CN109134434B - Quinoline or quinazoline compound and preparation method and application thereof - Google Patents

Quinoline or quinazoline compound and preparation method and application thereof Download PDF

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CN109134434B
CN109134434B CN201711079618.1A CN201711079618A CN109134434B CN 109134434 B CN109134434 B CN 109134434B CN 201711079618 A CN201711079618 A CN 201711079618A CN 109134434 B CN109134434 B CN 109134434B
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quinoline
quinazoline
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CN109134434A (en
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车超
许正双
全军民
黄湧
洪梅
李勤凯
李志明
杨震
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Peking University Shenzhen Graduate School
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to a quinoline or quinazoline compound and a preparation method and application thereof, wherein the quinoline or quinazoline compound has the following structural formula:

Description

Quinoline or quinazoline compound and preparation method and application thereof
Technical Field
The invention relates to the field of organic compounds, in particular to a quinoline or quinazoline compound and a preparation method and application thereof.
Background
The tumor cell is an abnormal cell capable of rapidly propagating and regenerating, and has the characteristics of unlimited proliferation, transformation and easy metastasis. The energy metabolism of normal cells is mainly achieved by oxidative phosphorylation of glucose in mitochondria, the energy metabolism of tumor cells is different from that of normal cells, and tumor cells acquire energy mainly by taking up glucose in large quantities and performing glycolysis (Warburg effect) to satisfy the growth and proliferation of tumor cells. Glycolysis is the main metabolic pathway in almost all organisms, and the expression, activity and regulation of receptors, transport molecules and key enzymes in the glycolysis process play a crucial role in the generation, development, metastasis and regression of tumors, and become targets for the research of new anti-tumor drugs.
Currently, the study of thiophenesulfonamides, phenoxyindoles, benzopyrones, benzindoles, and triazolopyridazinones has been focused mainly on candidate drugs for inhibiting tumor cell proliferation by inhibiting glycolytic metabolism of tumor cells. Despite advances in the diagnosis and treatment of tumors, there is still a lack of antineoplastic drugs that effectively block the energy supply to tumor cells from the source.
Disclosure of Invention
Based on the above, there is a need for quinoline or quinazoline compounds capable of blocking energy supply of tumor cells from the source, and a preparation method and applications thereof.
A quinoline or quinazoline compound has the following structural formula:
Figure BDA0001458748950000011
wherein when-X-is-CH-, Y is
Figure BDA0001458748950000021
when-X-is-N-, Y is
Figure BDA0001458748950000022
or-O-R5，
-R1、-R2、-R5Each independently selected from-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl;
-R3one selected from the group consisting of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl;
-R4is alkyl or aryl.
In one embodiment, the compound has the following structural formula:
Figure BDA0001458748950000023
Figure BDA0001458748950000024
in one embodiment, the compound has the following structural formula:
Figure BDA0001458748950000025
Figure BDA0001458748950000026
in one embodiment, the compound has the following structural formula:
Figure BDA0001458748950000031
Figure BDA0001458748950000032
in one embodiment, the compound has the following structural formula:
Figure BDA0001458748950000033
Figure BDA0001458748950000034
a preparation method of quinoline compounds comprises the following steps:
nucleophilic substitution reaction is carried out on the compound A2 and 4-fluoronitrobenzene to obtain a compound A3, wherein the structural formula of the compound A2 is shown in the specification
Figure BDA0001458748950000035
The structural formula of the compound A3 is
Figure BDA0001458748950000036
Carrying out condensation cyclization reaction on the compound A3 and a compound D to obtain a compound A4, wherein the structural formula of the compound D is shown in the specification
Figure BDA0001458748950000041
-Y is
Figure BDA0001458748950000042
-R1、-R2Are respectively and independently selected from one of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidyl and tetrahydropyrrolyl, and the compound A4 has a structural formula of
Figure BDA0001458748950000043
Carrying out substitution reaction on the compound A4 and a compound E to obtain a compound A5, wherein the compound E contains-R3Halogenated hydrocarbon of-R3One selected from the group consisting of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl, and combinations thereofThe compound A5 has a structural formula
Figure BDA0001458748950000044
Reducing the nitro group on the benzene ring of the compound A5 into amino group to obtain a compound A6, wherein the structural formula of the compound A6 is shown in the specification
Figure BDA0001458748950000045
And the compound A6 and a compound F undergo a condensation reaction to obtain the quinoline compound, wherein the structure of the compound F is
Figure BDA0001458748950000046
-R4Is alkyl or aryl.
A preparation method of quinazoline compounds comprises the following steps:
nucleophilic substitution reaction is carried out on the compound A2 and 4-fluoronitrobenzene to obtain a compound A3, wherein the structural formula of the compound A2 is shown in the specification
Figure BDA0001458748950000047
The structural formula of the compound A3 is
Figure BDA0001458748950000048
Condensing and cyclizing the compound A3 and chloral hydrate to obtain a compound B1, wherein the structural formula of the compound B1 is shown in the specification
Figure BDA0001458748950000049
Opening the ring of the compound B1 to obtain a compound B2, wherein the structural formula of the compound B2 is shown in the specification
Figure BDA0001458748950000051
Carrying out condensation reaction on the compound B2 and urea to obtain a compound B3, wherein the structural formula of the compound B3 is shown in the specification
Figure BDA0001458748950000052
The compound B3 is chloridized to obtain a compound B4, and the structural formula of the compound B4 is shown in the specification
Figure BDA0001458748950000053
Carrying out substitution reaction on the compound B4 and a compound G to obtain a compound B5, wherein the compound G contains-R3Alcohol compounds of (2), -R3One selected from-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidyl and tetrahydropyrrolyl, wherein the compound B5 has a structural formula
Figure BDA0001458748950000054
Carrying out substitution reaction on the compound B5 and a compound H to obtain a compound B6, wherein the structural formula of the compound H is Y-H, and-Y is
Figure BDA0001458748950000055
or-O-R5，-R1、-R2、-R5Are respectively and independently selected from one of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidyl and tetrahydropyrrolyl, and the compound B6 has a structural formula of
Figure BDA0001458748950000056
Reducing the nitro group of the compound B6 into amino group to obtain a compound B7, wherein the structural formula of the compound B7 is shown in the specification
Figure BDA0001458748950000061
And the compound B7 and a compound F undergo a condensation reaction to obtain the quinazoline compound, wherein the compound F is carboxylic acid and has a structure of
Figure BDA0001458748950000062
-R4Is alkylOr an aryl group.
