CN113845485B - Amino acid derivative and preparation method and application thereof - Google Patents
Amino acid derivative and preparation method and application thereof Download PDFInfo
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Abstract
The present invention relates to amino acid derivatives anda preparation method and application thereof. The amino acid derivative has one of the following structural formulas:
the amino acid derivative has good water solubility and good binding force with target protein, and the gefitinib is used as a positive control, and the result shows that the amino acid derivative has good activity compared with the gefitinib, so that the amino acid derivative has higher reference and reference values for further modification and discovery of a new antitumor drug candidate. The invention also provides a preparation method of the amino acid derivative and application of the amino acid derivative in preparing anti-cancer drugs.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an amino acid derivative and a preparation method and application thereof.
Background
Amino acid is a basic unit for forming protein, has good biocompatibility and affinity, can increase the solubility of the drug, enhance the absorption rate of the drug by small intestine, promote the active transport process of the drug in vivo, improve the bioavailability, improve the selectivity of the drug to tumor cells, reduce the toxicity to normal cells, improve the anti-tumor activity and the metabolic stability, and open up a way for seeking high-efficiency and low-toxicity anti-tumor drugs by introducing the amino acid into drug molecules.
Quinazoline has been an important parent nucleus of EGFR inhibitors and is an advantageous structure for designing targeted therapeutic drugs for NSCLC. However, in the prior art, the antitumor drug prepared by using the quinazoline ring as the skeleton has poor solubility and unsatisfactory absorption effect.
Disclosure of Invention
Based on the technical problems, the invention provides an amino acid derivative, and a preparation method and application thereof.
The amino acid derivative provided by the invention has one of the following structural formulas:
in the formula, -R 1 One selected from hydrogen or C1-C6 alkane; -R 2 One selected from the group consisting of dimethylaminopropyl, morpholinopropyl, dibutylamine propyl, diethylaminopropyl, dihexylaminopropyl, and dioctylaminopropyl; -R 3 One selected from hydrogen, acetyl, propionyl or butyryl.
Further, the structural formula of the amino acid derivative is selected from one of the following structural formulas:
the invention also provides a preparation method of the amino acid derivative, which comprises the following steps:
1) Dissolving a compound A1 or B1 in a sodium hydroxide solution, dropwise adding acid anhydride at normal temperature for acylation reaction to obtain a compound A2 and a compound B2 respectively, wherein the structural formula of the compound A1 is shown in the specification
The structural formula of the compound B1 is shown in the specification
The structural formula of the compound A2 is
The structural formula of the compound B2 is
Wherein, -R 3 One selected from acetyl, propionyl and butyryl;
2) Adding the compound A2 into the mixed acid solution in batches for nitration reaction to respectively obtain a compound A3 and a compound B3, wherein the structural formula of the compound A3 is shown in the specification
The structural formula of the compound B3 is shown in the specification
3) Dissolving the compound A3 or B3 in an alcohol solution, heating, slowly dripping a sulfuric acid solution for esterification reaction to respectively obtain a compound A4 and a compound B4, wherein the structural formula of the compound A4 is shown in the specification
The structural formula of the compound B4 is as follows:
wherein, -R 1 One selected from C1-C6 alkanes;
4) Reducing the nitro on the benzene ring of the compound A4 or B4 into amino to respectively obtain a compound A5 and a compound B5, wherein the structural formula of the compound A5 is shown in the specification
The structural formula of B5 is as follows:
5) Reacting compound C3 with said compound A5 or B5Performing substitution reaction to obtain a compound A6 or B6, wherein the structural formula of the compound A6 is shown in the specification
The structural formula of B6 is as follows:
the structural formula of the compound C3 is
6) Hydrolyzing the compound A6 or B6 with ammonia water to obtain a compound A7 or B7, wherein the structural formula of the compound A7 is shown in the specification
The structural formula of the compound B7 is as follows:
7) Reacting said compound A7 or B7 with a compound containing-R 2 The compound M is subjected to substitution reaction to respectively obtain a compound A8 and a compound B8, wherein the structural formula of the compound A8 is shown in the specification
The structural formula of the compound B8 is as follows:
when-R 1 Is hydrogen, -R 3 When the hydrogen is hydrogen, the compound A8 or the compound B8 and hydrochloric acid and glacial acetic acid are subjected to hydrolysis reaction to respectively obtain a compound A9 and a compound B9, wherein the structural formula of the compound A9 is shown in the specification
The structural formula of the compound B9 is
when-R 1 Is hydrogen, -R 3 Reacting the compound A8 or B8 with hydrochloric acid, wherein the compound A is one of acetyl, propionyl or butyryl;
when-R 1 Is one of C1-C6 alkane, -R 3 For hydrogen, compounds A9 or B9 are esterified in the manner of stage 4).
Preferably, before step 5), the preparation of said compound C3 is also included: performing acylation reaction on the compound C1 and acetic anhydride to obtain a compound C2, wherein the structural formula of the compound C1 is shown in the specification
The structural formula of the compound C2 is
And carrying out halogenation reaction on the compound C2 and thionyl chloride to obtain the compound C3. Preferably, the compound B1 is subjected to the acylation reaction with acetic anhydride, pyridine and DMAP (4-dimethylaminopyridine) to obtain the compound C2; halogenating the compound C2 with thionyl chloride to generate the compound C3.
