ethyoxyl is betrayed base, Z=- NH-) (0.8g, 0.00236mol) be dissolved in THF (20ml), and power mouthful enters Raney Ni (0.2g), and room temperature hydrogenation 12h, reaction terminates.Filtering, is evaporated compound VIII (1^=acetyl group, R that filtrate obtains Tan solid2=ethyl, X=ethoxy is betrayed base, Z=- NH-) 0.67g, yield 91.5%.1H-NMR (300MHz, CDC13) 51.22 (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 6- acetamido -7- second Gas base -3- J l^-4- hydroxyls the quinoline of embodiment 27 drenches（Compound A, acetyl group, R2=ethyl, X=second HiJ^, Z=- NH-) synthesis
By compound VI (1^=acetyl group, R2=ethyl, X=ethyoxyl is betrayed base, Y=- N (CH3)2, Z=- NH-) and (0.4g, lmmol) be dissolved in DMF (3mL), and power mouth enters Raney Ni O.lg, and normal pressure hydrogenation reaction 4h, reaction terminates.Filtering, filtrate is concentrated into half volume, then uses water（4mL) dilute, separate out white solid, suction filtration is washed, dries, obtain the 6- acetamido -7- ethyoxyl -3- amino carbonyl -4- oxyquinolines of pale yellow powder（Compound A, Ri=acetyl group, R2=ethyl, X=ethoxy carbonyl, Z=- NH-) 0.20g, yield 62%.1H-NMR (300MHz, DMSO) 51.26 (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- second Gas base -3- J l^-4- oxyquinolines (compound A, acetyl group, R2=ethyl, X=second U ^, Z=- NH-) synthesis Normal temperature, compound VIII (R corpse acetyl group, R2=ethyl, X=ethoxy carbonyl, Z=- NH-) (0.31g, lmmol) be suspended in the Yue ethers of ethylene glycol two（4mL); add N; the Yue acetals (DMF-DMA) (0.16mL, 1.2mol) of bis- Yue acid amides of N- two, react 2h; khaki powder is separated out in reaction solution; suction filtration, washing, dry khaki solid 6- acetamido -7- ethyoxyl -3- ^-4- oxyquinolines (compound A; Ri=acetyl group, R2=ethyl, X=ethoxy carbonyl, Z=- NH-) 0.22g, yield 69%.6- acetamido -7- second Gas base -3- L^-4- the chloroquinolines of embodiment 29（Compound A, acetyl group, R2=ethyl, X=H^, Z=- NH-) synthesis
By compound VI (1^=acetyl group, R2=ethyl, X=cyano group, Y=N (CH3)2, Z=- NH-) and (15.5g, 0.045mol) be dissolved in DMF (130ml), adds Raney Ni 6g, normal pressure hydrogenation reacts 5 6h, and TLC detection reactions terminate.Filtering, filtrate is concentrated to dryness, and products therefrom uses the Yue ethers of diethylene glycol two again（120ml) dissolve, add trichlorine oxygen（9.3ml, 0.099mol), in 80 °C of (outer temperature）Lower reaction.4hr to 4.5hr reactions are finished, and reaction solution Slow is poured into 2 volume frozen water slowly and lh is stirred, and separate out yellow powder, suction filtration; washing, then washed with a small amount of Yue ethers of ethylene glycol two, dried under 40 °C; the compound for obtaining yellow powder enters, ^ corpse acetyl group, R2=ethyl, X=ethyoxyl is betrayed base, Z=- NH-) 9.12g, the 1HNMR of yield 70.6% (300MHz, DMSO) 51.49 (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).6- acetamido -7- ethyoxyl -3- L base -4- the chloroquines of ESI-Ms (m/z) 289 (M-l) embodiment 30 drench（Compound A, acetyl group, R2=ethyl, X=FU- Z=- NH-) synthesis