The quinoline or quinazoline compound is applied to a PFKFB inhibitor.
A PFKFB inhibitor, which comprises the quinoline or quinazoline compound.
The quinoline or quinazoline compound is applied to preparing anti-tumor drugs.
Experimental results show that the quinoline or quinazoline compound can inhibit the activity of PFKFB (6-phosphofructose-2-kinase/fructose-2, 6-diphosphatase, 6-phosphofructito-2-kinase/fluctose-2, 6-biphosphatase) in tumor cells and effectively block the activation of key enzymes in the glycolysis process, so that the energy supply of the tumor cells is blocked from the energy source of the tumor cells, a new medicament is provided for the effective treatment of tumor diseases, and a new idea is provided for the development of new antitumor medicaments.
The preparation method of the quinoline or quinazoline compound is simple and easy to implement, raw materials are easy to obtain, preparation conditions are not harsh, and industrial production is easy to realize.
Detailed Description
In order to facilitate understanding of the present invention, the present invention will be described more fully below mainly in connection with quinoline or quinazoline compounds, their preparation and use. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
An embodiment quinoline or quinazoline compound has the following structural formula:
Figure BDA0001458748950000071
wherein when-X-is-CH-, Y is
Figure BDA0001458748950000072
when-X-is-N-, Y is
Figure BDA0001458748950000073
or-O-R5，
-R1、-R2、-R5Each independently selected from-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl.
-R3One selected from the group consisting of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinyl and tetrahydropyrrolyl.
-R4Is alkyl or aryl.
Specifically, the quinoline or quinazoline compound is selected from one of the following structural formulas:
Figure BDA0001458748950000074
Figure BDA0001458748950000081
Figure BDA0001458748950000091
Figure BDA0001458748950000101
PFKFB is an important bifunctional enzyme, which is composed of an N-terminal kinase (6-phospho-2-kinase, PFK-2) domain and a C-terminal esterase (Fructose-2,6-biphosphatase, FBPase-2) domain, and can catalyze the synthesis and hydrolysis reactions of Fructose-2, 6-diphosphate (Fructose2, 6-biphosphate, Fru-2,6-BP), respectively. Mammalian PFKFBs generally have 4 subtypes: PFKFB1, PFKFB2, PFKFB3 and PFKFB 4. Wherein the kinase activity of PFKFB3 is far greater than that of esterase, and the synthesis of Fru-2,6-BP is more prone.
Experimental results show that the quinoline or quinazoline compound can effectively inhibit the activity of PFKFB in tumor cells, particularly can effectively inhibit the kinase activity of PFKFB3, thereby reducing the Fru-2,6-BP level. In the glycolysis process, the activity of 6-phosphofructose-1-kinase (PFK-1), a rate-limiting enzyme, is regulated by ATP, ADP, AMP and Fru-2,6-BP, wherein the Fru-2,6-BP is the strongest activator. Therefore, the inhibition of Fru-2,6-BP can effectively inhibit the activity of PFK-1, inhibit the glycolytic metabolism of tumor cells, limit the energy supply required by the proliferation and growth of the tumor cells, and block the energy supply of the tumor cells from the source. The quinoline or quinazoline compound can provide a new way for effectively treating tumor diseases, and also provides a new idea for researching and developing new antitumor drugs.
A method for producing a quinoline compound (method a) according to an embodiment includes the steps of:
s110, reacting the compound A1 with Boc anhydride to obtain a compound A2.
In one example, compound A1 and Boc anhydride are dissolved in methanol, triethylamine is added under stirring, the mixture is stirred at room temperature for 12 to 18 hours, 2mol/L hydrochloric acid solution is added, and pure compound A2 is obtained after separation and purification.
Specifically, the compound A1 is 4-aminophenol
Figure BDA0001458748950000111
The structural formula is that Boc anhydride has the chemical formula (Boc)2O, compound A2 has the formula
Figure BDA0001458748950000112
Specifically, the molar ratio of the compound A1 to Boc anhydride is 1: 1-1.2, preferably 1: 1.2.
Specifically, the molar ratio of the compound A1 to triethylamine is 1: 1.5-2.3, and preferably 1: 2.2.
Specifically, the specific method for separation and purification comprises the following steps: extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating in vacuum to obtain a crude product, and purifying the crude product through silica gel column chromatography, wherein the eluent is n-hexane and ethyl acetate, and the volume ratio of the n-hexane to the ethyl acetate is 4-8: 1), so as to obtain a pure compound A2.
Specifically, the reaction formula for preparing compound a2 from compound a1 is as follows:
Figure BDA0001458748950000121
of course, in other embodiments, compound a2 is also commercially available.
And carrying out nucleophilic substitution reaction on the S120, the compound A2 and 4-fluoronitrobenzene to obtain a compound A3.
In one example, compound A2 and fluoronitrobenzene are dissolved in acetonitrile, potassium carbonate is added, the mixture is stirred and reacted at 70-90 ℃ for 18 hours, the mixture is extracted and concentrated, then the mixture is dissolved in dichloromethane, trifluoroacetic acid is added, and the reaction is stirred and reacted at room temperature for 6 hours. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added, and the pure compound A3 is separated and purified.
Specifically, the structural formula of the 4-fluoronitrobenzene is shown as
Figure BDA0001458748950000122
The structural formula of the compound A3 is
Figure BDA0001458748950000123
Specifically, the molar ratio of the compound A2 to potassium carbonate is 1: 1.5-2.5, and preferably 1: 2.5.
Specifically, the specific method for extraction and concentration comprises the following steps: cooling to room temperature, adding water to dilute the reaction solution, extracting with ethyl acetate, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product.
Specifically, the specific method for separation and purification comprises the following steps: extracting with dichloromethane, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating in vacuum to obtain a crude product, and purifying by silica gel column chromatography (eluent n-hexane/ethyl acetate in a volume ratio of 3-6: 1) to obtain a pure compound A3.