Preferably, the molar ratio of the compound A1 or B1 in the step 1) to the acetic anhydride in the acetic anhydride solution is 1.5-1.8, and the reaction time is 3-4 h.
Preferably, the mixed acid used in the nitration reaction in the step 2) is an acid solution prepared by mixing 98% of sulfuric acid and 68% of nitric acid in a volume ratio of 1.2.
Preferably, in the step 3), the compound A3 or B3 is esterified by using methanol as a solvent and sulfuric acid as a catalyst, wherein the molar ratio of the compound A3 or B3 to the methanol is 1.65-0.8, the reaction temperature is 90-95 ℃, and the reaction time is 7-8 h.
Preferably, the method for reducing the nitro group on the benzene ring of the compound A4 or B4 to amino group in step 4) adopts an iron powder reduction method, specifically: mixing iron powder, ammonium chloride, absolute ethyl alcohol, water and glacial acetic acid with a compound A4 or B4 for reduction reaction; the molar ratio of the compound A4 or B4 to the iron powder is 1-11, the reaction temperature is 90-95 ℃, and the reaction time is 4-6 h.
Preferably, the reaction temperature of the acylation reaction of the compound C1 and acetic anhydride is 95-100 ℃, and the reaction time is 4-5 h.
Preferably, the molar ratio of the compound A5 or B5 to the compound B3 in the step 5) for substitution reaction is 1.2-1.5, the reaction temperature is 90-100 ℃, and the reaction time is 4-6 h.
Preferably, the molar ratio of the compound A6 or B6 to the ammonia water in the step 6) is 1:4-7, the reaction temperature is 70-75 ℃, and the reaction time is 5-6 h.
Preferably, the molar ratio of the compound A7 or B7 to the compound M in the step 7) is 1; the reaction temperature is 90-95 ℃; the reaction time is 6-8 h.
Preferably, the molar ratio of the compound A8 or B8 and glacial acetic acid in the step 8) is 1; the reaction temperature is 110 ℃; the reaction time is 6-8 h.
In addition, the invention also provides application of the amino acid derivative in preparing anti-cancer drugs.
Preferably, the drug is an anti-lung cancer drug.
Compared with the prior art, the invention has the advantages that:
the amino acid derivative provided by the invention adopts a quinazoline framework, different amino acid derivatives and other related groups are introduced into a quinazoline ring to obtain a series of compounds with anti-tumor activity, and gefitinib is used as a positive control, and the result shows that the amino acid derivative has good activity compared with gefitinib, and has higher reference and reference values for finding new anti-tumor drug candidates. The amino acid derivative also has the advantages of good solubility and easy absorption.
The embodiment of the invention also provides a preparation method of the amino acid derivative, which adopts a quinazoline framework and obtains a series of compounds with antitumor activity by introducing different amino acid derivatives and other related groups on a quinazoline ring. The method can efficiently obtain various amino acid derivatives with high quality, is simple and convenient to operate, has low requirements on equipment, and is suitable for large-scale production and application.
Drawings
FIG. 1 is a schematic representation of the docking of the compound prepared in example 19 with a 2ITY target protein and the docking results.
Detailed Description
The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
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. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The present embodiment provides an amino acid derivative having one of the following structural formulae:
in the formula, -R 1 One selected from hydrogen or C1-C6 alkane; -R 2 One selected from the group consisting of dimethylaminopropyl, morpholinopropyl, dibutylamine propyl, diethylamine propyl, dihexylaminopropyl, and dioctylaminopropyl; -R 3 One selected from hydrogen, acetyl, propionyl or butyryl. The structural formula of the amino acid derivative can be any one of the above structural formulas, and in order to further illustrate the preparation method and performance of the amino acid derivative provided by the invention, the preparation method and performance research of part of the structural formulas are listedThe details are described.
The 7-methoxy-6-acetoxy-4-chloroquinazoline (i.e., compound C3) in this particular example embodiment was prepared by the following method
Adding 6-hydroxy-7-methoxy-4-keto quinazoline (10g, 0.052mol, namely compound C1), acetic anhydride (108mL, 1.14mol) and pyridine (22.4mL, 0.278mol) into a 500mL round-bottom flask in sequence, heating to 100 ℃, refluxing for 1h, adding 4-dimethylaminopyridine (1.4g, 0.0115mol), continuing for 4h, stopping the reaction, pouring a large amount of ice water into the filtrate, stirring, filtering, and drying a filter cake to obtain a yellow white solid (namely compound C2). The obtained solution and thionyl chloride (107mL, 1.47mol) were sequentially added to a 500mL three-necked round-bottomed flask, the temperature was raised to 80 ℃ and reflux reaction was carried out for 30min, and N, N-dimethylformamide (4.6 mL, 0.059mol) was slowly added dropwise to the reaction solution from a constant-pressure dropping funnel. Reacting for 4 hours, stopping the reaction, cooling, recovering thionyl chloride under reduced pressure, adding ice water (250 mL) into the reaction, stirring for about 1 hour, filtering, and drying the filter cake to obtain an off-white solid 10.5g with the yield of 80.0%.
