CN102105433B - 6-nitroacetophenone compound, its preparation method and use - Google Patents

Abstract

The present invention relates to 6-nitroacetophenone compounds shown in formula I and preparation method thereof, wherein the substituents are as defined in the description, and used for the preparation of 3-substituted-4-hydroxyquinoline compounds and 3- Uses of substituted-4-chloroquinoline compounds, and intermediates of compounds of formula I.

Description

6-nitroacetophenone compound, its preparation method and use

technical field

The present invention relates to the 6-nitroacetophenone compound that can be used for preparing 3-substituted-4-hydroxyquinoline compound and 3-substituted-4-chloroquinoline compound and its preparation method and application, and its intermediate body. More specifically, it relates to a 6-nitroacetophenone compound whose structural formula is shown in the following formula I and its preparation method and its use in the preparation of 3-substituted-4-hydroxyquinoline compounds (compounds shown in formula A) and 3-substituted-4-chloroquinoline compounds (compounds shown in formula A').

Background technique

3-substituted-4-hydroxyquinoline compounds (formula A) and 3-substituted-4-chloroquinoline compounds (formula A') are important pharmaceutical intermediates and are used to prepare 3,4-disubstituted quinolines important intermediates of compounds. For example, 3,4-disubstituted quinoline compounds are irreversible small molecule tyrosine kinase inhibitors (Journal of Medicinal Chemistry, 46(1):49-63), which have anticancer activity, and some compounds such as EKB- 569 and HKI-272 (Journal of Medicinal Chemistry, 48(4): 1107-1131) are effective in the treatment of colorectal cancer, breast cancer and non-small cell lung cancer. Promising new antitumor drugs. There is also Bosutinib (SKI-606) (Journal of Medicinal Chemistry, 2001, 44(23), 3965-3977), which is also a clinically promising new anti-tumor drug.

When X in formula A is an ester group, different 3,4-disubstituted quinoline compounds are also widely used in antimalarial, anti-coccidiosis (US3542781) or treatment of type II diabetes (WO2005073229). Therefore, optimizing the synthesis process of 3-substituted-4-hydroxyquinoline compounds and 3-substituted-4-chloroquinoline compounds has important practical value.

The key synthetic step of this kind of compound lies in the formation of quinoline mother ring, and the synthesis of quinoline mother ring usually requires high temperature conditions. For example, when X is a cyano group, the preparation method of the compound of formula A is to heat the compound of formula C in a high boiling point solvent to 240°C-260°C for 10-20 hours (reaction formula I) (WO03093241, WO2005065181, CN101012225). The reaction conditions used are relatively harsh, and the yield is low, only 40 to 50%, and the unavoidable volatilization of high boiling point solvents such as Dowtherm at high temperature has adverse effects on the working environment and the health of operators, and has a negative impact on the environment. Pollution, not suitable for large-scale industrial production. Therefore, it is particularly urgent to find a preparation method with mild conditions, high yield, low cost, little environmental pollution and suitable for industrial production.

Reaction I

Contents of the invention

The inventors are committed to finding 3-substituted-4-hydroxyquinoline compounds and 3-substituted-4-chloroquine with mild conditions, easy operation, high yield, low cost, safety and environmental protection, suitable for large-scale commercial production The preparation method of morphine compound. The 6-nitroacetophenone compound shown in the following formula I has thus been invented, and the 6-nitroacetophenone compound shown in formula I is used to synthesize 3-substituted- 4-hydroxyquinoline compounds and 3-substituted-4-chloroquinoline compounds.

One object of the present invention is to provide 6-nitroacetophenones.

Another object of the present invention is to provide a preparation method of the above-mentioned 6-nitroacetophenone compounds.

Another object of the present invention is to provide the use of the above-mentioned 6-nitroacetophenone compounds.

Another object of the present invention is to provide intermediates involved in the above preparation method.

The present invention provides 6-nitroacetophenone compounds shown in the following formula I:

In formula I,

X is cyano, trifluoromethyl, nitro, -NHCOR ₃ , -NHCOOR ₃ , -CONR ₃ R ₃ ', -N=CHR ₃ or -CO ₂ R ₃ , wherein R ₃ and R ₃ 'are identical to each other or Variously hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or C1～C10 alkyl substituted by aryl;

Z is -NH-, -O- or

R ₁ and R ₁ ' are the same or different from each other as formyl, C1-C10 alkyl, C1-C10 alkenyl, aryl, aryl-substituted C1-C10 alkyl, C1-C10 alkanoyl, aroyl, Aryl substituted C1~C10 alkanoyl, C1~C10 alkoxycarbonyl or aryl substituted C1~C10 alkoxycarbonyl;

R ₂ is C1～C10 alkyl, C1～C10 alkenyl or aryl, and said alkyl is not necessarily replaced by halogen, alkoxy, aryl or heterocyclic group containing 1～2 O or N (such as Pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl), wherein the heterocyclic group is not necessarily substituted by C1～C10 alkyl or C1～C10 alkoxy;

And when Z is -O-, R ₁ is methyl, R ₂ is not methyl.

In a preferred embodiment of the present invention, in formula I,

X is cyano, trifluoromethyl, -NHCOR ₃ , -NHCOOR ₃ , -N=CHR ₃ , C1～C10 alkoxycarbonyl or carboxyl;

Z is -NH- or -O-;

R ₁ is C1～C5 alkyl, acetyl, propionyl, benzoyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl or trityl;

R ₂ is methyl, ethyl, propyl, benzyl, -(CH ₂ ) _n -Cl, -(CH ₂ ) _n -Br, or Wherein n=1-5 integer, Alkyl is C1-C5 alkyl.

In a further preferred embodiment of the present invention, in formula I,

X is cyano (-CN), ethoxycarbonyl (-COOC ₂ H ₅ ), methoxycarbonyl (-COOCH ₃ );

Z is -NH- or -O-;

_R is acetyl, benzoyl, benzyl or methyl;

R ₂ is ethyl, -(CH ₂ ) ₃ -Cl, -(CH ₂ ) ₃ -Br, or

In a further preferred embodiment of the present invention, formula I is:

3'-acetamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone;

3'-benzamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone;

3'-Benzylamino-4'-ethoxy-6'-nitro-2-cyanoacetophenone;

3'-acetamido-4'-ethoxy-6'-nitro-2-ethoxycarbonylacetophenone;

3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-6'-nitro-2-cyanoacetophenone.

The present invention relates to the preparation method of the 6-nitroacetophenone compound shown in formula I, it is characterized in that, this method comprises:

(1) When X is cyano, trifluoromethyl, nitro, -NHCOR ₃ , -NHCOOR ₃ , -CONR ₃ R ₃ ', -N=CHR ₃ or -CO ₂ R ₃ , wherein R ₃ and R ₃ When 'the same or different are hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or C1～C10 alkyl substituted by aryl, compound I is obtained from compound V through decarboxylation; its reaction formula is :

in,

Z is -NH-, -O- or

R ₁ and R ₁ ' are the same or different from each other as formyl, C1-C10 alkyl, C1-C10 alkenyl, aryl, aryl-substituted C1-C10 alkyl, C1-C10 alkanoyl, aroyl, Aryl substituted C1~C10 alkanoyl, C1~C10 alkoxycarbonyl or aryl substituted C1~C10 alkoxycarbonyl;

R ₂ is C1～C10 alkyl, C1～C10 alkenyl or aryl, and said alkyl is not necessarily replaced by halogen, alkoxy, aryl or heterocyclic group containing 1～2 O or N (such as pyrrole Alkyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl), wherein the heterocyclic group is not necessarily substituted by C1～C10 alkyl or C1～C10 alkoxy;

_R4 is hydrogen, C1～C10 alkyl, C1～C10 alkenyl, aryl or C1～C10 alkyl substituted by aryl;

And when Z is -O-, R ₁ is methyl, R ₂ is not methyl.