Specifically, the reaction formula for preparing compound A3 from compound A2 and 4-fluoronitrobenzene is as follows:
Figure BDA0001458748950000124
s130, reacting the compound A3 with the compound D to obtain a compound A4.
In one embodiment, compound A3 and compound D are mixed, protonic acid is added, the mixture is stirred and reacted for 18 hours at 120-140 ℃, and pure compound A4 is obtained after separation and purification.
Specifically, the structural formula of the compound D is
Figure BDA0001458748950000131
-Y-is
Figure BDA0001458748950000132
-R1、-R2Are respectively and independently selected from one of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidyl and tetrahydropyrrolyl, and the compound A4 has a structural formula
Figure BDA0001458748950000133
In the present embodiment, the protonic acid is polyphosphoric acid (PPA), and in other embodiments, it may be concentrated sulfuric acid.
Further, the compound D is selected from one of ethyl acetoacetate, ethyl propionylacetate, ethyl butyrylacetate, ethyl acetoacetisobutyrate and other aliphatic or aromatic substituted ethyl acetoacetate.
The molar ratio of compound a3 to compound D was: 1: 1.3-1.5, preferably 1: 1.5.
Specifically, the specific method for separation and purification comprises the following steps: cooling to room temperature, adding water, filtering, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying by silica gel column chromatography (eluent dichloromethane/methanol with volume ratio of 20-30: 1) to obtain pure compound A4. More preferably, the ratio of water added to compound A3 is 20mL:1.0 mmol.
Specifically, the reaction formula for preparing compound a4 from compound A3 and compound D is:
Figure BDA0001458748950000134
s140, carrying out substitution reaction on the compound A4 and the compound E to obtain a compound A5.
In one embodiment, compound A4 and compound E are dissolved in acetonitrile, anhydrous potassium carbonate is added, the mixture is stirred and reacted for 12 hours at 80-90 ℃, and pure compound A5 is obtained after separation and purification.
Specifically, the compound E is a compound containing-R3Halogenated hydrocarbon of-R3Selecting one of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidyl and tetrahydropyrrolyl, and the compound A5 has a structural formula of
Figure BDA0001458748950000141
Specifically, the compound E is selected from one of methyl iodide, allyl bromide, propargyl bromide, ethyl bromide, 1-iodopropane, 1-iodo-2-methylpropane, 1-iodobutane and benzyl bromide.
The molar ratio of compound a4 to compound E was: 1: 1.0-1.3, preferably 1: 1.2.
The molar ratio of the compound A4 to anhydrous potassium carbonate is: 1: 3.0-4.0, preferably 1: 4.0.
Specifically, the specific method for separation and purification comprises the following steps: cooling to room temperature, adding water for dilution, filtering, extracting the filtrate with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, and vacuum-concentrating to obtain a crude product, and purifying by silica gel column chromatography (eluent is n-hexane/ethyl acetate, volume ratio is 5-10: 1) to obtain pure compound A5. More preferably, the ratio of water to compound A4 is 15mL:1.0 mmol.
Specifically, in other embodiments, anhydrous potassium carbonate may also be replaced by other inorganic bases such as anhydrous sodium carbonate, and also by organic bases such as triethylamine, pyridine, and the like.
Or an organic base: triethylamine, pyridine and the like
In this embodiment, the reaction scheme for preparing compound a5 from compound a4 and compound b is:
Figure BDA0001458748950000142
s150, reducing the nitro group on the benzene ring of the compound A5 into amino to obtain a compound A6.
In one embodiment, the compound A5 is dissolved in organic solution, a reducing agent is added, the mixture is stirred for 8 to 12 hours at room temperature, and the pure compound A6 is obtained by separation and purification, wherein the structural formula of the compound A6 is shown in the specification
Figure BDA0001458748950000151
In this embodiment, the organic solvent is a mixed solution of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is 1:1, and the ratio of compound a5 to the mixed solution of dichloromethane and methanol is 1mmol:10 mL. Of course, in other embodiments, the organic solvents methylene chloride and methanol may be replaced by at least one of water or ethanol.
In this embodiment, the reducing agent is a mixture of zinc powder and ammonium chloride, and the molar ratio of the compound a5 to the zinc powder to the ammonium chloride is: 1: 6.0-8.0: 8.0-10.0. Preferably 1:8: 10. In other embodiments, the reducing agent may also be iron powder, palladium-carbon hydrogenation, platinum metal hydrogenation, nickel metal hydrogenation, or other reducing agents commonly used in the art.
Specifically, the separation and purification method specifically comprises the following steps: filtering with diatomite, washing with dichloromethane and saturated brine, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain pure compound A6.
Specifically, in this embodiment, the reaction scheme for preparing compound a6 from compound a5 is:
Figure BDA0001458748950000152
and S160, carrying out condensation reaction on the compound A6 and the compound F to obtain the quinoline compound.
In one embodiment, the compound a6 and the compound F are dissolved in dichloromethane, a condensing agent is added, the mixture is stirred for 16 hours at room temperature, and the pure compound a7 is obtained after separation and purification, namely the pure quinoline compound.
Specifically, the structure of the compound F is
Figure BDA0001458748950000153
-R4Is alkyl or aryl. Further, the compound F can be various aromatic acids or fatty acids, and is selected from one of N-tert-butoxycarbonylproline, N-tert-butoxycarbonylalanine, N-tert-butoxycarbonylvaline, thiazole-2-carboxylic acid, 1H-imidazole-5-carboxylic acid, oxazole-4-carboxylic acid, pyrrole-2-carboxylic acid, indole-2-carboxylic acid, pyridine-2-carboxylic acid, 3-chlorobenzothiophene-2-carboxylic acid, 2-acetoxyacetic acid, 2-bromoacetic acid, 2-chloroacetic acid and trifluoroacetic acid.
Specifically, the molar ratio of the compound A6 to the compound F is 1: 1.0-1.2, preferably 1:1.
In this embodiment, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI, the molar ratio of compound a4 to EDCI is 1:1 to 1.3, preferably 1:1.2, and in other embodiments, the condensing agent may be DCC (1, 3-dicyclohexylcarbodiimide), HATU (2- (7-benzotriazole oxide) -N, N' -tetramethylurea hexafluorophosphate), BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), or DPPA (diphenyl phosphorazidate).