Example 1
Preparation of methyl (S) -2-acetylamino-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
(1) Preparation of (S) -2-acetamido-3-phenylpropionic acid (i.e. a compound A2)
Stirring L-phenylalanine (15g, 0.091mol, namely a compound A1) and water (200 mL) at room temperature for 10min, slowly dropwise adding saturated NaOH aqueous solution, adjusting the pH value of the solution to be completely dissolved in the phenylalanine, and slowly dropwise adding acetic anhydride (15mL, 0.159mol); in the process of dropwise adding acetic anhydride, due to the change of the pH value, L-phenylalanine is separated out, and a saturated NaOH aqueous solution is dropwise added to maintain the alkalescent environment (pH = 8.0) of the reaction solution; reacting at room temperature for 3h, after TLC detection reaction is complete, dropwise adding hydrochloric acid to adjust the pH value of the reaction solution to 2, completely separating out the product, performing suction filtration, and drying to obtain 16.6g of white solid with the yield of 88.2%.
(2) Preparation of (S) -2-acetamido-3- (4-nitrophenyl) propionic acid, i.e. a Compound A3
A250 mL flask was slowly charged with 98% sulfuric acid (9.6 mL) and nitric acid (8.0 mL), stirred at-20 ℃ for 0.5h, taken out, placed in an ice bath at room temperature, and stirred with (S) -2-acetylamino-3-phenylpropionic acid (10g, 0.048mol) added in portions; stirring for 18h, and stopping the reaction after the TLC detection reaction is complete; the reaction solution was poured into 200mL of ice water, stirred, and the product precipitated, filtered under vacuum, and dried to give 6.9g of a white solid with a yield of 56.7%.
(3) Preparation of (S) -2-acetylamino-3- (4-nitrophenyl) propionic acid methyl ester, i.e. a Compound A4
Dissolving (S) -2-acetamido-3- (4-nitrophenyl) propionic acid (6 g, 0.024mol) in methanol (60 mL) at 85 ℃, stirring for 0.5h, slowly dropwise adding 98% concentrated sulfuric acid (0.843 mL), refluxing for 7h, stopping reaction, and cooling to room temperature; distilling under reduced pressure to remove methanol, extracting with ethyl acetate (100 mL), and adding saturated Na dropwise 2 CO 3 Adjusting the pH value of the solution to 7, extracting the water phase by using ethyl acetate (50 mL multiplied by 2), combining the organic phases, adding water (50 mL multiplied by 2) for washing, and drying the organic phases for 4 hours by using anhydrous magnesium sulfate; filtering, decompressing and concentrating the filtrate to obtain 5.8g of yellow solid with the yield of 91.6 percent.
(4) Preparation of (S) -methyl 2-acetylamino-3- (4-aminophenyl) propionate, a Compound A5
Adding reduced iron powder (11.1g, 0.199mol), ammonium chloride (0.68g, 0.013mol), ethanol (56 mL), water (14 mL) and glacial acetic acid (3.4 mL) into a 250mL three-neck flask provided with a drying tube device in sequence, heating to 90 ℃, carrying out reflux reaction, mechanically stirring for 1.5h, adding (S) -2-acetamido-3- (4-nitrophenyl) methyl propionate (5.1g, 0.019mol), continuing to react for 3h, carrying out suction filtration while the solution is hot, concentrating the filtrate under reduced pressure, adding dichloromethane (150 mL) for extraction, adding water (50 mL multiplied by 2) for washing, and drying an organic phase for 4h by anhydrous magnesium sulfate; filtering, decompressing and concentrating the filtrate to obtain yellow white solid 3.4g with the yield of 75.2 percent.
(5) Preparation of methyl (S) -2-acetylamino-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (i.e. a compound A6)
Methyl (S) -2-acetylamino-3- (4-aminophenyl) propionate (3.7g, 0.016mol) was dissolved in isopropanol (37 mL), stirred at 95 ℃ for 0.5h, and 7-methoxy-6-acetoxy-4-chloroquinazoline (4.8g, 0.014mol) was added; and (4) continuously carrying out reflux reaction for 4h, stopping the reaction after the TLC detection reaction is completed, carrying out suction filtration while the reaction is hot, and drying a filter cake to obtain 5.0g of white solid with the yield of 70.6%.
(6) Preparation of methyl (S) -2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (i.e. a compound A7)
Methyl (S) -2-acetylamino-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (3g, 0.007mol) was dissolved in methanol (20 mL), heated to 65 ℃ for 0.5h under reflux, and aqueous ammonia (5.2 mL) was added. Continuing to react for 5h, stopping the reaction after the TLC detection reaction is complete, cooling to room temperature, and concentrating the reaction liquid under reduced pressure to obtain a yellow oily substance; ethyl acetate (30 mL) was added and stirred to give a yellow solid, which was filtered under suction and the filter cake was dried to give 2.5g of a yellow solid with a yield of 91.9%.
(7) Preparation of methyl (S) -2-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propionate
Dissolving methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate (2.5 g, 0.006mol) in DMF (10 mL), heating to 75 ℃ and refluxing for 0.5h, adding potassium carbonate (1.0g, 0.017mol), potassium iodide (0.02 g) and 1,3-bromochloropropane (0.78mL, 0.008mol); the reaction was continued for 8h, and stopped after completion of the reaction as detected by TLC. Cooling to room temperature, adding ice water (50 mL), stirring for 2h, performing suction filtration to obtain a crude product, adding acetone for washing, and drying a filter cake to obtain 2.3g of yellow solid with the yield of 77.4%.