Among them, compound V can be purchased from the market; or it can be prepared by referring to the method of Example 15 or Example 23 by using 3,4-disubstituted-6-nitrobenzoic acid as a raw material. 3,4-disubstituted-6-nitrobenzoic acid can be purchased from the market or prepared from 3,4-disubstituted methyl benzoate through nitration and hydrolysis of the ester group, and 3-amino-4-substituted-6- Nitrobenzoic acid can be obtained by amination or by etherification of 3-substituted-4-hydroxy-6-nitro-benzoic acid methyl ester.

or

(2) When X=cyano group, compound D is obtained by nitration of compound B, compound D is brominated to obtain compound II, and compound II obtains compound I through cyano substitution reaction; its reaction formula is:

Wherein Z, R ₁ and R ₂ are as defined above;

or

(3) When X=cyano group, compound III is obtained by bromination of compound B, compound III is nitrated to obtain compound II, and compound II obtains compound I through cyano substitution reaction; its reaction formula is:

Wherein Z, R ₁ and R ₂ are as defined above;

or

(4) When X = cyano group, compound III is obtained by bromination of compound B, compound III is subjected to cyano substitution reaction to obtain compound IV, and compound IV is nitrated to obtain compound I; its reaction formula is:

Wherein Z, R ₁ and R ₂ are as defined above;

In the above reactions, in the preparation of the compound of formula I, the decarboxylation, bromination, nitration, cyano substitution and other reactions are all conventional reactions in the technical field. Compound B can be purchased from the market, or synthesized by referring to the method of Example 1 using p-hydroxyacetophenone as a raw material, or using 3-methoxy-4-hydroxyacetophenone as a raw material by referring to the method of Example 35.

The present invention also relates to the purposes of 6-nitroacetophenone compound shown in formula I, it is characterized in that,

The 6-nitroacetophenone compound shown in formula I can prepare the compound shown in formula A as follows,

in,

X is cyano, trifluoromethyl, nitro, -NHCOR ₃ , -NHCOOR ₃ , -CONR ₃ R ₃ ', -N=CHR ₃ , or CO ₂ R ₃ , wherein R ₃ and R ₃ 'are identical to each other or Variously hydrogen, C1~C10 alkyl, C1~C10 alkenyl, aryl or C1~C10 alkyl substituted by aryl;

Z is -NH-, -O- or

R ₁ and R ₁ ' are the same or different from each other as formyl, C1-C10 alkyl, C1-C10 alkenyl, aryl, aryl-substituted C1-C10 alkyl, C1-C10 alkanoyl, aroyl, Aryl substituted C1~C10 alkanoyl, C1~C10 alkoxycarbonyl or aryl substituted C1~C10 alkoxycarbonyl;

R ₂ is C1～C10 alkyl, C1～C10 alkenyl or aryl, and said alkyl is not necessarily substituted by halogen, alkoxy, aryl or heterocyclic group containing 1 to 2 O or N, For example, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, wherein the heterocycle may be optionally substituted by C1～C10 alkyl or C1～C10 alkoxy;

(1) compound I and compound E carry out condensation reaction to obtain the compound shown in formula VI,

Wherein, Y is -N(R ₅ ) ₂ or -OR ₅ , R ₅ , R ₆ and R ₇ are the same or different selected from C1~C10 alkyl, C1~C10 alkenyl, aryl and aryl substituted Among C1～C10 alkyl groups.

Compound VI obtains the compound shown in formula VII under reducing conditions, and the compound shown in formula A is obtained by cyclization of the compound shown in formula VII; or compound VII can directly carry out cyclization reaction without separation to obtain the compound shown in formula A; its reaction formula is :

or

(2) Compound I obtains compound VIII or an acid addition salt of compound VIII under reducing conditions, and compound VIII (or its acid addition salt) is condensed with compound E to obtain compound VII and/or compound IX, compound VII and/or Or compound IX cyclization obtains the compound shown in formula A; Or compound VII and compound IX can directly carry out cyclization reaction to obtain the compound shown in formula A without separation; Its reaction formula is:

or

;or

(3) Compound I obtains Compound VIII under reducing conditions. The arylamino group of Compound VIII reacts with an acid anhydride ((R ₈ ) ₂ O) or a halide (such as R ₈ Cl, R ₈ Br) to obtain Compound X. Compound X and Compound E carries out condensation reaction and obtains compound XI, and compound XI obtains compound XII through cyclization, and compound XII removes R ₈ protecting group obtains compound A; Its reaction formula is:

Where _R8 can be a general amino protecting group, namely formyl, C1～C10 alkanoyl, aroyl, aryl substituted C1～C10 alkanoyl, C1～C10 alkoxycarbonyl or aryl substituted C1～C10 alkane Oxycarbonyl. The reaction of preparing compound A from compound X can be accomplished in one pot, and intermediates XI and XII can be carried out without isolation.

In the above method for preparing compound A, the conditions for the condensation reaction with E may be directly mixing the substrate with E without adding a catalyst, and then reacting at normal temperature or under heating conditions. Described reduction condition can be: in the presence condition of hydrogenation catalyst, pass into hydrogen to react, hydrogenation catalyst can be palladium carbon, active nickel or PtO ₂ ; Also can be: add reducing agent, for example add iron powder, zinc powder or stannous chloride. Compound A can be prepared from compound VI by reducing and ring-closing in one step in the presence of a reducing agent, without the need to separate intermediate VII; by compound VIII, compound A can be prepared by mixing compound VIII and E, at normal temperature or under heating The condensation and cyclization reactions are accomplished in one step without isolation of intermediates VII and/or IX. Compound X is obtained by conventional acylation or halogenation reaction of compound VIII with acid anhydride or halide containing R ₈ substituent. Compound E is preferably N,N-dimethylformamide dimethyl acetal (DMF-DMA), trimethyl orthoformate or triethyl orthoformate.

In the above-mentioned method for preparing compound A, the preferred reduction condition is: in the presence of a hydrogenation catalyst, feed hydrogen to react, the hydrogenation catalyst is palladium carbon, and the solvent used is acetic acid; or the reduction condition is: add a reducing agent, and the reducing agent is Iron powder or zinc powder, further adding calcium chloride or glacial acetic acid, the solvent used is alcohol or alcohol-water mixed solvent.

The present invention also relates to another use of the 6-nitroacetophenone compound shown in formula I, characterized in that the 6-nitroacetophenone compound shown in formula I can be prepared as follows: Show compounds,

Wherein, the definitions of R ₁ , R ₂ , X and Z are the same as those of the compound of formula A.

(1) compound I and compound E carry out condensation reaction to obtain the compound shown in formula VI,

Wherein, Y is -N(R ₅ ) ₂ or -OR ₅ , R ₅ , R ₆ and R ₇ are the same or different selected from C1~C10 alkyl, C1~C10 alkenyl, aryl and aryl substituted Among C1～C10 alkyl groups.

Compound VI is reduced, cyclized, and chlorinated to obtain a compound of formula A'; or wherein intermediate compound VII and compound A can be directly reacted without separation to obtain a compound of formula A'; its reaction formula is:

or

(2) Compound I obtains compound VIII under reducing conditions, compound VIII and compound E undergo condensation reaction to obtain compound VII and/or compound IX, compound VII and/or compound IX undergoes cyclization and chlorination to obtain the compound shown in formula A' or intermediate compound VII/compound IX and compound A directly prepare the compound shown in formula A' without separation; its reaction formula is:

or

In the above-mentioned method for preparing compound A', the conditions for the reduction, cyclization, and condensation reaction with E are the same as the preparation method of the above-mentioned formula A. The chlorination reaction can be carried out using a chlorinating reagent, for example, using a chlorinating reagent such as phosphorus oxychloride or phosphorus pentachloride.

The present invention also provides compounds of the following formulas II to XI:

Wherein, X is cyano, trifluoromethyl, nitro, -NHCOR ₃ , -NHCOOR ₃ , -CONR ₃ R ₃ ', -N=CHR ₃ or -CO ₂ R ₃ , wherein R ₃ and R ₃ ' are mutually The same or different hydrogen, C1~C10 alkyl, C1~C10 alkenyl, aryl or C1~C10 alkyl substituted by aryl; Z is -NH-, -O- or R ₁ and R ₁ ' are the same or different from each other as formyl, C1-C10 alkyl, C1-C10 alkenyl, aryl, aryl-substituted C1-C10 alkyl, C1-C10 alkanoyl, aroyl, Aryl substituted C1~C10 alkanoyl, C1~C10 alkoxycarbonyl or aryl substituted C1~C10 alkoxycarbonyl; _R2 is C1~C10 alkyl, C1~C10 alkenyl or aryl, so The alkyl group is not necessarily substituted by halogen, alkoxy, aryl or heterocyclic group containing 1 to 2 O or N, such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazine group, wherein the heterocyclic group may be optionally substituted by C1～C10 alkyl or C1～C10 alkoxy; and when Z is -O-, R ₁ is methyl, R ₂ is not methyl; Y is -N(R ₅ ) ₂ or -OR ₅ , R ₅ is selected from C1～C10 alkyl, C1～C10 alkenyl, aryl and C1～C10 alkyl substituted by aryl; R ₈ can be a general amino group The protecting group is formyl, C1-C10 alkanoyl, aroyl, C1-C10 alkanoyl substituted by aryl, C1-C10 alkoxycarbonyl or C1-C10 alkoxycarbonyl substituted by aryl.