Specifically, the specific method for separation and purification comprises the following steps: adding water for dilution, extracting by using dichloromethane, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, purifying by using silica gel column chromatography after vacuum concentration (eluent is dichloromethane/methanol with the volume ratio of 20-30: 1) to obtain a pure compound A7, namely the pure quinoline compound.
Specifically, the reaction formula for preparing the quinoline compound from the compound A6 is as follows:
Figure BDA0001458748950000161
when the compound F is N-tert-butoxycarbonylproline, the obtained compound A7 also needs to be subjected to tert-butoxycarbonyl removal.
Specifically, compound A7 is dissolved in dichloromethane, trifluoroacetic acid is added into the dichloromethane, the mixture is stirred for 6 hours at room temperature, sodium bicarbonate aqueous solution is added, and pure quinoline compounds without tert-butyloxycarbonyl groups are obtained through separation and purification.
Specifically, the ratio of compound A7 to dichloromethane was 1mmol:5 mL.
Specifically, the ratio of the compound A7 to trifluoroacetic acid (TFA) is 1mmol:0.8 mL-1.2 mL, preferably 1mmol:1mL, and the t-butoxycarbonyl group of the above-mentioned quinoline compound containing the t-butoxycarbonyl group (Boc) is removed by the action of trifluoroacetic acid, and in other embodiments, the trifluoroacetic acid may be replaced by hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid or formic acid.
Specifically, the specific method for separation and purification comprises the following steps: extracting with dichloromethane, mixing organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain residue, which is purified by silica gel column chromatography to obtain pure quinoline compound without tert-butyloxycarbonyl group. Wherein, the eluent of the silica gel column chromatography is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 5-10: 1.
Specifically, the reaction formula of compound A7 for removing tert-butyloxycarbonyl is as follows:
Figure BDA0001458748950000171
the preparation method of the quinoline compound is simple and easy to implement, raw materials are easy to obtain, preparation conditions are mild, and industrial production is easy to realize.
A method for preparing a quinazoline compound according to an embodiment (method B) includes the steps of:
s210, Compound A2 is obtained according to step S110 of Process A for preparing quinolines.
S220, Compound A3 was prepared according to step S120 of Process A for preparing quinolines.
S230, carrying out condensation cyclization on the compound A3 and hydrated chloracetaldehyde amine to obtain a compound B1, wherein the structural formula of the compound B1 is shown in the specification
Figure BDA0001458748950000172
In one example, chloral hydrate, water, sodium sulfate, compound A3, hydrochloric acid solution (6mL water prepared with 1mL concentrated hydrochloric acid), and hydroxylamine hydrochloride aqueous solution are added in sequence, stirred and reacted at 110 ℃ for 2 hours, heated to 130 ℃ and stirred and reacted for 1 hour. Then cooling to room temperature, filtering, drying, gradually adding into concentrated sulfuric acid at 50 ℃, and reacting for 2 hours at 65 ℃. Cooling to room temperature, pouring into crushed ice with the volume 10 times that of the reactant, filtering after 30min, washing with cold water, and drying to obtain the compound B1.
Specifically, the molar ratio of the compound A3 to the chloral hydrate is 1: 1.0-1.2, and preferably 1: 1.1. The molar ratio of the compound A3 to the sodium sulfate is 1: 8.0-9.0, preferably 1: 8.0. The ratio of the compound A3 to hydroxylamine hydrochloride is 1mmol:3.0 mmol/mL-3.6 mmol/mL, preferably 1mmol:3.3 mmol/mL.
Specifically, in this embodiment, the reaction scheme for preparing compound B1 from compound a3 is as follows:
Figure BDA0001458748950000181
s230, opening the ring of the compound B1 to obtain a compound B2, wherein the structural formula of the compound B2 is shown in the specification
Figure BDA0001458748950000182
In one embodiment, the compound B1 is dissolved in sodium hydroxide aqueous solution, hydrogen peroxide is gradually added, and the mixture is stirred and reacted for 3 hours at the temperature of 60 ℃. Cooling to room temperature, adding HCl, adjusting pH of the reaction solution to 2-4, filtering, washing with cold water, and drying to obtain compound B2.
Specifically, the ring opening of compound B1 produces compound B2 according to the following reaction scheme:
Figure BDA0001458748950000183
s240, carrying out condensation reaction on the compound B2 and urea to obtain a compound B3, wherein the structural formula of the compound B3 is shown in the specification
Figure BDA0001458748950000184
In one embodiment, compound B2 and urea (urea) are stirred to react at 160-170 ℃ for 12-18 hours. Cooling to room temperature, adding water, filtering, washing with water, and drying to obtain compound B3.
Specifically, the molar ratio of the compound B2 to urea is 1: 6.0-7.0, and preferably 1: 7.0.
Specifically, the reaction formula for preparing compound B3 from compound B2 is as follows:
Figure BDA0001458748950000191
s250, chlorinating the compound B3 to obtain a compound B4, wherein the structural formula of the compound B4 is shown in the specification
Figure BDA0001458748950000192
In one example, compound B3, phosphorus pentachloride, and phosphorus oxychloride were reacted at 110 ℃ with stirring for 6 hours. Cooling to room temperature, concentrating, adding saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying by silica gel column chromatography (eluent n-hexane/ethyl acetate with volume ratio of 10-20: 1) to obtain pure compound B4.
Specifically, the proportion of the compound B3, phosphorus pentachloride and phosphorus oxychloride is 10.0 mmol: 35-45.0 mmol: 8mL, preferably 10.0 mmol: 40.0 mmol: 8 mL.
Specifically, the reaction formula for preparing compound B4 from compound B3 is as follows:
Figure BDA0001458748950000193
and S260, carrying out substitution reaction on the compound B4 and the compound G to obtain a compound B5.
In one embodiment, compound B4 is dissolved in tetrahydrofuran, triethylamine and compound G are added, and the mixture is stirred and reacted at 50-70 ℃ for 12-16 hours. Cooled to room temperature, concentrated and added with saturated aqueous sodium bicarbonate. And then extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying by silica gel column chromatography (eluent: n-hexane/ethyl acetate with volume ratio of 5-10: 1) to obtain pure compound B5.