(8) Preparation of methyl (S) -2-acetylamino-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Dissolving (S) -methyl 2-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propionate (2.3g, 0.005mol) in DMF (10 mL), heating to 95 ℃ and refluxing for 0.5h, adding potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02 g) and diethylamine (0.8mL, 0.007mol); the reaction is continued for 8h, and the reaction is stopped after the TLC detection reaction is completed; cooling to room temperature, adding ice water (50 mL), stirring for 2h, and performing suction filtration to obtain a crude product; dissolving the crude product in methanol (10 mL), slowly dropwise adding hydrochloric acid to generate white solid, performing suction filtration, and drying the filter cake to obtain 1.0g of yellow-white solid with the yield of 40.4%. m.p.176.3-177.9 ℃.
In other embodiments, methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (i.e., compound A8) can also be produced by direct substitution of methyl (S) -2-acetamido-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate with N, N-diethyl-3-chloropropylamine compound.
Example 2
Preparation of methyl (S) -2-acetylamino-3- (4- ((6- (3- (dihexylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (2.3 g, 0.005mol) was dissolved in DMF (10 mL), and after refluxing reaction at 95 ℃ for 0.5h, potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02 g) and dihexylamine (1.53mL, 0.007mol) were added. Continuing to react for 8h, and stopping the reaction after the TLC detection reaction is complete; cooling to room temperature, adding ice water (50 mL), stirring for 2h, and performing suction filtration to obtain a crude product; dissolving the crude product in methanol (10 mL), slowly dropwise adding hydrochloric acid to generate white solid, performing suction filtration, and drying the filter cake to obtain 1.4g of yellow-white solid with the yield of 45.4%. m.p.186.3-188.9 ℃.
In other embodiments, methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (i.e., compound A8) can also be produced by direct substitution of methyl (S) -2-acetamido-3- (4- ((6- (3- (dihexylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate with N- (3-chloropropyl) -dihexylamine compound.
Example 3
Preparation of methyl (S) -2-acetylamino-3- (4- ((6- (3- (dioctylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (2.3g, 0.005mol) was dissolved in DMF (10 mL), heated to 95 ℃ and reacted under reflux for 0.5h, followed by addition of potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02 g) and dioctylamine (1.5g, 0.006mol). Continuing to react for 8h, and stopping the reaction after the TLC detection reaction is complete; cooling to room temperature, adding ice water (50 mL), stirring for 2h, and performing suction filtration to obtain a crude product; dissolving the crude product in methanol (10 mL), slowly dropwise adding hydrochloric acid to generate white solid, performing suction filtration, and drying the filter cake to obtain 1.4g of yellow-white solid with the yield of 43.3%. m.p.202.6-204.1 deg.C.
In other embodiments, methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate (i.e., compound A8) can also be produced by direct substitution of methyl (S) -2-acetamido-3- (4- ((6- (3- (dioctylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate with an N- (3-chloropropyl) -dioctylamine compound.
Example 4
(S) -2-acetylamino-3- (4- ((6- (3- (dimethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid methyl ester
Dissolving (S) -methyl 2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate (2.8g, 0.007mol) in DMF (14 mL), heating to 95 ℃ and carrying out reflux reaction for 0.5h, and then adding potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02 g) and N, N-dimethyl-3-chloropropylamine (1.5mL, 0.011mol); continuing to react for 8h, and stopping the reaction after the TLC detection reaction is complete; cooling to room temperature, adding ice water (70 mL), stirring for 2h, and performing suction filtration to obtain a crude product; dissolving the crude product in methanol (10 mL), stirring, slowly dropwise adding hydrochloric acid until white solid is generated, performing suction filtration, and drying the filter cake to obtain 1.4g of white solid with the yield of 41.6%. m.p.165.1-167.5 ℃.
Example 5
Preparation of methyl (S) -2-acetylamino-3- (4- ((6- (3-morpholinopropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Dissolving (S) -methyl 2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate (2.8g, 0.007mol) in DMF (14 mL), heating to 95 ℃ and refluxing for 0.5h, followed by addition of potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02 g) and N- (3-chloropropyl) -morpholine (1.3mL, 0.008mol); continuing to react for 8h, and stopping the reaction after the TLC detection reaction is complete; cooling to room temperature, adding ice water (70 mL), stirring for 2h, and performing suction filtration to obtain a crude product; dissolving the crude product in methanol (10 mL), stirring, slowly dropwise adding hydrochloric acid until white solid is generated, performing suction filtration, and drying a filter cake to obtain 1.4g of white solid with the yield of 36.7%. m.p.168.0-170.2 deg.c.
Example 6
Preparation of methyl (S) -2-acetylamino-3- (4- ((6- (3- (dibutylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Dissolving (S) -methyl 2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate (2.8g, 0.007mol) in DMF (14 mL), heating to 95 ℃ and refluxing for 0.5h, adding potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02 g) and N- (3-chloropropyl) -dibutylamine (1.9mL, 0.008mol); continuing to react for 8h, and stopping the reaction after the TLC detection reaction is complete; and cooling to room temperature, adding ice water (70 mL), stirring for 2h, and filtering to obtain a crude product. Dissolving the crude product in methanol (10 mL), stirring, slowly dropwise adding hydrochloric acid until white solid is generated, performing suction filtration, and drying the filter cake to obtain 1.8g of white solid with the yield of 46.2%. m.p.180.4-182.1 deg.C.