Among the above compounds, _R1 is preferably C1～C5 alkyl, acetyl, propionyl, benzoyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl or trityl; _R2 is preferably methyl, ethyl , Propyl, Benzyl, -(CH ₂ )n-Cl, -(CH ₂ )n-Br, or Where n=1~5, Alkyl is C1~C5 alkyl; X is preferably cyano, trifluoromethyl, -NHCOOR ₃ , -NHCOOR ₃ , -N=CHR ₃ , C1~C10 alkoxycarbonyl or carboxyl; Z Preferably -NH- or -O-; Y is preferably -N(CH ₃ ) ₂ , -OCH ₃ , OC ₂ H ₅ ; R ₈ is preferably acetyl, tert-butoxycarbonyl, benzyloxycarbonyl.

The above compounds are further preferably:

Compounds of formula II are preferably:

3'-acetamido-4'-ethoxy-6'-nitro-2-bromoacetophenone;

3'-benzamido-4'-ethoxy-6'-nitro-2-bromoacetophenone;

3'-Benzylamino-4'-ethoxy-6'-nitro-2-bromoacetophenone;

3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-6'-nitro-2-bromoacetophenone;

Compounds of formula III are preferably:

3'-acetamido-4'-ethoxy-2-bromoacetophenone;

3'-benzamido-4'-ethoxy-2-bromoacetophenone;

3'-Benzylamino-4'-ethoxy-2-bromoacetophenone;

3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-2-bromoacetophenone;

Compounds of formula IV are preferably:

3'-acetamido-4'-ethoxy-2-cyanoacetophenone;

3'-benzamido-4'-ethoxy-2-cyanoacetophenone;

3'-Benzylamino-4'-ethoxy-2-cyanoacetophenone;

3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-2-cyanoacetophenone;

Compounds of formula V are preferably:

3-(5-acetamido-4-ethoxy-2-nitrophenyl)-2-cyano-3-carbonyl-propionic acid ethyl ester;

Diethyl 2-(5-acetylamino-4-ethoxy-2-nitrobenzoyl)malonate;

Compounds of formula VI are preferably:

N-(5-(2-cyano-3-(dimethylamino)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide;

N-(5-(2-cyano-3-(methoxy)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide;

N-(5-(2-ethoxycarbonyl-3-(dimethylamino)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide;

Compounds of formula VIII are preferably:

3'-acetamido-4'-ethoxy-6'-amino-2-cyanoacetophenone;

3'-benzamido-4'-ethoxy-6'-amino-2-cyanoacetophenone;

3'-Benzylamino-4'-ethoxy-6'-amino-2-cyanoacetophenone;

3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-6'-amino-2-cyanoacetophenone.

The technical effect that the present invention realizes is as follows:

(1) In the present invention, the method for preparing compound A and A' with compound I, compared to the literature method of the preparation of existing quinoline ring, can avoid using high temperature conditions, avoid using high boiling point solvent, environmental protection and safety. In particular, when X=cyano group or ester group, the yield can reach more than 80%, which is obviously superior to the existing methods.

(2) Compound I can be obtained from industrial raw materials conveniently and in high yield.

(3) The conversion rate of the reaction is high, the operation is simple and convenient, and the reaction conditions are mild. The multi-step intermediate does not need to be separated and purified, and can be directly used in the next step reaction, which greatly improves the yield and simplifies the operation. Industrialized production can be realized.

(4) In the method for preparing compound A or A' with compound I, preferred method (2) has mild reaction conditions, stable intermediates, easier purification, higher yield, and greatly reduced cost. The reaction to prepare the target substance A or A' produces less impurities, the product is easy to purify, the operation is simple, the total yield is high, and it is easier to realize industrial production.

In a word, through the present invention, a brand-new synthetic route of 3-substituted-4-hydroxyquinoline compounds and 3-substituted-4-chloroquinoline compounds is realized, with mild conditions, simple operation, safe and effective.

Detailed ways

The present invention is further illustrated by the following examples, which are only used to more specifically illustrate preferred embodiments of the present invention, and are not intended to limit the technical solutions of the present invention. The above-mentioned technical solutions of the present invention are all technical solutions that can realize the purpose of the present invention. That is, the temperature and reagents used in the following examples can be replaced by the corresponding temperatures and reagents described above to achieve the purpose of the present invention.

In the following preparation examples, nuclear magnetic resonance is measured by Bruker AMX-400 type and INVOA-600 type nuclear magnetic resonance instrument, TMS is an internal standard, and the chemical shift unit is ppm; Mass spectrum is measured by MAT-711 type and MAT-95 type mass spectrometer; The silica gel for column chromatography is 200-300 mesh, produced by Qingdao Ocean Chemical Factory; the TLC silica gel plate is the HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Factory; the boiling range of petroleum ether is 60-90°C; Iodine cylinder color. If the operation method is not specified in the preparation examples, the concentration refers to evaporating the solvent in the solution of the prepared compound with a rotary evaporator; the drying refers to drying the prepared compound at 60° C. with a DHG-9240A constant temperature drying oven.

Example 1 Synthesis of 3-acetamido-4-ethoxyacetophenone (compound B, R ₁ = acetyl, R ₂ = ethyl, Z = -NH-)

(1) Preparation of 3-nitro-4-hydroxyacetophenone

In an ice bath, p-hydroxyacetophenone (136.2 g, 1.0 mol) was added to concentrated sulfuric acid (1000 ml), stirred for 10 min, potassium nitrate (103.0 g, 1.02 mol) was added, stirred for 2 h, and the reaction was completed. The reaction solution was poured into 3000ml of crushed ice, a large amount of solid was precipitated, suction filtered, washed with water, and dried to obtain 171.2g of 3-nitro-4-hydroxyacetophenone as light yellow powder with a yield of 94.5%.

(2) Preparation of 3-amino-4-hydroxyacetophenone

At room temperature, 3-nitro-4-hydroxyacetophenone (171.2g, 0.945mol) was dissolved in THF (1500ml), and Raney Ni 20g was added, hydrogenated at normal pressure for 24h, and the reaction was completed. Filter, concentrate, and dry to obtain 132.8 g of 3-amino-4-hydroxyacetophenone as a yellow-brown solid, with a yield of 93.0%.

(3) Preparation of 3-acetamido-4-hydroxyacetophenone

Dissolve 3-amino-4-hydroxyacetophenone (121.0g, 0.8mol) in glacial acetic acid (1000ml), stir at 60°C, add acetic anhydride (115.0ml, 1.2mol) dropwise, add 1h, then stir for 30min , the reaction ends. The reaction solution was poured into 2000ml of ice water, a large amount of solid precipitated out, stirred for 2 hours, suction filtered, washed with water, and dried to obtain 134.8g of 3-acetamido-4-hydroxyacetophenone as a yellowish brown powder with a yield of 87.2%.

(4) Preparation of 3-acetamido-4-ethoxyacetophenone

Dissolve 3-acetamido-4-hydroxyacetophenone (96.6g, 0.5mol) and potassium carbonate (138.2g, 1.0mol) in DMF (500ml), stir at 60°C for 10min, add bromoethane (60ml , 0.75mol), 1h added, and then stirred for 30min, the reaction ended. The reaction solution was poured into 2000ml ice water, extracted with ethyl acetate (600ml×4), the organic layer was washed with water, dried, and concentrated to obtain 3-acetamido-4-ethoxyacetophenone (compound B, R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) 100.9 g, yield 91.2%. ¹ HNMR (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).

Example 2 Synthesis of 3-acetamido-4-ethoxy-6-nitroacetophenone (compound D, R ₁ = acetyl, R ₂ = ethyl, Z = -NH-)

Compound B (R ₁ =acetyl, R ₂ =ethyl, Z=-NH-) (88.5g, 0.4mol) was dissolved in nitromethane (1000ml), and fuming nitric acid (17.7ml, 0.4mol) was added , stirred at 40°C for 12h, added fuming nitric acid (15.5ml, 0.35mol), stirred for 10h, and the reaction ended. Pour the reaction solution into saturated sodium bicarbonate solution (1000ml), stir, separate liquids, wash the organic layer with water, dry, filter, add 10g of activated carbon to the filtrate, reflux for 20min, heat filter, concentrate to obtain a red oily substance, 40°C under normal pressure 86.5 g of 3-acetamido-4-ethoxy-6-nitroacetophenone (compound D, R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) was dried as a light red solid, Yield 81.2%. ¹ HNMR (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).