In particular, the compound G is R3-OH，-R3Selected from the group consisting of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidinylAnd tetrahydropyrrolyl, the structural formula of the compound B5 is
Figure BDA0001458748950000201
Further, the compound G is selected from one of methanol, ethanol, propanol, butanol, allyl alcohol, isopropanol, isobutanol, pentanol, propargyl alcohol, phenol, 3-chlorophenol, 3-hydroxypyridine and benzyl alcohol.
Specifically, the molar ratio of the compound B4 to the compound G is 1: 1.5-2.0, and preferably 1: 2.0. The molar ratio of the compound B4 to triethylamine is 1: 1.5-2.0, preferably 1: 2.0.
Specifically, the reaction formula for preparing compound B5 from compound B4 is as follows:
Figure BDA0001458748950000202
and S270, carrying out substitution reaction on the compound B5 and the compound H to obtain a compound B6.
In one embodiment, compound B5, compound H and n-butanol are mixed, concentrated hydrochloric acid is added, and the mixture is stirred and reacted at 100-110 ℃ for 12-16 hours. Cooling to room temperature, concentrating, adding water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying by silica gel column chromatography (eluent n-hexane/ethyl acetate in a volume ratio of 2-4: 1) to obtain pure compound B6.
Specifically, compound H is Y-H, wherein-Y is
Figure BDA0001458748950000203
or-O-R5，-R1、-R2、-R5Are respectively and independently selected from one of-H, -Cl, -Br, alkyl, alkoxy, aryl, aryloxy, N-dialkylamino, N-alkyl-N-acylamino, pyridyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, morpholinyl, N-alkylpiperazinyl, piperidyl and tetrahydropyrrolyl, and the compound B6 has a structural formula
Figure BDA0001458748950000211
Specifically, the compound H is selected from one of N-methyl piperazine, morpholine, piperidine, tetrahydropyrrole, diethylamine, dimethylamine, dipropylamine, methanol and azetidine.
Specifically, the molar ratio of the compound B5 to the compound H is 1: 1.2-1.5, and preferably 1: 1.5.
Specifically, the reaction formula for preparing compound B6 from compound B5 is as follows:
Figure BDA0001458748950000212
s280, reducing the nitro group of the compound B6 into amino group to obtain a compound B7, wherein the structural formula of the compound B7 is shown in the specification
Figure BDA0001458748950000213
In one example, compound B6 was dissolved in methylene chloride and methanol mixed in equal proportions, and zinc powder and ammonium chloride were added to the above solution and stirred at room temperature for 8 to 12 hours. Then, the mixture was filtered through celite, washed with dichloromethane, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound B7.
Specifically, the molar ratio of the compound B6 to the zinc powder to the ammonium chloride is 1: 6-8: 8-10, and preferably 1:8: 10.
Specifically, the reaction formula for preparing compound B7 from compound B6 is as follows:
Figure BDA0001458748950000214
and S290, the compound B7 and the compound F are subjected to condensation reaction to obtain the quinazoline compound.
Wherein the compound F is carboxylic acid and has the structure
Figure BDA0001458748950000221
-R4Is alkyl or aryl.
In one example, compound B7 and compound F were dissolved in dichloromethane, and the condensing agent EDCI was added thereto, and the reaction solution was stirred at room temperature for 12 to 16 hours. Separating and purifying to obtain pure compound B8, namely the pure quinazoline compound.
Specifically, the compound F is various aromatic acids or fatty acids, and is selected from one of N-tert-butoxycarbonylproline, N-tert-butoxycarbonylalanine, N-tert-butoxycarbonylvaline, thiazole-2-carboxylic acid, 1H-imidazole-5-carboxylic acid, oxazole-4-carboxylic acid, pyrrole-2-carboxylic acid, indole-2-carboxylic acid, pyridine-2-carboxylic acid, 3-chlorobenzothiophene-2-carboxylic acid, 2-acetoxy acetic acid, 2-bromoacetic acid, 2-chloroacetic acid and trifluoroacetic acid.
Specifically, the molar ratio of the compound B7 to the compound F is 1: 1.0-1.2, preferably 1: 1.0. The molar ratio of the compound B7 to the condensing agent is 1: 1.1-1.3, preferably 1: 1.2.
Specifically, the specific method for separation and purification comprises the following steps: adding water into the reaction solution, extracting with dichloromethane, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating in vacuum, and purifying by silica gel column chromatography (eluent: dichloromethane/methanol with volume ratio of 20-30: 1) to obtain a pure compound, namely the quinazoline compound.
When the compound F is N-tert-butoxycarbonylproline, the obtained compound B8 also needs to be subjected to tert-butoxycarbonyl removal.
Specifically, compound B8 is dissolved in dichloromethane, trifluoroacetic acid is added into the dichloromethane, the mixture is stirred for 6 hours at room temperature, sodium bicarbonate aqueous solution is added, and the pure quinazoline compound which does not contain the tert-butoxycarbonyl is obtained after separation and purification.
Specifically, the ratio of compound B8 to dichloromethane was 1mmol:5 mL.
Specifically, the ratio of the compound B8 to trifluoroacetic acid (TFA) is 1mmol:0.8 mL-1.2 mL, preferably 1mmol:1.0mL, and the trifluoroacetic acid is used to remove the tert-butoxycarbonyl group of the quinoline compound containing the tert-butoxycarbonyl group (Boc). In other embodiments, trifluoroacetic acid can also be replaced with hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, or formic acid.
Specifically, the specific method for separation and purification comprises the following steps: extracting with dichloromethane, mixing organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, and vacuum concentrating to obtain residue, which is purified by silica gel column chromatography to obtain pure quinoline compound without tert-butyloxycarbonyl group. Wherein, the eluent of the silica gel column chromatography is a mixed solution of dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 10-20: 1.
Specifically, the reaction formula of the compound B8 for removing tert-butyloxycarbonyl is as follows:
Figure BDA0001458748950000231
the preparation method of the quinazoline compound is simple and easy to implement, raw materials are easy to obtain, preparation conditions are mild, and industrial production is easy to realize.