Example 7
Preparation of (S) -2-amino-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid
Dissolving (S) -methyl 2-acetamido-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propionate (1g, 0.002mol) in glacial acetic acid (4 mL, 0.07mol), adding HCl (12 mL), heating to 110 ℃, refluxing for 7 hours, and stopping the reaction after TLC detection reaction is complete; cooling to room temperature, concentrating the reaction solution under reduced pressure, adding ethyl acetate (50 mL), stirring for 2h, filtering, and drying the filter cake to obtain 0.4g of a yellow-white solid with a yield of 44.9%. m.p.156.5-157.3 ℃.
Example 8
Preparation of methyl (R) -2-acetylamino-3- (4- ((6- (3- (dimethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
(1) Preparation of (R) -2-acetamido-3-phenylpropionic acid
The L-phenylalanine was replaced with D-phenylalanine in the step (2) of example 1 under the same reaction conditions as in the step (2) of example 1 to give a yellow solid product in a yield of 85.1%.
(2) Preparation of (R) -2-acetamido-3- (4-nitrophenyl) propionic acid
The other reaction conditions of the step (2) (S) -2-acetylamino-3-phenylpropionic acid of example 1 were changed to (R) -2-acetylamino-3-phenylpropionic acid, and the same as in the step (2) of example 1, to obtain a yellow solid product with a yield of 60.1%.
(3) Preparation of (R) -2-acetamido-3- (4-nitrophenyl) propionic acid methyl ester
The other reaction conditions of the step (S) -2-acetylamino-3- (4-nitrophenyl) propionic acid of example 1, in which (S) -2-acetylamino-3- (4-nitrophenyl) propionic acid was replaced with (R) -2-acetylamino-3- (4-nitrophenyl) propionic acid, were the same as in the step (3) of example 1, gave a yellow solid with a yield of 90.9%.
(4) Preparation of (R) -2-acetamido-3- (4-aminophenyl) propionic acid methyl ester
The other reaction conditions of the step (S) -methyl 2-acetylamino-3- (4-nitrophenyl) propionate of example 1, in which methyl (S) -2-acetylamino-3- (4-nitrophenyl) propionate was replaced with methyl (R) -2-acetylamino-3- (4-nitrophenyl) propionate of example 1, gave a yellowish white solid in a yield of 78.8%.
(5) Preparation of methyl (R) -2-acetamido-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Other reaction conditions of step (5) of example 1, in which methyl (S) -2-acetylamino-3- (4-aminophenyl) propionate was replaced with methyl (R) -2-acetylamino-3- (4-aminophenyl) propionate, were the same as in step (5) of example 1, gave a white solid in a yield of 72.5%.
(6) Preparation of methyl (R) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Step (6) of example 1, in which methyl (S) -2-acetylamino-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate was replaced with methyl (R) -2-acetylamino-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, was performed under the same reaction conditions as in step (6) of example 1, gave a yellow solid in a yield of 89.5%.
(7) Preparation of methyl (R) -2-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propionate
The methyl (7) (S) -2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 1 was replaced with methyl (R) -2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (7) of example 1, to give a pale yellow solid in a yield of 70.8%.
(R) -2-acetylamino-3- (4- ((6- (3- (dimethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid methyl ester
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 4 was replaced with methyl (R) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 4 to give a white solid with a yield of 38.9%. m.p.153.3-154.5 ℃.
Example 9
Preparation of methyl (R) -2-acetylamino-3- (4- ((6- (3-morpholinopropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 5 was replaced with methyl (R) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 5 to give a white solid with a yield of 41.6%. m.p.153.0-155.2 deg.C.
Example 10
Preparation of methyl (R) -2-acetylamino-3- (4- ((6- (3- (dibutylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate from example 6 was replaced with methyl (R) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions and procedures were the same as in example 6 to give a white solid in 46.2% yield. m.p.171.9-173.8 ℃.
Example 11
Preparation of methyl 2-acetamido-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
(1) Preparation of 2-acetamido-3-phenylpropionic acid
The L-phenylalanine was replaced with DL-phenylalanine in the step (1) of example 1 under the same reaction conditions as in the step (1) of example 1 to give a yellow solid product in a yield of 84.0%.
(2) Preparation of 2-acetamido-3- (4-nitrophenyl) propionic acid
The other reaction conditions of the step (2) (S) -2-acetylamino-3-phenylpropionic acid of example 1 were the same as those of the step (2) of example 1 except that 2-acetylamino-3-phenylpropionic acid was replaced with the step (2), to obtain a yellow solid product with a yield of 64.3%.
(3) Preparation of methyl 2-acetamido-3- (4-nitrophenyl) propionate
The other reaction conditions of the step (S) -2-acetylamino-3- (4-nitrophenyl) propionic acid of example 1, in which (S) -2-acetylamino-3- (4-nitrophenyl) propionic acid was replaced with 2-acetylamino-3- (4-nitrophenyl) propionic acid, were the same as in step (3) of example 1, gave a yellow solid with a yield of 92.0%.
(4) Preparation of methyl 2-acetamido-3- (4-aminophenyl) propionate
The other reaction conditions of step (4) of example 1, in which methyl (S) -2-acetylamino-3- (4-nitrophenyl) propionate was replaced with methyl 2-acetylamino-3- (4-nitrophenyl) propionate, were the same as in step (4) of example 1, gave a yellowish white solid in a yield of 76.7%.