Example 3 3'-acetamido-4'-ethoxy-6'-nitro-2-bromoacetophenone (Compound II, R ₁ =acetyl, R ₂ =ethyl, Z=-NH- )Synthesis

Compound D (R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) (79.9 g, 0.3 mol) was dissolved in dichloromethane (1000 ml), liquid bromine (15.7 ml, 0.306 mol) was added, After stirring at room temperature for 12 hours, the reaction solution changed from light red to light yellow, and the reaction was completed. 3'-acetamido-4'-ethoxy-6'-nitro-2-bromoacetophenone (compound II, R ₁ = acetyl, R ₂ = ethyl, Z =-NH-) 110.0g, can be directly used in the next reaction. ¹ HNMR (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).

Example 4 3'-acetamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano , Z=-NH-) synthesis

Compound II (R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) (110.0 g, 0.3 mol) was dissolved in ethanol (600 ml) and DMSO (200 ml), cooled in an ice bath, and cyanide was added dropwise Sodium (29.4g, 0.6mol) in water (300ml) solution was added after 1 hour, and the reaction solution was dark brown. After 6 hours at room temperature, the reaction was completed. Pour the reaction solution into 2000ml of water, adjust the pH value of the solution to 5 with 1M hydrochloric acid, precipitate a large amount of solid, suction filter, wash with water, and dry to obtain 3'-acetamido-4'-ethoxy-6' as grayish yellow powder -Nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 68.3 g, yield 78.2%. ¹ HNMR (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).

Example 5 N-(5-(2-cyano-3-(dimethylamino)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide (compound VI, R ₁ =acetyl group, R ₂ = ethyl, X = cyano, Y = -N(CH ₃ ) ₂ , Z = -NH-)

Compound I (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (58.3 g, 0.2 mol) was dissolved in ethylene glycol dimethyl ether (600 ml), N was added, N-Diformamide dimethyl acetal (DMF-DMA) (29.2ml, 0.22mol) was stirred at room temperature, a light yellow powder gradually precipitated out of the reaction solution, and the reaction ended after 1h. Suction filtration, washing, and drying to obtain N-(5-(2-cyano-3-(dimethylamino)acryloyl)-2-ethoxy-4-nitrophenyl)ethane as light yellow powder Amide (compound VI, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Y = -N(CH ₃ ) ₂ , Z = -NH-) 93.0 g, yield 91.0%. ¹ HNMR (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).

Example 6 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH -)Synthesis

Compound VI (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Y = -N(CH ₃ ) ₂ , Z = -NH-) (34.6 g, 0.1 mol) was dissolved in DMF (300 ml) , add Raney Ni 6g, hydrogenation reaction at normal pressure for 3h, and the reaction ends. Filtrate, concentrate the filtrate to half its volume, then dilute with water (600ml) to precipitate a solid, leave it overnight at room temperature, filter with suction, wash with water, and dry to obtain 6-acetamido-7-ethoxy-3-cyano as a light yellow powder - 4-Hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 16.6 g, yield 61%. ¹ HNMR (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).

Example 7 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH -)Synthesis

Compound VI (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Y = -N(CH ₃ ) ₂ , Z = -NH-) (5.0 g, 0.0144 mol) was dissolved in DMF (60 ml) and ethanol (10ml), add calcium chloride (7.2g, 0.0648mol) in water (10ml) solution, add reduced iron powder (3.6g, 0.0648mol), react at 75°C, after 6h the reaction is over, add activated carbon (0.5g ), decolorize at 75°C for 20min. Suction filtration, the filtrate was concentrated to half volume, the filtrate was poured into crushed ice (100g), and left for 1h, a khaki solid was precipitated, suction filtered, washed with water, and dried to obtain a khaki solid 6-acetamido-7-ethoxy-3 -Cyano-4-hydroxyquinoline (compound A, R ₁ =acetyl, R ₂ =ethyl, X = cyano, Z = -NH-) 3.1 g, yield 79%. ¹ HNMR (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).

Example 8 N-(5-(2-cyano-3-(methoxy)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide (compound VI, R ₁ =acetyl, Synthesis of R ₂ = ethyl, X = cyano, Y = -OCH ₃ , Z = -NH-)

Compound I (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (58.3 g, 0.2 mol) was suspended in ethylene glycol dimethyl ether (600 ml), and orthoformic acid was added Trimethyl ester (compound E, Y=OCH ₃ ) (63.6 g, 0.6 mol) was protected by nitrogen gas, heated to reflux, and the reaction was completed within 5-6 hours. The solvent was distilled off to obtain a brownish-yellow solid, which was recrystallized from ethyl acetate/petroleum ether to obtain N-(5-(2-cyano-3-(methoxy)acryloyl)-2-ethoxy -4-nitrophenyl)acetamide (Compound VI, R ₁ =acetyl, R ₂ =ethyl, X = cyano, Y = -OCH ₃ , Z = -NH-) 50.2g, yield 81% . ¹ HNMR (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).

Example 9 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH -)Synthesis

Compound VI (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Y = -OCH ₃ , Z = -NH-) (30.5 g, 0.1 mol) was dissolved in DMF (300 ml), and Raney Ni 6g, atmospheric pressure hydrogenation reaction 4h, the reaction is over. Filtrate, concentrate the filtrate to half its volume, and then dilute with water (600ml) to precipitate a white solid, leave it overnight at room temperature, filter with suction, wash with water, and dry to obtain 6-acetamido-7-ethoxy-3-cyanide as a pale yellow powder 20.5 g of 4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-), yield 76%. ¹ HNMR (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).

Example 10 Synthesis of 3'-acetamido-4'-ethoxy-2-bromoacetophenone (compound III, R ₁ = acetyl, R ₂ = ethyl, Z = -NH-)

Compound B (R ₁ =acetyl, R ₂ =ethyl, Z=-NH-) (66.4g, 0.3mol) was dissolved in dichloromethane (1000ml), liquid bromine (15.7ml, 0.306mol) was added, After stirring at room temperature for 2 h, a gray solid precipitated out of the reaction solution, and the reaction was completed. Concentrate the reaction solution to 300 mL, suction filter, wash, and dry to obtain 3'-acetamido-4'-ethoxy-2-bromoacetophenone (compound III, R ₁ = acetyl, R ₂ = Ethyl, Z=-NH-) 98.0 g, yield 80%. ¹ HNMR (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).

Example 11 3'-acetamido-4'-ethoxy-6'-nitro-2-bromoacetophenone (compound II, R ₁ = acetyl, R ₂ = ethyl, Z = -NH -)Synthesis

Compound III (R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) (98.0 g, 0.3 mol) was dissolved in nitromethane (1000 ml), and fuming nitric acid (15.1 ml, 0.36 mol) was added , stirred at 40°C for 5h, added fuming nitric acid (13.3ml, 0.3mol), stirred for 2h, and the reaction ended. Pour the reaction solution into saturated sodium bicarbonate solution (1000ml), stir, wash the organic layer with water, dry, filter, add 10g of activated carbon to the filtrate, reflux for 20min, heat filter, concentrate to obtain a brown oil, dry at 40°C under normal pressure to obtain a brown Solid 3'-acetamido-4'-ethoxy-6'-nitro-2-bromoacetophenone (compound II, R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) 86.1 g, yield 83.2%. ¹ HNMR (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).

Example 12 3'-acetamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano base, Z=-NH-) synthesis

Compound II (R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) (110.0 g, 0.3 mol) was dissolved in ethanol (600 ml) and DMSO (200 ml), the solid was not fully dissolved, cooled in an ice bath , Add a solution of sodium cyanide (29.4g, 0.6mol) in water (300ml) dropwise, finish adding in 1h, react at room temperature for 6h, and the reaction ends. Pour the reaction solution into 2000ml of water, adjust the pH value of the solution to 5 with 1M hydrochloric acid, precipitate a large amount of solid, suction filter, wash with water, and dry to obtain 3'-acetamido-4'-ethoxy-6' as light yellow powder -Nitro-2-cyanoacetophenone (compound I, R ₁ =acetyl, R2 = ethyl, X = cyano, Z = -NH-) 68.3 g, yield 80%. ¹ HNMR (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).

Example 13 3'-acetamido-4'-ethoxy-2-cyanoacetophenone (compound IV, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH -)Synthesis

Compound III (R ₁ = acetyl, R ₂ = ethyl, Z = -NH-) (98.0 g, 0.3 mol) was dissolved in ethanol (500 ml) and DMSO (300 ml), the solid was not fully dissolved, cooled in an ice bath , Add a solution of sodium cyanide (29.4g, 0.6mol) in water (300ml) dropwise, after 1h, the solids in the reaction solution gradually dissolve, react at room temperature for 2h, and the reaction ends. The reaction solution was poured into 2000ml of water, and the pH of the solution was adjusted to 5 with 1M hydrochloric acid. A large amount of solid precipitated, filtered with suction, washed with water, and dried to obtain 3'-acetamido-4'-ethoxy-2- Cyanoacetophenone (compound IV, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 57.0 g, yield 77.2%. ¹ HNMR (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 ⁺ ).