Compound VIII (R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) (11.75g, 0.045mol) be suspended in the Yue ethers of ethylene glycol two（250 ml), add original Yue triethylenetetraminehexaacetic acid esters（20.0ml, 0.12mol), back flow reaction 3h, reaction terminates.It is cooled to room temperature, adds POCl3（1 lml), In 80 °C of (outer temperature）Lower reaction.4hr to 4.5hr reactions are finished, and reaction solution Slow is poured into 2 volume frozen water slowly and ih is stirred, and separate out yellow powder, suction filtration; washing, then washed with a small amount of Yue ethers of ethylene glycol two, dried under 40 °C; obtain the compound A of yellow powder, (R corpse acetyl group, R2=ethyl, X=ethyoxyl is betrayed base, Z=- NH-) 8.9g, yield 68.5%.1HNMR (300MHz, DMSO) 51.49 (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-l).Embodiment 31,-acetamido -4,-ethyoxyl -6,-^-2-H^ acetophenone（Compound X, acetyl group, R2=ethyl, X=H^, R8Fourth oxygen Z=- NH-) synthesis by the title compound of embodiment 19（Lg, 0.0038mol) 12mL pyridines are dissolved in, add (BOC) at room temperature20 (0.83mL, 0.0046mol, X react at room temperature 12hr, and reaction solution adds 20mL water, are extracted 3 times with dichloro Yue alkane（10mL/time）, merge organic phase, organic phase anhydrous sodium sulfate drying, rear solvent evaporated obtains faint yellow solid 1.10g, yield 80%.6- acetamido -7- ethyoxyl -3-4fU^-4- the oxyquinolines of embodiment 32（Compound A, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
Under ice bath, compound X (Ri=acetyl group, R2=ethyl, X=cyano group, R8=tertbutyloxycarbonyl, Z=- NH-) (O. lmol) be dissolved in the Yue ethers of ethylene glycol two（250 mL), N is added, the Yue acetals (DMF-DMA) (16.0ml, 0.12mol) of bis- Yue acid amides of N- two react 5h, added to Yue benzene sulfonic acids（O.lmol), khaki powder is separated out in reaction solution, suction filtration, washing, dry khaki solid 6- acetamido -7- ethyoxyl -3- cyano group -4- oxyquinolines（Compound A, R corpse acetyl group, R2=ethyl, X=cyano group, Z=- NH-) 22.5g, yield 83.0%.1HNMR (300MHz, DMSO) 51.45 (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-l). 6- benzamido -7- ethyoxyl -3-H^-4- the oxyquinolines of embodiment 33（Compound A, benzoyl, R2=ethyl, X=FU^, Z=- NH-) synthesis
Using the title compound of embodiment 17 as raw material, according to the operation of embodiment 19 ~ 20, the title compound of embodiment 33, the % of total recovery 71 are prepared with method.ESI-MS (m/z) 332(M-1).6- benzamido group -7- second Gas base -3-H^-4- the oxyquinolines of embodiment 34（Compound A, benzyl, R2=ethyl, X=FU- Z=- NH-) synthesis
Using the title compound of embodiment 18 as raw material, according to the operation of embodiment 19 ~ 20, the title compound of embodiment 34 is prepared with method, yellow solid, the % of total recovery 69 is obtained.ESI-MS (m/z) 318 (M-l) embodiment 35 3- methoxyl groups -4- (4- methyl isophthalic acids-piperazinyl) propoxyl group acetophenone（Compound B, methyl, R2=(4- methyl isophthalic acids-piperazinyl) propyl group, Z=- 0-) synthesis
By 3- Yue epoxides -4- (3- chlorine propoxyl group) acetophenone（Compound B, Ri=Yue base, R2=3- chloropropyls, Z=- 0-) (prepared using 3- Yue epoxides -4-hydroxyacetophenone as raw material according to document（Journal of Medicinal Chemistry, 1989,32 (1):105-118)) mixed with DMF, potassium carbonate, 60 °C are reacted 5 hours, are post-processed the step 4 of be the same as Example one, are obtained the title compound of embodiment 35. EI-MS (m/z) 306(M+).Embodiment 36,-methoxyl group -4,-(4- methyl isophthalic acids-piperazinyl) propyl- 6,-nitro -2- L benzoylformaldoximes（Compound I, methyl, R2=(4- methyl isophthalic acids-piperazinyl) propyl group, X=l^, Z=- 0-) synthesis