(5) Preparation of methyl 2-acetamido-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate
The other reaction conditions of the step (5) (S) -methyl 2-acetylamino-3- (4-aminophenyl) propionate of example 1 were the same as those of the step (5) of example 1 except that methyl 2-acetylamino-3- (4-aminophenyl) propionate was replaced with methyl 2-acetylamino-3- (4-aminophenyl) propionate, to obtain a white solid with a yield of 70.5%.
(6) Preparation of methyl 2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate
Step (6) of (S) -methyl 2-acetylamino-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 1 was replaced with methyl 2-acetylamino-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (6) of example 1, to give a yellow solid in a yield of 90.5%.
(7) Preparation of methyl 2-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propionate
The methyl (7) (S) -2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 1 was replaced with methyl 2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (7) of example 1, to give a pale yellow solid with a yield of 72.5%.
(8) Preparation of methyl 2-acetamido-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
The methyl (8) (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 1 was replaced with methyl 2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (8) of example 1, yielding a yellow-white solid in 48.8% yield. m.p.179.9-181.8 deg.c.
Example 12
Preparation of methyl 2-acetamido-3- (4- ((6- (3- (dihexylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 2 was replaced with methyl 2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions and procedures were the same as in example 2 to give a white solid with a yield of 40.5%. m.p191.1-193.6 ℃.
Example 13
Preparation of methyl 2-acetamido-3- (4- ((6- (3- (dioctylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate from example 2 was replaced with methyl 2-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions and procedures were the same as in example 3 to give a white solid with a yield of 44.5%. m.p.206.0-208.9 ℃.
Example 14
2-acetylamino-3- (4- ((6- (3- (dimethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid methyl ester
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 4 was replaced with methyl 2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 4 to give a white solid in 47.3% yield. m.p.171.7-174.6 deg.c.
Example 15
Preparation of methyl 2-acetamido-3- (4- ((6- (3-morpholinopropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 5 was replaced with methyl 2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 5 to give a white solid in 33.7% yield. m.p.171.0-172.9 ℃.
Example 16
Preparation of methyl 2-acetamido-3- (4- ((6- (3- (dibutylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 6 was replaced with methyl 2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 6 to give a white solid in 51.2% yield. m.p.184.2-186.6 ℃.
Example 17
Preparation of methyl 3-acetylamino-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
(1) Preparation of 3-acetamido-3-phenylpropionic acid
The other reaction conditions of the step (2) of example 1 in which L-phenylalanine was replaced with 3-amino-3-phenylpropionic acid were the same as those of the step (2) of example 1, giving a yellow solid product with a yield of 79.0%.
(2) Preparation of 3-acetamido-3- (4-nitrophenyl) propionic acid
The other reaction conditions of the step (2) (S) -2-acetylamino-3-phenylpropionic acid of example 1 were the same as those of the step (2) of example 1 except that 3-acetylamino-3-phenylpropionic acid was replaced with the step (2) of example 1 to obtain a yellow solid product with a yield of 60.9%.
(3) Preparation of methyl 3-acetamido-3- (4-nitrophenyl) propionate
The other reaction conditions of the step (S) -2-acetylamino-3- (4-nitrophenyl) propionic acid of example 1, which was replaced with 3-acetylamino-3- (4-nitrophenyl) propionic acid, were the same as in the step (3) of example 1, to obtain a yellow solid with a yield of 90.0%.
(4) Preparation of methyl 3-acetylamino-3- (4-aminophenyl) propionate
The other reaction conditions of the step (4) (S) -methyl 2-acetylamino-3- (4-nitrophenyl) propionate of example 1 were the same as those of the step (4) of example 1, except that methyl 3-acetylamino-3- (4-nitrophenyl) propionate was replaced with methyl 3-acetylamino-3- (4-nitrophenyl) propionate, to obtain a yellowish white solid with a yield of 77.0%.
(5) Preparation of methyl 3-acetamido-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate
The other reaction conditions of the step (5) (S) -methyl 2-acetylamino-3- (4-aminophenyl) propionate of example 1 were the same as those of the step (5) of example 1 except that methyl 3-acetylamino-3- (4-aminophenyl) propionate was replaced with methyl 3-acetylamino-3- (4-aminophenyl) propionate, to obtain a white solid with a yield of 74.5%.
(6) Preparation of methyl 3-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate
The methyl (S) -2-acetamido-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate of step (6) in example 1 was replaced with methyl 3-acetamido-3- (4- ((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (6) of example 1, to give a yellow solid in a yield of 89.5%.
(7) Preparation of methyl 3-acetamido-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
The methyl (7) (S) -2-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 1 was replaced with methyl 3-acetylamino-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (7) of example 1, to give a pale yellow solid with a yield of 70.5%.
(8) Preparation of methyl 3-acetylamino-3- (4- ((6- (3- (diethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
The methyl (8) (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate in example 1 was replaced with methyl 3-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions for this step were the same as in step (8) of example 1, to give a white solid in a yield of 40.4%. m.p.166.6-168.3 ℃.
Example 18
Preparation of methyl 3-acetylamino-3- (4- ((6- (3- (dihexylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate from example 2 was replaced with methyl 3-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions and procedures were the same as in example 2 to give a white solid with a yield of 48.5%. m.p.191.3-192.9 ℃.