Example 14 3'-acetamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano base, Z=-NH-) synthesis

Compound IV (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (73.8 g, 0.3 mol) was dissolved in nitromethane (1000 ml), fuming nitric acid (15.1 ml, 0.36mol), stirred for 2h, added fuming nitric acid (13.3ml, 0.3mol), stirred for 5h, and the reaction ended. Pour the reaction solution into saturated sodium bicarbonate solution (1000ml), stir, wash the organic layer with water, dry, filter, add 10g of activated carbon to the filtrate, reflux for 20min, heat filter, concentrate, and dry to obtain 3'-acetamide as a brown solid Acyl-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 71g , yield 81%. ¹ HNMR (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).

Example 15 3-(5-acetamido-4-ethoxy-2-nitrophenyl)-2-cyano-3-carbonyl-propionic acid ethyl ester (compound V, R ₁ = acetyl, Synthesis of R ₂ = ethyl, R ₄ = ethyl, X = cyano, Z = -NH-)

Dissolve 3-amino-4-hydroxybenzoic acid methyl ester (133.7g, 0.8mol) in glacial acetic acid (1000mL), stir at 60°C, if not fully dissolved, add acetic anhydride (115.0mL, 1.2mol) dropwise, 1h After the addition was complete, the reaction ended, and a large amount of solid was precipitated. The reaction solution was poured into 2000 mL of ice water, a large amount of solids were precipitated, stirred for 1 h, filtered with suction, washed with water, and dried to obtain 154.3 g of methyl 3-acetamido-4-hydroxybenzoate as a milky white solid, with a yield of 92.2%.

Dissolve methyl 3-acetamido-4-hydroxybenzoate (104.6g, 0.5mol) and potassium carbonate (138.2g, 1.0mol) in DMF (500mL), stir at 60°C for 10min, until they are not completely dissolved, add dropwise Ethyl bromide (60.0 mL, 0.75 mol) was added after 1 h, and the reaction was completed, and a large amount of solids were precipitated. The reaction solution was poured into 2000 mL of ice water, a large amount of solid precipitated out, suction filtered, washed with water, and dried to obtain 112.0 g of methyl 3-acetamido-4-ethoxybenzoate as a pale pink solid, with a yield of 94.5%. ¹ H-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).

Dissolve methyl 3-acetamido-4-ethoxybenzoate (95.0 g, 0.4 mol) in nitromethane (1500 mL) at room temperature, add fuming nitric acid (50.0 mL, 1.2 mol), and Stirred for 3h, the reaction ended. Pour the reaction solution into sodium carbonate (80.0g, 0.75mol) aqueous solution (1200mL), stir, separate the layers, wash the organic layer with water, dry, evaporate the solvent to obtain 3-acetamido-4-ethoxy 104.0 g of methyl-6-nitrobenzoate, yield 92.0%. ¹ H-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).

3-Acetamido-4-ethoxy-6-nitrobenzoic acid methyl ester (85.0g, 0.3mol) was dissolved in THF (500mL) and 10% aqueous sodium hydroxide solution (500mL, 1.3mol), reflux reaction 4h, the reaction ended. Cool to room temperature, the reaction solution is layered, the upper layer is light yellow, the lower layer is dark brown, separate the layers, adjust the pH value of the lower layer to 4-5 with glacial acetic acid, extract with ethyl acetate (200mL×5 times), wash the organic layer with water, and dry , the solvent was distilled off to obtain 63.8 g of methyl 3-amino-4-ethoxy-6-nitrobenzoate as a brown blocky solid, with a yield of 94%. used directly in the next reaction. ¹ H-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).

Dissolve methyl 3-amino-4-ethoxy-6-nitrobenzoate (63.8g, 0.282mol) in glacial acetic acid (600mL), stir at 60°C, add dropwise acetic anhydride (29.0mL, 0.3mol ), 1h added, the reaction ended. The reaction solution was poured into ice water (1000mL), a large amount of gray powder was precipitated, left for 1h, suction filtered, washed with water, and dried to obtain 3-acetamido-4-ethoxy-6-nitrobenzoic acid as a pale yellow solid 63.0 g, yield 83%. ¹ H-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).

Dissolve 3-acetamido-4-ethoxy-6-nitrobenzoic acid (54.0g, 0.2mol) in dichloromethane (300ml), and add thionyl chloride (58.0ml, 0.8 mol), reflux reaction, anhydrous calcium chloride drying tube is placed on the upper end of the condenser tube, the reaction ends after 2h, and the reaction solution is clarified. Concentration afforded 3-acetamido-4-ethoxy-6-nitrobenzoyl chloride as a brown solid.

Sodium metal (9.2g, 0.4mol) was dissolved in ethanol (150ml), and after the sodium was completely dissolved, it was refluxed for 10 minutes. After the reaction solution was cooled to 50°C-60°C, ethyl cyanoacetate (47.0ml, 0.44 mol), after 10 minutes, a large amount of white powder was formed in the reaction solution, and then refluxed for 30 minutes, and then cooled to -8°C in an ice-salt bath. Add dropwise anhydrous THF solution (150ml) of 3-acetamido-4-ethoxy-6-nitrobenzoyl chloride to the reaction liquid, and finish adding after 1h, keeping the reaction temperature below 0°C, and the reaction is complete after the dropwise addition Finish. Add ice water (100ml) dropwise to the reaction solution, keep the temperature of the reaction solution below 10°C, then add a solution of concentrated sulfuric acid (10ml, 0.15mol) in ice water (1000ml) to the reaction solution, adjust the pH value of the reaction solution to 1 -2, a large amount of solids were precipitated, stirred for 1 hour, suction filtered, washed, and dried to obtain 3-(5-acetamido-4-ethoxy-2-nitrophenyl)-2-cyano- 3-Carbonyl-propionic acid ethyl ester (compound V, R ₁ = acetyl, R ₂ = ethyl, R ₄ = ethyl, X = cyano, Z = -NH-) 68.0 g, yield 93.5%. ¹ HNMR (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).

Example 16 3'-acetamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano base, Z=-NH-) synthesis

Compound V (R ₁ = acetyl, R ₂ = ethyl, R ₄ = ethyl, X = cyano, Z = -NH-) (36.3 g, 0.1 mol) was dissolved in 96% DMSO/water (160 ml) , reacted at 110°C for 30min. After the reaction solution was cooled, it was diluted with water (800ml), and a yellow powder was precipitated. The pH of the solution was adjusted to 1-2 with 1N sulfuric acid, filtered with suction, washed with water, and dried to obtain 3'-acetamido-4'-ethoxy -6'-nitro-2-cyanoacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 25.8 g, yield 88.6%. ¹ HNMR (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).

Example 17 3'-benzamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ = benzoyl, R ₂ = ethyl, X = cyano group, Z = -NH-) synthesis

Using 3-amino-4-hydroxyacetophenone as a raw material, according to the steps 3 and 4 of Example 1 and the operations of Examples 2 to 4, through benzoylation, ethylation, nitration, bromination, and cyanation The title compound was prepared to give the title compound 3'-benzamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone (compound I, R ₁ =benzoyl, R ₂ = ethyl, X = cyano, Z = -NH-), the total yield was 56%. ESI-MS (m/z) 352 (M-1).

Example 18 3'-benzylamino-4'-ethoxy-6'-nitro-2-cyanoacetophenone (Compound I, R ₁ = benzyl, R ₂ = ethyl, X = cyano base, Z=-NH-) synthesis

Using 3-benzylamino-4-ethoxyacetophenone as raw material, according to the operation of Examples 2 to 4, the title compound was prepared in the same way to obtain the title compound 3'-benzylamino-4'-B as a yellow powder Oxy-6'-nitro-2-cyanoacetophenone (Compound I, R ₁ =benzyl, R ₂ =ethyl, X=cyano, Z=-NH-). ESI-MS (m/z) 338 (M-1).

Example 19 3'-acetamido-4'-ethoxy-6'-amino-2-cyanoacetophenone (compound VIII, R ₁ = acetyl, R ₂ = ethyl, X = cyano , Z=-NH-) synthesis

Compound I (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (29.1g, 0.1mol), iron powder (28g, 0.5mol) and 400ml tetrahydrofuran, 50ml ethanol, 20ml Mix with water, add dilute hydrochloric acid to adjust pH=4-5, reflux for 2h, and the reaction is over. Filter and evaporate the solvent to obtain a brown solid, which was slurried with tetrahydrofuran/ethyl acetate (1:1, 200ml) to obtain compound VIII (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 21.5g, yield 81%. ¹ HNMR (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 ⁺ ).