The following are specific examples.
Examples 1 to 56
Examples 1 to 28 the quinoline compounds were prepared by the method for preparing quinoline compounds (method A). The specific preparation parameters are shown in table 1, and the specific steps are as follows:
step one, 20.0mmol 4-aminophenol and 24.0mmol Boc anhydride were dissolved in 150mL methanol, and 44.0mmol triethylamine was added with stirring and the reaction was stirred at room temperature for 18 hours. After the reaction, 20mL of 2mol/L hydrochloric acid solution is added, extraction is carried out by using 3X 50mL of ethyl acetate, organic phases are combined and washed by using 2X 50mL of saturated saline solution, drying is carried out by anhydrous sodium sulfate, and vacuum concentration is carried out to obtain a crude product which is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, volume ratio is 4:1) to obtain pure compound A2.
Step two, 12.0mmol of compound A2 and 10.0mmol of 4-fluoronitrobenzene are dissolved in 50mL of acetonitrile, 30.0mmol of potassium carbonate is added to the above solution, and the reaction mixture is stirred at 90 ℃ for 18 hours. Then, the reaction mixture was cooled to room temperature, 40mL of water was added to dilute the reaction mixture, the mixture was extracted with 3X 40mL of ethyl acetate, the organic phases were combined, the mixture was washed with 2X 50mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 6 hours. After the reaction, 10mL of saturated aqueous sodium bicarbonate solution was added, extraction was performed with 3X 20mL of dichloromethane, the organic phases were combined, washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate in a volume ratio of 3:1) to give pure compound A3.
Step three, mixing 1.0mmol of compound A3 and compound D (same as D in Table 1) in a three-neck flask, wherein the molar ratio of compound A3 to compound D is C1, adding 5g of polyphosphoric acid (PPA), and reacting for 18 hours with stirring at 130 ℃. After cooling to room temperature, 20mL of water was added, filtration was carried out, the filtrate was extracted with 3X 30mL of ethyl acetate, the organic phases were combined, washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product which was purified by silica gel column chromatography (eluent: dichloromethane/methanol, volume ratio 20:1) to give pure compound A4.
Step four, 1.0mmol of compound A4 and compound E (same as E in Table 1) was dissolved in 8mL of acetonitrile, compound A4 and compound E at a molar ratio of C2, and 4.0mmol of anhydrous potassium carbonate was added and the reaction was stirred at 90 ℃ for 12 hours. Cooling to room temperature, adding 15mL of water, filtering, extracting the filtrate with 3X 20mL of ethyl acetate, combining the organic phases, washing with 20mL of saturated brine, drying over anhydrous sodium sulfate, and vacuum concentrating to obtain a crude product, which is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, volume ratio 5:1) to obtain pure compound A5.
Step five, dissolving 1.0mmol of compound A5 in 10mL of dichloromethane and methanol mixed in equal proportion, and adding zinc powder and ammonium chloride into the solution, wherein the molar ratio of the compound A5 to the zinc powder to the ammonium chloride is C3. The reaction solution was stirred at room temperature for 12 hours. Then filtered through celite, washed with dichloromethane, and the filtrate washed with 2X 20mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give pure Compound A6.
Step six, 1.0mmol of compound A6 and compound F (same as F in Table 1) were dissolved in 8mL of dichloromethane with the molar ratio of compound A6 to compound F being C4, and 1.2mmol of EDCI was added thereto, and the reaction was stirred at room temperature for 16 hours. Then 10mL of water is added, extraction is carried out by using 3X 15mL of dichloromethane, organic phases are combined and washed by using 2X 20mL of saturated saline solution, the obtained mixture is dried by anhydrous sodium sulfate and concentrated in vacuum, and the obtained residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol with the volume ratio of 20:1) to obtain pure compound A7, namely the quinoline compound.
When the compound F is N-tert-butyloxycarbonyl proline, Boc protecting group removal is required, and the specific steps are as follows: 1.0mmol of Compound A7 was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added thereto, and the reaction mixture was stirred at room temperature for 6 hours. Then, aqueous sodium hydrogencarbonate (10mL) was added thereto, followed by extraction with 3X 15mL of dichloromethane, and the organic phases were combined, washed with 2X 20mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10:1) to obtain the above quinoline compound with Boc protecting group removed.
TABLE 1
Figure BDA0001458748950000251
Figure BDA0001458748950000261
In examples 29 to 56, the quinazoline compound was prepared by the method (method B) of preparing the quinazoline compound, the preparation parameters are shown in table 2, and the specific steps are as follows:
step one, preparing a compound A3 according to the step one and the step two in the preparation method A adopted in the embodiment 1-31, and then adding trichloroacetaldehyde hydrate (11.0mmol) and 40mL of water into a flask; then, sodium sulfate (80.0mmol), Compound A3(10.0mmol), a hydrochloric acid solution (prepared from 6mL of water and 1mL of concentrated hydrochloric acid) and finally a solution of hydroxylamine hydrochloride (33.0mmol) dissolved in 10mL of water were added in this order. The reaction mixture is stirred and reacted for 2h at 110 ℃, heated to 130 ℃, stirred and reacted for 1h, cooled to room temperature, filtered, gradually (after about 20 min), added into concentrated sulfuric acid (20mL) at 50 ℃ after being dried, and reacted for 2h at 65 ℃. Cooling to room temperature, pouring into crushed ice with the volume 10 times that of the reactant, filtering after 30min, washing with cold water, and drying to obtain the compound B1.
Step two, dissolving the compound B1(2.0mmol) in sodium hydroxide aqueous solution (2M, 15mL), gradually adding hydrogen peroxide (2mL), and stirring at 60 ℃ for reaction for 3 h. Cooling to room temperature, adding HCl (6M), adjusting the pH of the reaction solution to 2-4, filtering, washing with cold water, and drying to obtain compound B2.
Step three, compound B2(5.0mmol) and urea (35.0mmol) were added to a reaction flask and the reaction stirred at 160 ℃ for 18 h. Cooled to room temperature, added with 50mL of water, filtered, washed with water and dried to give compound B3.