The synthetic operation of embodiment 4 is arrived with reference to embodiment 2, using the title compound of embodiment 36 as raw material, the title compound of embodiment 36, the % of three step total recovery 69 are prepared with method.EI-MS (m/z) 376(M+)。 Embodiment 37,-methoxyl group -4,-(4- methyl isophthalic acids-piperazinyl) propyl- 6,-amino -2- L benzoylformaldoximes（Compound VIII, methyl, R2=(4- methyl isophthalic acids-piperazinyl) propyl group, X=L^, Z=- 0-) synthesis
Compound 1 (=Yue bases, R2=(4- Yue base -1- piperazinyls) propyl group, X=cyano group, Z=- 0-) iron powder reducing is used, with reference to the preparation method of embodiment 19, obtain compound VIII (Ri=Yue bases, R of yellow solid2=(4- Yue base -1- piperazinyls) propyl group, X=cyano group, Z=- 0-), yield 85%. EI-MS (m/z) 346(M+).6- methoxyl groups -7- (4- methyl isophthalic acids-piperazinyl) propoxyl group -3-H^-4- oxyquinolines of embodiment 38 (compound A, methyl, R2=(4- methyl isophthalic acids-piperazinyl) propyl group, X=l^, Z=- 0-) synthesis
Under ice bath, compound VIII (Rf Yue bases, R2=(the small piperazinyl of 4- Yue bases) propyl group, X=cyano group, Z=- 0-) (34.6g, O.lmol) be suspended in the Yue ethers of ethylene glycol two（250 mL), add N, bis- Yue acid amides of N- two Yue acetals (DMF-DMA) (16.0ml, 0.12mol), react in 4h, reaction solution and separate out khaki powder, suction filtration, washing, dry khaki solid 6- Yue epoxides -7- (the small piperazinyl of 4- Yue bases) propoxyl group -3- cyano group -4- oxyquinolines（Compound A, Yue base, R2=(the small piperazinyl of 4- Yue bases) propyl group, X=L＆, Z=- 0-) 29.5g, yield 82.8%. ESI-MS (m/z) 357(M+1).Embodiment 39 6- methoxyl groups -7- (4- methyl isophthalic acids-piperazinyl) third Gas base -3-H^-4- chloroquines drench（Compound A, methyl, R2=(4- methyl isophthalic acids-piperazinyl) propyl group, X=l^, Z=- 0-) synthesis
Compound VIII (R corpse Yue bases, R2=(4- Yue base -1- piperazinyls) propyl group, X=L＆, Z=- 0-) (15.6g, 0.045mol) be suspended in the Yue ethers of ethylene glycol two（250 ml), original Yue triethylenetetraminehexaacetic acids ester (20.0ml, 0.12mol) is added, back flow reaction 3h, reaction terminates.It is cooled to room temperature, adds POCl3（), llml in 80 °C of (outer temperature）Lower reaction.4hr to 4.5hr reactions are finished, by reaction solution Slow Slowly pour into 2 volume frozen water and stir lh, separate out yellow powder, suction filtration, washing, then washed with a small amount of Yue ethers of ethylene glycol two, dried under 40 °C, obtain the compound A of yellow powder, (R corpse Yue bases, R2=(4- Yue-1-piperazinyls of base）Propyl group, X=cyano group, Z=- 0-) 11.5g, yield 68%. EI-MS (m/z) 376(M+).6- acetamido -7- ethyl -3- 1^-4- hydroxyls the quinoline of example IV ten drenches（Compound A, acetyl group, R2=ethyl, X=H^, Z=- NH-) synthesis
By compound VI (1^=acetyl group, R2=ethyl, X=cyano group, Y=- N (CH3)2, Z=- NH-) and (15 g, 0.0433 mol) be suspended in ethanol（200 mL), water（200mL) and glacial acetic acid（4mL, 0.065 mol), add zinc powder (22 g, 0.35 mol), after 100 °C of back flow reaction about 12 h, TLC detection reactions completely, slightly cool down, the power p NaOH (0.13mol) directly into reaction solution, reaction solution is muddy.Then suction filtration is carried out, following steps are then carried out：
Above-mentioned filtrate is adjusted into pH to less than 3 at 50-60 °C, product is separated out.Filtering, is washed, and is dried, is obtained title compound（Ketone form structure）10.1 g, yield 86%.1HNMR (300MHz, DMSO) 51.45 (t, 3H), 2.14 (s, 3H), 4.20 (q, 2H), 7.05 (s, 1H), 8.60 (d, 1H), 8.70 (s, 1H), 9.21 (s, 1H), 12.58 (d, 1H). ESI-Ms (m/z) 270 (M-l).