Example 20 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = - Synthesis of NH-)

At room temperature, compound VIII (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (26.1 g, 0.1 mol) was dissolved in ethylene glycol dimethyl ether (250 mL), N was added, N-diformamide dimethyl acetal (DMF-DMA) (16.0ml, 0.12mol), reacted for 4h, gray-yellow powder precipitated in the reaction solution, suction filtered, washed, dried to give gray-yellow solid 6-acetamido-7 - Ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 22.5 g, yield 83.0%. ¹ HNMR (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).

Example 21 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) Synthesis

Under ice bath, compound VIII·HCl (the hydrochloride salt of VIII, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (29.7 g, 0.1 mol) and ethylene glycol Dimethyl ether was mixed, ice bathed, N,N-dimethylamide dimethyl acetal (DMF-DMA) (13.3ml, 0.1mol) was added dropwise, reacted for 4h, and the reaction was completed. Concentrate the reaction solution to half its volume, pour the filtrate into crushed ice (100g), and let it stand for 1h. A khaki solid precipitates, which is filtered with suction, washed with water, and dried to obtain a khaki solid 6-acetamido-7-ethoxy-3- Cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) 23.5 g, yield 80%. ¹ HNMR (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).

Example 22 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) Synthesis

Compound VIII (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (26.1 g, 0.1 mol) was suspended in ethylene glycol dimethyl ether (250 ml), and triethyl orthoformate was added Ester (20.0ml, 0.12mol) was refluxed for 3h, and the reaction was completed. A khaki powder was precipitated in the reaction solution, filtered by suction, washed, and dried to obtain 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ =acetyl , R ₂ = ethyl, X = cyano, Z = -NH-) 20.5 g, yield 76%. ¹ HNMR (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).

Example 23 Diethyl 2-(5-acetylamino-4-ethoxy-2-nitrobenzoyl)malonate (compound V, R ₁ = ethyl, R ₂ = ethyl, X = ethoxycarbonyl, R ₄ = ethyl, Z = -NH-) synthesis

At room temperature, 3-acetamido-4-ethoxy-6-nitrobenzoic acid (5.3g, 0.02mol) was suspended in dichloromethane (60ml), and thionyl chloride (7.2ml, 0.1mol ), reflux reaction, the reaction ended after 1h, and the reaction solution was clarified. The solvent was evaporated to dryness to obtain a brown solid, which was added with anhydrous THF solution (30ml) and evaporated to dryness to obtain 3-acetamido-4-ethoxy-6-nitrobenzoyl chloride, which could be directly used in the next reaction.

At room temperature, dissolve metal sodium (1.0g, 0.043mol) in ethanol (30ml), and then reflux for 10 minutes after the sodium is completely dissolved. After the reaction solution is cooled to 50°C-60°C, diethyl malonate ( 7.0ml, 0.046mol), the addition was completed in 3 minutes, and the reaction was refluxed for 30 minutes. The solution was clear, and then cooled to -10°C. Add dropwise anhydrous THF solution (30ml) of 3-acetamido-4-ethoxy-6-nitrobenzoyl chloride to the reaction solution, and finish adding in 20 minutes, keep the reaction temperature below 0°C, and the reaction is complete after the dropwise addition Finish. Add ice water (20ml) dropwise to the reaction solution, keep the temperature of the reaction solution below 0°C, then use dilute sulfuric acid to adjust the pH of the reaction solution to 1-2, stir and let it stand, precipitate solid, suction filter, wash, and dry to obtain yellowish brown Solid diethyl 2-(5-acetylamino-4-ethoxy-2-nitrobenzoyl)malonate (compound V, R ₁ = ethyl, R ₂ = ethyl, X = ethoxy Carbonyl, R ₄ = ethyl, Z = -NH-) 6.4 g, yield 78.0%. ¹ H-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 ⁺ ).

Example 24 3'-acetamido-4'-ethoxy-6'-nitro-2-ethoxycarbonylacetophenone (compound I, R ₁ = acetyl, R ₂ = ethyl, Synthesis of X=ethoxycarbonyl, Z=-NH-)

Compound V (R ₁ = ethyl, R ₂ = ethyl, X = ethoxycarbonyl, R ₄ = ethyl, Z = -NH-) (3.1 g, 0.0076 mol) was dissolved in 90% DMSO/water ( 20ml), react at 110°C for 30min. After the reaction solution was cooled, it was diluted with water (150ml), and a yellow powder was precipitated. The pH value of the reaction solution was adjusted to 2-3 with dilute sulfuric acid, stirred and placed, and a solid was precipitated, filtered by suction, washed, and dried to obtain compound I (R1=acetyl base, R2=ethyl, X=ethoxycarbonyl, Z=-NH-) 2.3 g, yield 91.0%. ¹ H-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 ⁺ ).

Example 25 N-(5-(2-ethoxycarbonyl-3-(dimethylamino)acryloyl)-2-ethoxy-4-nitrophenyl)acetamide (compound VI, Synthesis of R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Y = -N(CH ₃ ) ₂ , Z = -NH-)

Compound I (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) (0.8 g, 0.00236 mol) was dissolved in ethylene glycol dimethyl ether (20 ml), and N , N-diformamide dimethyl acetal (DMF-DMA) (0.93ml, 0.007mol), reflux reaction for 6-8h, the reaction ended. The solvent was evaporated to dryness to obtain 0.95 g of light yellow solid compound VI (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Y = -N(CH ₃ ) ₂ , Z = -NH-), which can be directly for the next reaction. ¹ H-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 ⁺ ).

Example 26 Synthesis of Compound VIII (R ₁ = Acetyl, R ₂ = Ethyl, X = Ethoxycarbonyl, Z = -NH-)

Compound I (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) (0.8 g, 0.00236 mol) was dissolved in THF (20 ml), and Raney Ni (0.2 g) was added , hydrogenation reaction at room temperature for 12h, the reaction ended. After filtration, the filtrate was evaporated to dryness to obtain 0.67 g of compound VIII (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) as a tan solid, with a yield of 91.5%. ¹ H-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).

Example 27 6-acetamido-7-ethoxy-3-aminocarbonyl-4-hydroxyquinoline (Compound A, R ₁ =acetyl, R2 =ethyl, X =ethoxycarbonyl, Z =-NH-) Synthesis

Compound VI (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Y = -N(CH ₃ ) ₂ , Z = -NH-) (0.4 g, 1 mmol) was dissolved in DMF (3 mL ), adding RaneyNi 0.1g, atmospheric pressure hydrogenation reaction 4h, the reaction ended. Filtration, the filtrate was concentrated to half volume, and then diluted with water (4mL), a white solid was precipitated, filtered with suction, washed with water, and dried to obtain 6-acetamido-7-ethoxy-3-aminocarbonyl-4- Hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) 0.20 g, yield 62%. ¹ H-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 ⁺ ).

Example 28 6-acetamido-7-ethoxy-3-aminocarbonyl-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Synthesis of Z=-NH-)

At room temperature, compound VIII (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) (0.31 g, 1 mmol) was suspended in ethylene glycol dimethyl ether (4 mL), and N , N-diformamide dimethyl acetal (DMF-DMA) (0.16mL, 1.2mol), reacted for 2h, a khaki powder was precipitated in the reaction solution, suction filtered, washed, and dried to obtain a khaki solid 6-acetamido- 7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) 0.22 g, yield 69%.

Example 29 6-acetamido-7-ethoxy-3-cyano-4-chloroquinoline (compound A', R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) Synthesis

Compound VI (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Y = N(CH ₃ ) ₂ , Z = -NH-) (15.5 g, 0.045 mol) was dissolved in DMF (130 ml), Add 6g of Raney Ni, hydrogenation reaction at atmospheric pressure for 5-6h, TLC detection of the end of the reaction. After filtration, the filtrate was concentrated to dryness, and the obtained product was dissolved in diethylene glycol dimethyl ether (120ml), and phosphorus oxychloride (9.3ml, 0.099mol) was added to react at 80°C (external temperature). After 4hr to 4.5hr, the reaction is completed. Slowly pour the reaction solution into 2 volumes of ice water and stir for 1 hour. A yellow powder precipitates. Suction filtration, washing with water, washing with a small amount of ethylene glycol dimethyl ether, and drying at 40°C gives a yellow powder. Compound A' (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) 9.12 g, yield 70.6%. ¹ HNMR (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).