Step four, compound B3(10.0mmol), phosphorus pentachloride (40.0mmol) and phosphorus oxychloride (8mL) were added to the reaction flask and the reaction was stirred at 110 ℃ for 6 hours. After cooling to room temperature, the solvent was concentrated, 20mL of a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate (3 × 20mL), the organic phases were combined, washed with a saturated brine (2 × 20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 10:1) to obtain intermediate B4.
Step five, compound B4(2.0mmol) was dissolved in tetrahydrofuran (8mL), and triethylamine (4.0mmol) and compound G (same as G in Table 2) were added, the molar ratio of compound B4 to compound G was C5, and the reaction was stirred at 60 ℃ for 16 hours. After cooling to room temperature, the solvent was concentrated, 10mL of a saturated aqueous solution of sodium hydrogencarbonate was added, extraction was performed with ethyl acetate (3X 20mL), the organic phases were combined, washed with a saturated brine (2X 20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, volume ratio 5:1) to obtain compound B5.
Step six, compound B5(1.0mmol), compound H (same as H in table 2), and n-butanol (4mL) were mixed in a reaction flask with the molar ratio of compound B5 to compound H being C6, concentrated hydrochloric acid (1 drop) was added, and the reaction was stirred at 110 ℃ for 16 hours. After cooling to room temperature, the solvent was concentrated, 10mL of water was added, extraction was performed with ethyl acetate (3X 20mL), the organic phases were combined, washed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, volume ratio 2:1) to give compound B6.
Step seven, compound B6(1.0mmol) was dissolved in dichloromethane and methanol (10mL) mixed in equal proportion, and zinc powder (8.0mmol) and ammonium chloride (10.0mmol) were added to the above solution, and the reaction solution was stirred at room temperature for 12 hours. Then, the mixture was filtered through celite, washed with dichloromethane, and the filtrate was washed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue which was intermediate B7.
Step eight, dissolving compound B7(1.0mmol) and compound F (same as F in table 2) in dichloromethane (8mL), the molar ratio of compound B7(1.0mmol) to compound F being C7, and adding the condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI (1.2mmol), the reaction solution was stirred at room temperature for 16 hours. Then, water (10mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3X 15mL), the organic phases were combined and washed with saturated brine (2X 20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol, volume ratio 20:1) to obtain compound B8, which was the pure quinazoline compound.
When the compound was N-t-butoxycarbonylproline, compound B8(1.0mmol) was dissolved in methylene chloride (5mL), and trifluoroacetic acid (1mL) was added thereto, and the reaction mixture was stirred at room temperature for 6 hours. Then, an aqueous sodium hydrogencarbonate solution (10mL) was added thereto, followed by extraction with dichloromethane (3X 15mL), and the organic phases were combined, washed with a saturated brine (2X 20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol in a volume ratio of 10:1) to obtain a pure quinazoline compound described above which does not contain a tert-butylcarbonyl group.
TABLE 2
Figure BDA0001458748950000281
Figure BDA0001458748950000291
The prepared quinoline or quinazoline compound is determined by a nuclear magnetic resonance hydrogen spectrum structure, or a nuclear magnetic resonance hydrogen spectrum and a high-resolution mass spectrum structure, and the results are shown in table 3.
TABLE 3
Figure BDA0001458748950000292
Figure BDA0001458748950000301
Figure BDA0001458748950000311
Figure BDA0001458748950000321
Figure BDA0001458748950000331
Figure BDA0001458748950000341
Figure BDA0001458748950000351
Figure BDA0001458748950000361
Figure BDA0001458748950000371
Figure BDA0001458748950000381
Figure BDA0001458748950000391
Figure BDA0001458748950000401
Figure BDA0001458748950000411
Figure BDA0001458748950000421
Figure BDA0001458748950000431
PFKFB3 enzyme Activity assay
The quinoline or quinazoline compounds of examples 1 to 56 were subjected to the PFKFB3 enzyme activity test which mainly comprised two reaction steps, i.e.
The method comprises the following steps: PFKFB3 catalyzes the formation of F-2,6-BP from F6P and ATP; step two: the generated F-2,6-BP activates PFK1, PFK1 catalyzes and consumes NADH, a change of NADH content is detected by an enzyme-labeling instrument, and the activity of PFKFB3 enzyme is quantified according to the NADH content.
The reaction system in the first step consists of Buffer A and Buffer B + or Buffer B-. Wherein, Buffer A: mainly contains enzyme and target product; buffer B +: containing a substrate, fructose-6-phosphate (F6P); buffer B-: substrate F6P was not included and was used to detect the background of the reaction.
A certain amount of Buffer A is prepared, wherein the Buffer A contains DTT (final concentration: 1mM), PFKFB3 (adding a proper volume according to enzyme activity) and Mops Buffer, and the mixture is evenly mixed and then distributed into a marked ice Ep tube with 200 mu L per tube. Adding 4 μ L of target products with diluted gradient concentration into the Ep tube, wherein the final concentration of the target products is respectively: 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M, 0.03. mu.M, 0.01. mu.M, 0.003. mu.M, 0.001. mu.M, and an equal volume of DMSO was added to the negative control group. After mixing, centrifugation is carried out, and incubation is carried out for 30 minutes at room temperature, assuming that a certain time is required for binding of the target product to the enzyme.
Preparing Buffer B + and Buffer B-, wherein the Buffer B + contains MgCl2(working concentration: 2mM), ATP (working concentration: 50. mu.M), F6P (working concentration: 50. mu.M), and MOPS buffer; buffer B-contains MgCl2(working concentration: 2mM), ATP (working concentration: 50. mu.M), and MOPS buffer. And uniformly mixing the prepared Buffer B + or Buffer B-, subpackaging the mixture into Ep tubes corresponding to the Buffer A, adding 200 mu L of Buffer B into each tube, uniformly mixing, centrifuging, and incubating for one hour at 37 ℃ to ensure that the PFKFB 3-catalyzes F6P and ATP to generate F-2, 6-BP. After one hour, 40. mu.L of KOH/tube (stock concentration of KOH: 1M) was added to the Ep tube to terminate the reaction, and the mixture was centrifuged to mix well and placed on ice.