Or, above-mentioned filtrate is adjusted into pH to 5-6 at 50-60 °C, product is separated out.Filtering, is washed, and is dried, is obtained title compound (phenolic structure）10.0 g, yield 85%.1HNMR (300MHz, DMSO) 51.45 (t, 3H), 2.14 (s, 3H), 4.19 (q, 2H), 7.15 (s, 1H), 8.56 (s, 1H), 8.69 (s, 1H), 9.19 (s, 1H). ESI-Ms (m/z) 270 (M-l).
Ketone form structure phenolic structure 6- acetamido -7- ethyoxyl -3-4fU^-4- the oxyquinolines of example IV 11（Compound A, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
By compound VI (R corpse acetyl group, R2=ethyl, X=cyano group, Y=- N (C)2, Z=- NH-) and (15 g, 0.0433 mol) be suspended in ethanol (300 mL), adds Fe powder（11 g, 0.18 mol), CaCl2(lOg, 0.0866 mol), backflow 15 h reactions terminate.Slightly cool down, NaOH (0.13mol) is added directly into reaction solution, reaction solution is muddy, and suction filtration, above-mentioned filtrate adjusts pH to less than 3 at 50-60 °C, separates out product.Filtering, is washed, and is dried, is obtained the g of title compound 6.7, yield 57%.6- acetamido -7- ethyoxyl -3-4fU^-4- the oxyquinolines of example IV 12（Compound A, acetyl group, R2=ethyl, X=L^, Z=- NH-) synthesis
By Hua Hewu $1 (1^=acetyl group, R2=ethyl, X=cyano group, Y=- N (CH3)2, Z=- NH-) and (15 g, 0.0433 mol) be suspended in glacial acetic acid（300 mL), add the palladium carbons of lg 5%, room temperature normal pressure and lead to hydrogen reaction, 15h reactions terminate.Solid is gradually separated out in reaction solution.Suction filtration, is washed, and is dried, is obtained the g of title compound 7.1, yield 61%.

Claims (1)

  1. Claim
    1st, the 6- nitro-acetophenone class compounds as shown in following formula I： Wherein,
    X is cyano group, trifluoro Yue bases, nitro ,-NHCOR3、 -NHCOOR3、 -CONR3R3,-N=CHR3Or-C02R3, wherein R3And R3, the alkyl of 1 C of C 10 replaced for hydrogen, C1 C10 alkyl, the alkenyls of 1 C of C 10, aryl or aryl with being same to each other or different to each other；
    Z be-NH -, -0- or
    Ri and Ri, betrays base with being same to each other or different to each other for the betray C1 C10 alkoxies of base or aryl substitution of C1 C10 alkanoyls, C1 C10 alkoxies of Yue acyl groups, the alkyl of 1 C of C 10, the alkenyls of 1 C of C 10, aryl, the C1 C10 alkyl of aryl substitution, C1 C10 alkanoyls, aroyl, aryl substitution；
    R2For C1 C10 alkyl, C1 C10 alkenyls or aryl, the alkyl is unnecessarily replaced by halogen, alkoxy, aryl or heterocyclic radical containing 120 or N, wherein the heterocyclic radical is unnecessarily replaced by C1 C10 alkyl or C1 C10 alkoxies；
    And when it is Yue bases that Z, which is -0-, Ri, R2It is not Yue bases.
    2nd, the 6- nitro-acetophenone class compounds shown in Formulas I according to claim 1, wherein, X is cyano group, trifluoro Yue bases ,-NHCOR3、 -NHCOOR3、 -N=CHR3, C1-C10 alkoxy carbonyl groups or carboxyl；
    Z is-NH- or -0-；
    For 15 alkyl, acetyl group, propiono, benzene Yue acyl groups, tertbutyloxycarbonyl, benzyl, benzyloxycarbonyl group or triphen Yue bases； R2For Yue bases, ethyl, propyl group, benzyl ,-(CH2)n-Cl、 -(CH2)n-Br、 , wherein n is 15 integer, and Alkyl is C1 C5 alkyl.
    3rd, the 6- nitro-acetophenone class compounds shown in Formulas I according to claim 2, wherein, X is that cyano group, carbethoxyl group or Yue oxygen are betrayed base；
    Z is-NH- or -0-；
    For acetyl group, benzene Yue acyl groups, benzyl or Yue bases；
    R2For ethyl ,-(CH2)3-C1 、 -(CH2)3-Br
    4th, the 6- nitro-acetophenone class compounds shown in Formulas I according to claim 3, wherein, the compound is：
    3,-acetamido -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones,
    3,-benzene Yue amide groups -4,-ethyoxyl -6,-nitro -2- cyano-acetophenones,
    3,-benzamido group -4,-ethyoxyl -6,-nitro -2- ^ acetophenones,
    3,-acetamido -4,-ethyoxyl -6,-nitro -2- ethyoxyls betray benzoylformaldoxime or
    3 ,-Yue epoxide-4 ,-(- 1-piperazinyl of 4- Yue bases) propoxyl group-6 ,-nitro-2- cyano-acetophenones.