Example 30 6-acetamido-7-ethoxy-3-cyano-4-chloroquinoline (compound A', R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = - Synthesis of NH-)

Compound VIII (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) (11.75 g, 0.045 mol) was suspended in ethylene glycol dimethyl ether (250 ml), and triethyl orthoformate was added Ester (20.0ml, 0.12mol) was refluxed for 3h, and the reaction was completed. After cooling to room temperature, phosphorus oxychloride (11 ml) was added and reacted at 80°C (external temperature). After 4hr to 4.5hr, the reaction is completed. Slowly pour the reaction solution into 2 volumes of ice water and stir for 1 hour. A yellow powder precipitates. Suction filtration, washing with water, washing with a small amount of ethylene glycol dimethyl ether, and drying at 40°C gives a yellow powder. Compound A' (R ₁ = acetyl, R ₂ = ethyl, X = ethoxycarbonyl, Z = -NH-) 8.9 g, yield 68.5%. ¹ HNMR (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).

Example 31 3'-acetamido-4'-ethoxy-6'-amino-2-cyanoacetophenone (compound X, R ₁ = acetyl, R ₂ = ethyl, X = cyano group, R ₈ = tert-butoxycarbonyl, Z = -NH-) synthesis

The title compound of Example 19 (1 g, 0.0038 mol) was dissolved in 12 mL of pyridine, and (BOC) ₂ O (0.83 mL, 0.0046 mol,) was added at room temperature. React at room temperature for 12 hours, add 20 mL of water to the reaction solution, extract 3 times with dichloromethane (10 mL/time), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, and evaporate the solvent to obtain 1.10 g of a light yellow solid. 80%.

Example 32 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) Synthesis

Compound X (R ₁ = acetyl, R ₂ = ethyl, X = cyano, R ₈ = tert-butoxycarbonyl, Z = -NH-) (0.1 mol) was dissolved in ethylene glycol dimethyl ether under ice bath (250mL), add N,N-diformamide dimethyl acetal (DMF-DMA) (16.0ml, 0.12mol), react for 5h, add p-toluenesulfonic acid (0.1mol), the reaction solution precipitates khaki powder, Suction filtration, washing, and drying to obtain khaki solid 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (Compound A, R ₁ =acetyl, R ₂ =ethyl, X = Cyano, Z=-NH-) 22.5g, yield 83.0%. ¹ HNMR (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).

Example 33 6-benzamido-7-ethoxy-3-cyano-4-hydroxyquinoline (Compound A, R ₁ =benzoyl, R ₂ =ethyl, X = cyano, Synthesis of Z=-NH-)

Using the title compound of Example 17 as a raw material, the title compound of Example 33 was prepared in the same way as in Examples 19-20, with a total yield of 71%. ESI-MS (m/z) 332 (M-1).

Example 34 6-benzylamino-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = benzyl, R ₂ = ethyl, X = cyano, Z = -NH-) Synthesis

Using the title compound of Example 18 as a raw material, the title compound of Example 34 was prepared in the same way as in Examples 19-20 to obtain a yellow solid with a total yield of 69%. ESI-MS (m/z) 318 (M-1).

Example 35 3-Methoxy-4-(4-methyl-1-piperazinyl)propoxyacetophenone (compound B, R ₁ =methyl, R ₂ =(4-methyl- Synthesis of 1-piperazinyl)propyl, Z=-O-)

3-methoxy-4-(3-chloropropoxy)acetophenone (Compound B, R ₁ =methyl, R ₂ =3-chloropropyl, Z=-O-) (as 3-methyl Oxygen-4-hydroxyacetophenone was prepared according to the literature (Journal of Medicinal Chemistry, 1989, 32 (1): 105-118)), mixed with DMF and potassium carbonate, reacted at 60°C for 5 hours, and the post-treatment was the same as in Example 1. Step 4, the title compound of Example 35 was obtained. EI-MS (m/z) 306 (M ⁺ ).

Example 36 3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-6'-nitro-2-cyanoacetophenone (Compound I, R ₁ =methyl, R ₂ =(4-methyl-1-enhen)propyl, X=cyano, Z=-O-) synthesis

Referring to the synthesis operations of Examples 2 to 4, using the title compound of Example 36 as a raw material, the title compound of Example 36 was prepared in the same way, and the total yield of the three steps was 69%. EI-MS (m/z) 376 (M ⁺ ).

Example 37 3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-6'-amino-2-cyanoacetophenone (compound VIII, R ₁ = Synthesis of methyl group, R ₂ =(4-methyl-1-enhenyl)propyl group, X=cyano group, Z=-O-)

Compound I (R ₁ = methyl, R ₂ = (4-methyl-1-piperazinyl) propyl, X = cyano, Z = -O-) was reduced with iron powder, referring to the preparation of Example 19 Method to obtain compound VIII (R ₁ = methyl, R ₂ = (4-methyl-1-piperazinyl) propyl, X = cyano, Z = -O-) as a yellow solid with a yield of 85%. EI-MS (m/z) 346 (M ⁺ ).

Example 38 6-methoxy-7-(4-methyl-1-piperazinyl)propoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ =methyl, R ₂ = (4-methyl-1-piperazinyl) propyl, X = cyano, Z = -O-) synthesis

Compound VIII (R ₁ = methyl, R ₂ = (4-methyl-1-piperazinyl) propyl, X = cyano, Z = -O-) (34.6 g, 0.1 mol) was suspended under ice bath Add N,N-diformamide dimethyl acetal (DMF-DMA) (16.0ml, 0.12mol) to ethylene glycol dimethyl ether (250mL) and react for 4h. A khaki powder is precipitated in the reaction solution, which is suction filtered. Wash and dry to obtain khaki solid 6-methoxy-7-(4-methyl-1-piperazinyl)propoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ =methyl , R ₂ =(4-methyl-1-piperazinyl)propyl, X=cyano, Z=-O-) 29.5 g, yield 82.8%. ESI-MS (m/z) 357 (M+1).

Example 39 6-methoxy-7-(4-methyl-1-piperazinyl)propoxy-3-cyano-4-chloroquinoline (compound A', R ₁ =methyl, R ₂ = (4-methyl-1-piperazinyl) propyl, X = cyano, Z = -O-) synthesis

Compound VIII (R ₁ = methyl, R ₂ = (4-methyl-1-piperazinyl) propyl, X = cyano, Z = -O-) (15.6 g, 0.045 mol) suspended in ethylene glycol Dimethyl ether (250ml), triethyl orthoformate (20.0ml, 0.12mol) was added, refluxed for 3h, and the reaction was completed. After cooling to room temperature, phosphorus oxychloride (11 ml) was added and reacted at 80°C (external temperature). After 4hr to 4.5hr, the reaction is completed. Slowly pour the reaction solution into 2 volumes of ice water and stir for 1 hour. A yellow powder is precipitated, filtered with suction, washed with water, washed with a small amount of ethylene glycol dimethyl ether, and dried at 40°C to obtain a yellow powder. Compound A' (R ₁ =methyl, R ₂ =(4-methyl-1-piperazinyl)propyl, X=cyano, Z=-O-) 11.5g, yield 68%. EI-MS (m/z) 376 (M ⁺ ).

Example 40 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = - Synthesis of NH-)

Compound VI (R ₁ = acetyl, R ₂ = ethyl, X = cyano, Y = -N(CH ₃ ) ₂ , Z = -NH-) (15 g, 0.0433 mol) was suspended in ethanol (200 mL), Add water (200mL) and glacial acetic acid (4mL, 0.065mol), add zinc powder (22g, 0.35mol), reflux at 100°C for about 12h, after TLC detects that the reaction is complete, cool slightly, and directly add NaOH (0.13mol ), the reaction solution was turbid. Carry out suction filtration then, then carry out following steps:

Adjust the pH of the above filtrate to below 3 at 50-60°C to precipitate the product. Filter, wash with water, and dry to obtain 10.1 g of the title compound (ketone structure), with a yield of 86%. ¹ HNMR (300MHz, DMSO) δ1.45(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-1).

Alternatively, adjust the pH of the above filtrate to 5-6 at 50-60° C. to precipitate the product. Filter, wash with water, and dry to obtain 10.0 g of the title compound (phenolic structure), with a yield of 85%. ¹ HNMR (300MHz, DMSO) δ1.45(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-1).

Keto structure Phenolic structure

Example 41 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) Synthesis

Compound VI (R ₁ =acetyl, R ₂ =ethyl, X=cyano, Y=-N(CH ₃ ) ₂ , Z=-NH-) (15 g, 0.0433 mol) was suspended in ethanol (300 mL), Add Fe powder (11 g, 0.18 mol) and CaCl ₂ (10 g, 0.0866 mol) and reflux for 15 h to complete the reaction. After slightly cooling, NaOH (0.13 mol) was directly added to the reaction solution, the reaction solution was turbid, filtered with suction, the pH of the above filtrate was adjusted to below 3 at 50-60°C, and the product was precipitated. Filter, wash with water, and dry to obtain 6.7 g of the title compound, with a yield of 57%.