The reaction system in the second step contained NADH (final concentration: 0.2mM), DTT (final concentration: 5mM), F6P (final concentration: 1mM), MgCl2(final concentration: 2mM), Aldolase (final concentration: 0.7U/mL), GDH (final concentration: 0.45U/mL), TIM (final concentration: 0.6U/mL), PFK1 final concentration: 0.033. mu.g/. mu.L) and Tris-HCl buffer.
And (4) preparing the reaction liquid in the second step, uniformly mixing, and subpackaging into the marked Ep tubes with 450 mu L/tube. And adding the reaction solution obtained in the first step after termination into the reaction solution obtained in the second step, adding 6 mu L of the reaction solution into each tube, uniformly mixing and centrifuging. The reaction solution was transferred to a 96-well plate at 150. mu.L/well, and 2 wells were added to each sample. Then, PPi-Na was added to the 96-well plate at a stock concentration of 25mM, 3. mu.L/well, using a line gun. After the addition, the NADH consumption rate is detected by a microplate reader, the Mean V value is measured, and the IC50 of the target product is calculated by GraphPad Prism 5 software.
The IC50 of the target product of some of the examples is shown in table 4.
TABLE 4
Figure BDA0001458748950000441
Figure BDA0001458748950000451
As can be seen from Table 4, the quinoline or quinazoline compounds prepared according to the preparation method A and the preparation method B have good inhibition effect on the kinase activity of PFKFB3 enzyme. After the kinase activity of PFKFB3 enzyme is inhibited, the synthesis of Fru-2,6-BP is hindered, thereby inhibiting the activity of PFK-1 and further inhibiting the glycolytic metabolism of tumor cells, so that the energy supply required by the proliferation and growth of the tumor cells is limited.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A quinoline or quinazoline compound, characterized by the following structural formula:
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。
2. a preparation method of a quinoline compound, which is a compound 1-14 in the quinoline or quinazoline compound according to claim 1, and comprises the following steps:
nucleophilic substitution reaction is carried out on the compound A2 and 4-fluoronitrobenzene to obtain a compound A3, wherein the structural formula of the compound A2 is shown in the specification
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The structural formula of the compound A3 is shown in the specification
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；
Carrying out condensation cyclization reaction on the compound A3 and a compound D to obtain a compound A4, wherein the structural formula of the compound D is shown in the specification
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The structural formula of the compound A4 is shown in the specification
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；
Carrying out substitution reaction on the compound A4 and the compound E to obtain a compound A5,wherein said compound E is a compound containing-R3The structural formula of the compound A5 is shown in the specification
Figure 589775DEST_PATH_IMAGE010
；
Reducing the nitro group on the benzene ring of the compound A5 into amino group to obtain a compound A6, wherein the structural formula of the compound A6 is shown in the specification
Figure 78525DEST_PATH_IMAGE011
(ii) a And
carrying out condensation reaction on the compound A6 and a compound F to obtain the quinoline compound, wherein the structure of the compound F is
Figure 35111DEST_PATH_IMAGE012
，-R4Is tetrahydropyrrole;
wherein the Y group is substituted with-R3The groups correspond one to one according to the compounds 1-14.
3. The method for preparing quinoline compound according to claim 2, wherein the molar ratio of compound a3 to compound D is: 1: 1.3-1.5.
4. The method for preparing quinoline compound according to claim 2, wherein the molar ratio of compound a4 to compound E is: 1: 1.0-1.3.
5. The method for preparing quinoline compounds according to claim 2, wherein the molar ratio of the compound A6 to the compound F is 1: 1.0-1.2.
6. A preparation method of a quinazoline compound, which is characterized in that the quinazoline compound is a quinoline or a compound 29, 30, 33-51 in the quinazoline compound as described in claim 1, and the preparation method of the quinazoline compound comprises the following steps:
will combine withThe substance A2 and 4-fluoronitrobenzene are subjected to nucleophilic substitution reaction to obtain a compound A3, and the structural formula of the compound A2 is shown in the specification
Figure 27338DEST_PATH_IMAGE013
The structural formula of the compound A3 is shown in the specification
Figure 660445DEST_PATH_IMAGE014
；
Condensing and cyclizing the compound A3 and chloral hydrate to obtain a compound B1, wherein the structural formula of the compound B1 is shown in the specification
Figure 370912DEST_PATH_IMAGE015
；
Opening the ring of the compound B1 to obtain a compound B2, wherein the structural formula of the compound B2 is shown in the specification
Figure 364144DEST_PATH_IMAGE016
；
Carrying out condensation reaction on the compound B2 and urea to obtain a compound B3, wherein the structural formula of the compound B3 is shown in the specification
Figure 476457DEST_PATH_IMAGE017
；
The compound B3 is chloridized to obtain a compound B4, and the structural formula of the compound B4 is shown in the specification
Figure 280465DEST_PATH_IMAGE018
；
Carrying out substitution reaction on the compound B4 and a compound G to obtain a compound B5, wherein the compound G contains-R3The structural formula of the compound B5 is shown in the specification
Figure 478228DEST_PATH_IMAGE019
；
Performing substitution reaction on the compound B5 and a compound H to obtain a compound B6, wherein the compound H is Y-H, and the structural formula of the compound B6 is shown in the specification
Figure 773687DEST_PATH_IMAGE020
；
Reducing the nitro group of the compound B6 into amino group to obtain a compound B7, wherein the structural formula of the compound B7 is shown in the specification
Figure 537243DEST_PATH_IMAGE021
(ii) a And
carrying out condensation reaction on the compound B7 and a compound F to obtain the quinazoline compound, wherein the structure of the compound F is
Figure 777732DEST_PATH_IMAGE022
，-R4Is tetrahydropyrrole;
wherein the Y group is substituted with-R3The groups correspond to the compounds 29, 30 and 33-51 one by one.
7. The method for preparing a quinazoline compound according to claim 6, wherein the molar ratio of the compound B2 to the urea is 1: 6.0-7.0.
8. The use of a quinoline or quinazoline compound according to claim 1 in the preparation of a PFKFB inhibitor.
9. A PFKFB inhibitor comprising the quinoline or quinazoline compound according to claim 1.
10. The use of a quinoline or quinazoline compound according to claim 1 in the preparation of an anti-tumour medicament.
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