    5th, the preparation method of the 6- nitro-acetophenone class compounds shown in the Formulas I described in claim 1, it is characterised in that X is cyano group, trifluoro Yue bases, nitro ,-NHCOR3、 -NHCOOR3、 -CONR3R3'、 -N=CHR3Or-C02R3, wherein R3And R3, when being hydrogen, C1 C10 alkyl, C1 C10 alkenyls, aryl or the C1 C10 alkyl of aryl substitution with being same to each other or different to each other, compound I is obtained through decarboxylic reaction by compound V；Its reaction equation is： Wherein Ri, R2Definition with Z is with claim 1; R4The C1 C10 alkyl replaced for hydrogen, C1 C10 alkyl, C1-C10 alkenyls, aryl or aryl.
    6th, the preparation method of the 6- nitro-acetophenone class compounds shown in the Formulas I described in claim 1, it is characterised in that when X is cyano group, its preparation method is：
    (1) compound B nitrifications obtain compound D, and compound D bromos obtain compound II, and compound II obtains compound I through cyano group substitution reaction；Its reaction equation is：
    Wherein Ri, R2Definition with Z is with claim 1;Or
    (2) compound B brominations obtain compound III, and compound III nitrifications obtain compound II, and compound II obtains compound I through cyano group substitution reaction；Its reaction equation is：
    Wherein Ri, R2Definition with Z is with claim 1;Or
    (3) compound B bromos obtain compound III, and compound III obtains compound IV through cyano group substitution reaction, and compound IV nitrifications obtain compound I；Its reaction equation is： Wherein Ri, R2Definition with Z is with claim 1. 7th, purposes of the 6- nitro-acetophenone class compounds in compound shown in formula A shown in the Formulas I described in claim 1, wherein, as the compound as shown in method formula A, Wherein R R2, Z and X definition it is identical with claim 1；
    (1) compound I and compound E carries out condensation reaction and obtains compound shown in Formula IV, Wherein, Y is-N (R5)2Or-OR5, R5、 R6And R7In the C1 C10 alkyl replaced selected from C1 C10 alkyl, C1 C10 alkenyls, aryl and aryl identical or differently；
    Compound VI obtains compound shown in Formula VII under the reducing conditions, and compound cyclization shown in Formula VII obtains compound shown in formula A；Or compound VII directly carries out ring-closure reaction and obtains compound shown in formula A without isolation；Its reaction equation is：
    ；Or
    (2) compound I obtains compound VIII or compound VIII acid-addition salts under the reducing conditions, compound VIII or its sour addition salts carry out condensation reaction with compound E and obtain compound VII and/or compound IX, and compound VII and/or compound IX cyclizations obtain compound shown in formula A；Or compound VII and compound IX directly carry out ring-closure reaction and obtain compound shown in formula A without isolation；Its reaction equation is：
    ' reduction Ri'
    R2C ■N(¾ R20' 、NH2
    VIII
    ；Or
    (3) compound I obtains compound VIII, compound VIII fragrant amino and acid anhydrides (R under the reducing conditions8)20 or for thing R8C1、 R8Br reacts, and obtains compound X, compound X and compound E progress condensation reaction and obtains compound XI, compound XI obtains compound XII through cyclization, and compound XII takes off R8Protection group obtains compound A, and its reaction equation is：
    Wherein R8Betray 10 alkoxies of base or aryl substitution of C1 C10 alkanoyls, 0 alkoxy for Yue acyl groups, C1 C10 alkanoyls, aroyl, aryl substitution are betrayed base；Or by compound X prepare compounds A one pot of completion of reaction, intermediate X I and XII are without isolation.