Example 19
Preparation of methyl 3-acetylamino-3- (4- ((6- (3- (dioctylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate from example 2 was replaced with methyl 3-acetylamino-3- (4- ((6- (3-chloropropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions and procedures were the same as in example 3 to give a white solid in 43.2% yield. m.p. 199.7-201.4 deg.C.
Example 20
3-acetylamino-3- (4- ((6- (3- (dimethylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid methyl ester
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate from example 4 was replaced with methyl 3-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoate, and the other reaction conditions and procedures were the same as in example 4 to give a white solid in 47.3% yield. m.p.145.7-146.6 ℃.
Example 21
Preparation of methyl 3-acetylamino-3- (4- ((6- (3-morpholinopropoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 5 was replaced with methyl 3-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 5 to give a white solid with a yield of 41.6%. m.p.148.5-150.1 deg.C.
Example 22
Preparation of methyl 3-acetylamino-3- (4- ((6- (3- (dibutylamino) propoxy) -7-methoxyquinazolin-4-yl) amino) phenyl) propanoate
Methyl (S) -2-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate in example 6 was replaced with methyl 3-acetamido-3- (4- ((6-hydroxy-7-methoxyquinazolin-4-yl) amino) phenyl) propionate, and other reaction conditions and procedures were the same as in example 6 to give a white solid in 43.3% yield. m.p.152.6-153.9 ℃.
The final compound synthesized in the above example was subjected to nuclear magnetic resonance hydrogen spectrometry or high resolution mass spectrometry, and the structure is shown in table 1.
TABLE 1 structural formula of the compound synthesized in each example and the results of measuring the structure thereof
Preliminary evaluation test of antitumor bioactivity
To further verify the antitumor biological activities of the above examples, the compounds prepared in examples 7, 17 and 19 were selected and compared with commercially available gefitinib (Gifitinib) by using CCK-8 assay to perform pharmacological experiments, wherein the cell lines and culture media used in the experiments are shown in table 2.
TABLE 2 cell lines and media used for the experiments
The specific operation method comprises the following steps:
a549 carcinoma cells in logarithmic growth phase were digested in 96-well plates (8X 104. Multidot.mL) -1 ) After standing at 37 ℃ 5% CO 2 Carrying out adherent culture for 24h in an incubator under the condition, discarding the original culture medium, and carrying out the following steps: normal group: no treatment is carried out;
solvent control group (no solvent control is needed if the drug is readily soluble in the medium): DMSO was added to the cell culture medium to a concentration of 0.2%; positive drug control group: gefitinib (0.5. Mu.M; 1. Mu.M; 5. Mu.M; 10. Mu.M; 25. Mu.M; 50. Mu.M; 100. Mu.M);
administration group: the drug is 0.5 mu M according to the concentration gradient; 1 mu M;5 mu M;10 mu M;25 mu M;50 mu M;100 μ M (6 multiple wells per drug concentration), 100 μ L was administered, incubated at 37 deg.C, 5% 2 An incubator; after the cells are cultured for 48h/72h, adding CCK-8 microliter culture medium into each hole, placing the holes in an incubator for further culture for 1h, measuring the OD value of the cells by using an enzyme-labeling instrument at the wavelength of 450nm, and calculating the survival rate.
Statistical software SPSS Statistics21 processing was used to calculate IC 50 The results are shown in Table 3.
TABLE 3 growth inhibitory Effect of the Compounds of the present invention on human A549 Lung cancer cells
As can be seen from table 3, for the a549 cell line, the activities of the target compounds prepared in examples 7, 17, and 19 of the present invention are significantly better than or equal to that of Gefitinib, which indicates that the synthesized target compounds can be candidate drugs for antitumor drugs.
The invention also carries out a solubility test on the compound 7, and the result shows that the compound 7 is easy to dissolve in water and 0.1mol/L HCl.
In addition, the compound is subjected to a molecular docking test, and the molecular docking result shows that the compound disclosed by the invention has good binding force with 2ITY target protein. Most of the target compounds form hydrogen bonds with amino acid residues ASP-855 and LYS-745, and a small portion with amino acid residues ASP-800, LYS-716 and LYS-728. Minimum binding free energy Δ G (kcal. Mol.) of target compound of L configuration -1 ) Generally higher than the target compounds in the DL and D configurations. For example: the target compound 19 is well inserted into the binding pocket of the protein and interacts with different amino acids, mainly hydrophobic and hydrogen bonding (see A and B in FIG. 1). The nitrogen and oxygen of the acetamido moiety in compound 19 form hydrogen bonds with ASP-855 and LYS-745, respectively, and the carbon and benzene ring moieties form hydrophobic interactions with VAL-726, LEU-718, and LEU-792. The docking result of Ledock software basically accords with the in-vitro anti-tumor activity test result, and the action target of the target compound is presumed to be EGFR protein.
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. 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.
Claims (10)
1. An amino acid derivative having one of the following structural formulas:
in the formula, -R 1 One selected from hydrogen or C1-C6 alkane; -R 2 One selected from dimethylaminopropyl, N-morpholinopropyl, dibutylaminopropyl, diethylaminopropyl, dihexamidopropyl, and di Xin An propyl; -R 3 One selected from hydrogen, acetyl, propionyl or butyryl.