Example 42 6-acetamido-7-ethoxy-3-cyano-4-hydroxyquinoline (compound A, R ₁ = acetyl, R ₂ = ethyl, X = cyano, Z = -NH-) synthesis

Compound VI (R ₁ =acetyl, R ₂ =ethyl, X=cyano, Y=-N(CH ₃ ) ₂ , Z=-NH-) (15 g, 0.0433 mol) was suspended in glacial acetic acid (300 mL) , and then add 1g of 5% palladium carbon, and react with hydrogen gas at room temperature and pressure, and the reaction is completed in 15 hours. Solids gradually precipitated out of the reaction solution. Suction filtration, washing with water, and drying gave 7.1 g of the title compound with a yield of 61%.

Claims (14)

1. 6-nitroacetophenone compounds shown in the following formula I: in, X is cyano, trifluoromethyl, C1-C10 alkoxycarbonyl or carboxyl; Z is -NH- or -O-; _R1 is C1～C5 alkyl, acetyl, propionyl, benzoyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl or trityl; R ₂ is methyl, ethyl, propyl, benzyl, -(CH ₂ ) _n -Cl, -(CH ₂ ) _n -Br, or Wherein n is an integer of 1-5, and Alkyl is a C1-C5 alkyl group. 2. the 6-nitroacetophenone compound shown in formula I according to claim 1, wherein, X is cyano, ethoxycarbonyl or methoxycarbonyl; Z is -NH- or -O-; _R is acetyl, benzoyl, benzyl or methyl; R ₂ is ethyl, -(CH ₂ ) ₃ -Cl, _- (CH ₂ ) ₃ -Br, or 3. the 6-nitroacetophenone compound shown in formula I according to claim 2, wherein, said compound is: 3'-acetamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone, 3'-benzamido-4'-ethoxy-6'-nitro-2-cyanoacetophenone, 3'-Benzylamino-4'-ethoxy-6'-nitro-2-cyanoacetophenone, 3'-acetamido-4'-ethoxy-6'-nitro-2-ethoxycarbonylacetophenone, or 3'-methoxy-4'-(4-methyl-1-piperazinyl)propoxy-6'-nitro-2-cyanoacetophenone. 4. the preparation method of the 6-nitroacetophenone compound shown in formula I described in claim 1, is characterized in that, when X is cyano group, trifluoromethyl, C1～C10 alkoxycarbonyl or carboxyl, Obtain compound I through decarboxylation reaction by compound V; Its reaction formula is: The definitions of R ₁ , R ₂ and Z are the same as in claim 1; R ₄ is hydrogen, C1-C10 alkyl or C1-C10 alkenyl. 5. the preparation method of the 6-nitroacetophenone compound shown in the formula I described in claim 1 is characterized in that, when X is cyano group, its preparation method is: (1) Compound B is nitrated to obtain compound D, compound D is brominated to obtain compound II, and compound II is subjected to cyano substitution reaction to obtain compound I; the reaction formula is: wherein R ₁ , R ₂ and Z are as defined in claim 1; or (2) Compound B is brominated to obtain compound III, compound III is nitrated to obtain compound II, and compound II is subjected to a cyano substitution reaction to obtain compound I; the reaction formula is: wherein R ₁ , R ₂ and Z are as defined in claim 1; or (3) Compound B is brominated to obtain Compound III, Compound III is subjected to a cyano substitution reaction to obtain Compound IV, and Compound IV is nitrated to obtain Compound I; the reaction formula is: Wherein R ₁ , R ₂ and Z are as defined in claim 1. 6. the purposes of the 6-nitroacetophenone compound shown in the formula I shown in claim 1 in the compound shown in the preparation formula A, wherein, prepare the compound shown in the formula A as follows, Wherein the definitions of R ₁ , R ₂ , Z and X are the same as those in claim 1; (1) Condensation reaction of compound I and compound E to obtain the compound shown in formula VI, Wherein, Y is -N(R ₅ ) ₂ or -OR ₅ , and R ₅ , R ₆ and R ₇ are identically or differently selected from C1~C10 alkyl or C1~C10 alkenyl; Compound VI obtains the compound shown in formula VII under reducing conditions, and the compound shown in formula VII is cyclized to obtain the compound shown in formula A; or the compound VII is directly subjected to cyclization reaction without separation to obtain the compound shown in formula A; its reaction formula is: or (2) Compound I obtains Compound VIII or the acid addition salt of Compound VIII under reducing conditions, Compound VIII or its acid addition salt is condensed with Compound E to obtain Compound VII and/or Compound IX, Compound VII and/or Compound IX is cyclized to obtain a compound shown in Formula A; or Compound VII and Compound IX are directly subjected to a cyclization reaction without separation to obtain a compound shown in Formula A; the reaction formula is: or ;or (3) Compound I can obtain compound VIII under reducing conditions. The aniline of compound VIII reacts with acid anhydride (R ₈ ) ₂ O or halogenated products R ₈ Cl, R ₈ Br to obtain compound X, which undergoes condensation reaction with compound E Obtain compound XI, compound XI obtains compound XII through cyclization, compound XII removes R ₈ protecting group obtains compound A, and its reaction formula is: Wherein R ₈ is formyl, C1-C10 alkanoyl or C1-C10 alkoxycarbonyl; or the reaction of preparing compound A from compound X is completed in one pot, and intermediates XI and XII are not separated. 7. the purposes of the 6-nitroacetophenone compound shown in the formula I shown in claim 1 in the compound shown in preparation formula A ', wherein, prepare the compound shown in formula A ' as follows, Wherein the definitions of R ₁ , R ₂ , Z and X are the same as those in claim 1; (1) Condensation reaction of compound I and compound E to obtain the compound shown in formula VI, Wherein, Y is -N(R ₅ ) ₂ or -OR ₅ , and R ₅ , R ₆ and R ₇ are identically or differently selected from C1~C10 alkyl or C1~C10 alkenyl; Compound VI is reduced, cyclized, and chlorinated to obtain the compound of formula A'; or wherein the intermediate compound VII and compound A are directly reacted without separation to obtain the compound of formula A'; the reaction formula is: or (2) Compound I obtains compound VIII under reducing conditions, compound VIII and compound E undergo condensation reaction to obtain compound VII and/or compound IX, compound VII and/or compound IX undergoes cyclization and chlorination to obtain the compound shown in formula A' or intermediate compound VII/compound IX and compound A directly prepare the compound shown in formula A' without separation; its reaction formula is: or 8. according to the purposes of the 6-nitroacetophenone compounds shown in the formula I described in claim 6 or 7, it is characterized in that, reduction condition is: under the condition that hydrogenation catalyst exists, feed hydrogen to react, hydrogenation The catalyst is palladium carbon, active nickel or PtO ₂ ; or the reduction condition is: adding a reducing agent, which is iron powder, zinc powder or stannous chloride. 9. the purposes of the 6-nitroacetophenone compounds shown in formula I according to claim 8, it is characterized in that, reduction condition is: under hydrogenation catalyst existence condition, pass into hydrogen and react, hydrogenation catalyst is Palladium carbon, the solvent used is acetic acid; or the reduction condition is: add a reducing agent, the reducing agent is iron powder or zinc powder, and further add calcium chloride or glacial acetic acid, and the solvent used is alcohol or an alcohol-water mixed solvent. 10. The purposes of the 6-nitroacetophenone compound shown in the formula I according to claim 6 in the compound shown in the preparation formula A, it is characterized in that, X is the compound shown in the formula A of cyano group, according to Prepared as follows: (1) or (2) or Wherein, the definitions of R ₁ , R ₂ and Z are the same as in claim 1; the definition of Y is the same as in claim 6. 11. according to the purposes of the 6-nitroacetophenone compounds shown in formula I described in claim 6 or 7 or 10, it is characterized in that, the compound E described in its preparation method is N,N-dimethyl The reaction condition of amide dimethyl acetal, trimethyl orthoformate or triethyl orthoformate with E is to directly mix the substrate and E under normal temperature or heating conditions for reaction. 12. The compound shown in the following formula II: Wherein, the definitions of R ₁ , R ₂ and Z are the same as the definitions of R ₁ , R ₂ and Z in any one of claims 1-2. 13. The compound shown in the following formula IV: Wherein, the definitions of R ₁ , R ₂ and Z are the same as the definitions of R ₁ , R ₂ and Z in any one of claims 1-2. 14. The compound shown in the following formula V: The definition of R ₁ , R ₂ , X and Z is the same as that of R ₁ , R ₂ , X and Z in any one of claims 1-2; the definition of R ₄ is the same as that in claim 4.