    8th, the 6- nitro-acetophenone class compounds shown in the Formulas I described in claim 1 are in formula A, Purposes in shown compound, wherein, it is prepared as follows formula A, shown compound,
    A,
    Wherein R R2, Z and X definition it is identical with claim 1；
    (1) compound I and compound E carries out condensation reaction and obtains compound shown in Formula IV,
    ORe
    Y people OR7
    E
    Wherein, Y is-N (R5)2Or-OR5, R5、 R6And R7In the alkyl of 1 C of C 10 replaced selected from C1 C10 alkyl, C1 C10 alkenyls, aryl and aryl identical or differently；
    Compound VI obtains formula A, compound through reduction, cyclization, chloro；Or wherein midbody compound VII, compound A are without reversed A, compound；Its reaction equation is： Or
    (2) compound I obtains compound VIII under the reducing conditions, compound VIII and compound E carries out condensation reaction and obtains compound VII and/or compound IX, compound VII and/or compound IX obtains formula A, shown compound through cyclization, chloro；Or midbody compound VII/ compounds IX and compound A direct formula A, shown compound without isolation；Its reaction equation is：
    9th, the purposes of the 6- nitro-acetophenone class compounds shown in the Formulas I according to claim 7 or 8, it is characterised in that reducing condition is：Under hydrogenation catalyst existence condition, it is passed through hydrogen and is reacted, hydrogenation catalyst is palladium carbon, active nickel or Pt02;Or reducing condition is：Reducing agent is added, reducing agent is iron powder, zinc powder or stannous chloride.
    10th, the purposes of the 6- nitro-acetophenone class compounds shown in Formulas I according to claim 9, it is characterised in that reducing condition is：Under hydrogenation catalyst existence condition, it is passed through hydrogen and is reacted, hydrogenation catalyst is palladium carbon, solvent for use is acetic acid；Or reducing condition is：Reducing agent is added, reducing agent is iron powder or zinc powder, further add calcium chloride or glacial acetic acid, solvent for use is alcohol or alcohol-water mixed solvent.
    11st, purposes of the 6- nitro-acetophenone class compounds in compound shown in formula A shown in Formulas I according to claim 7, it is characterised in that X compounds shown in the formula A of cyano group, is prepared as follows：
    ( 1 )
    ( 2 )
    Wherein, wherein R2Definition with Z is identical with claim 1；Y definition is identical with claim 7.
    12nd, the purposes of the 6- nitro-acetophenone class compounds shown in the Formulas I according to claim 7 or 8 or 11, it is characterized in that, compound E described in its preparation method is N, the sour three Yue esters of the Yue acetals of bis- Yue acid amides of N- two, original Yue or original Yue triethylenetetraminehexaacetic acid esters, are directly to be reacted substrate with E mixing under normal temperature or heating condition with E reaction condition.
    13rd, the ^ as shown in Formula Il<Compound： Wherein, Ri, R2Definition with Z and the R in any one claim in claim 1-3: R2Defined with Z identical.
    14th, compound shown in following formula III：
    III
    Wherein, Ri, R2Definition with Z and the R in any one claim in claim 1-3: 112It is identical with 2 definition.
    15th, compound shown in following formula IV：
    Wherein, Ri, R2Definition with Z and the R in any one claim in claim 1-3: R2Defined with Z identical.
    16th, compound shown in following Formula V：
    V
    Wherein R2, Ri, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical； R4Definition it is identical with defined in claim 5.
    17th, compound shown in following Formula IV
    VI
    Wherein Ri, R2, Ri, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical；Y definition is identical with defined in claim 7.
    18th, ^ shown in following Formula VII<Compound： Wherein Ri, R2, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical；Y definition is identical with defined in claim 7.
    19th, compound shown in following Formula VIII： Wherein R R2, in X and Z definition and claim 1-3 in any one claim
    R2, X and Z define it is identical.
    20th, compound shown in following Formula IX： Wherein R R2, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical；Y definition is identical with defined in claim 7.
    21st, compound shown in following Formula X：
    Wherein R!、 R2, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical. R8Definition it is identical with defined in claim 7.
    22nd, compound shown in following Formula X I：
    Wherein Ri, R2, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical；Y and R8Definition it is identical with defined in claim 7.
    23rd, compound shown in following Formula X II：
    XII wherein R R2, R in X and Z definition and claim 1-3 in any one claim2, X and Z define it is identical； R8Definition it is identical with defined in claim 7.
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CN105461565B (en) * 2015-11-17 2017-12-29 阜宁县安勤化学有限公司 A kind of method for producing nitro-acetophenone
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