2. The amino acid derivative according to claim 1, wherein the amino acid derivative is selected from one of the following structural formulas:
3. a process for the preparation of an amino acid derivative according to any one of claims 1 to 2, comprising the steps of:
1) Dissolving a compound A1 or B1 in a sodium hydroxide solution, and dropwise adding acid anhydride at normal temperature to perform acylation reaction to obtain a compound A2 and a compound B2 respectively, wherein the structural formula of the compound A1 is shown in the specification
The structural formula of the compound B1 is
The structural formula of the compound A2 is
The structural formula of the compound B2 is
Wherein, -R 3 One selected from acetyl, propionyl and butyryl;
2) Respectively adding the compounds A2 and B2 into the mixed acid solution in batches for nitration reaction to respectively obtain compounds A3 and B3, wherein the structural formula of the compound A3 is shown in the specification
The structural formula of the compound B3 is
3) Dissolving the compound A3 or B3 in an alcohol solution, heating, slowly dripping a sulfuric acid solution for esterification reaction to respectively obtain a compound A4 and a compound B4, wherein the structural formula of the compound A4 is shown in the specification
The structural formula of the compound B4 is as follows:
wherein, -R 1 One selected from C1-C6 alkanes;
4) Reducing the nitro group on the benzene ring of the compound A4 or B4 into amino group to respectively obtain a compound A5 and a compound B5, wherein the structural formula of the compound A5 is
The structural formula of B5 is as follows:
5) Performing substitution reaction on a compound C3 and the compound A5 or B5 to obtain a compound A6 or B6, wherein the structural formula of the compound A6 is shown in the specification
The structural formula of B6 is as follows:
the structural formula of the compound C3 is
6) Hydrolyzing the compound A6 or B6 with ammonia water to obtain a compound A7 or B7, wherein the structural formula of the compound A7 is shown in the specification
The structural formula of the compound B7 is as follows:
7) Reacting said compound A7 or B7 with a compound containing-R 2 Respectively obtaining a compound A8 and a compound B8 by the substitution reaction of the compound M, wherein the structural formula of the compound A8 is shown in the specification
The structural formula of the compound B8 is as follows:
when-R 1 Is hydrogen, -R 3 When the hydrogen is contained, the compound A8 or the compound B8 and hydrochloric acid and glacial acetic acid are subjected to hydrolysis reaction to respectively obtain a compound A9 and a compound B9, wherein the structural formula of the compound A9 is shown in the specification
The structural formula of the compound B9 is
when-R 1 Is hydrogen, -R 3 Reacting the compound A8 or B8 with hydrochloric acid, wherein the compound A is one of acetyl, propionyl or butyryl;
when-R 1 Is one of C1-C6 alkane, -R 3 For hydrogen, compounds A9 or B9 are esterified in the manner of stage 4).
4. The process according to claim 3, characterized in that, before step 5), it further comprises the preparation of said compound C3: performing acylation reaction on the compound C1 and acetic anhydride to obtain a compound C2, wherein the structural formula of the compound C1 is shown in the specification
The structural formula of the compound C2 is
And carrying out halogenation reaction on the compound C2 and thionyl chloride to obtain the compound C3.
5. The preparation method according to claim 4, wherein the acylation reaction of the compound C1 with acetic anhydride is carried out at a temperature of 95-100 ℃ for 4-5 hours.
6. The process according to claim 3, wherein the molar ratio of the compound A1 or B1 to the acid anhydride used in step 1) is 1.5 to 1.8, and the reaction time is 3 to 4 hours.
7. The preparation method according to claim 3, wherein in the step 2), the mixed acid solution is 98% sulfuric acid and 68% nitric acid in a volume ratio of 1.2:1 phase mixed acid solution; and/or in the step 4), carrying out nitro reduction on the compound A4 or B4 by adopting iron powder, ammonium chloride, absolute ethyl alcohol, water and glacial acetic acid to obtain the compound A5 or B5.
8. The preparation method according to claim 3, characterized in that the compound A5 or B5 and the compound C3 are subjected to substitution reaction in the step 5) at a molar ratio of 1.2-1.5, a reaction temperature of 90-100 ℃ and a reaction time of 4-6 h.
9. Use of an amino acid derivative according to any one of claims 1 to 2 for the manufacture of an anti-cancer medicament.
10. The use of claim 9, wherein the anti-cancer drug is an anti-lung cancer drug.
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| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2007099326A1 (en) * | 2006-03-02 | 2007-09-07 | Astrazeneca Ab | Quinoline derivatives |
| CN103965174A (en) * | 2013-02-01 | 2014-08-06 | 通化济达医药有限公司 | Zinc binding group-containing quinazolinyl EGFR tyrosine kinase inhibitor |
| CN109942499A (en) * | 2019-03-29 | 2019-06-28 | 湖南中医药大学 | Quinazoline derivant and its preparation method and application |
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2021
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2007099326A1 (en) * | 2006-03-02 | 2007-09-07 | Astrazeneca Ab | Quinoline derivatives |
| CN103965174A (en) * | 2013-02-01 | 2014-08-06 | 通化济达医药有限公司 | Zinc binding group-containing quinazolinyl EGFR tyrosine kinase inhibitor |
| CN109942499A (en) * | 2019-03-29 | 2019-06-28 | 湖南中医药大学 | Quinazoline derivant and its preparation method and application |
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