CN109942499B - Quinazoline derivative and preparation method and application thereof - Google Patents
Quinazoline derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN109942499B CN109942499B CN201910249262.4A CN201910249262A CN109942499B CN 109942499 B CN109942499 B CN 109942499B CN 201910249262 A CN201910249262 A CN 201910249262A CN 109942499 B CN109942499 B CN 109942499B
- Authority
- CN
- China
- Prior art keywords
- compound
- methylethyl
- reaction
- phenylamino
- acetamido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to quinazoline derivatives, a preparation method and application thereof. The quinazoline derivative has
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a quinazoline derivative and a preparation method and application thereof.
Background
PBK/TOPK is a serine/threonine kinase that is phosphorylated during mitosis and is also an important intracellular signaling molecule. The initial research shows that PBK/TOPK can be combined with PDZ structural domain, can be combined with multiple molecules such as cancer suppressor gene hD1g, P53 protein and raf protein to play a role, can activate downstream MAPK (P38, ERK and JNK) signal channels, and plays an important role in tumor formation. With the continuous intensive and advanced research, it is found that PBK/TOPK is expressed in normal tissues with low expression or no expression, and in various malignant tumor cells with high expression, and it not only regulates the mitosis and cell cycle of tumor cells, but also participates in the processes of proliferation, migration, invasion and apoptosis of tumor cells. Therefore, PBK/TOPK can be a potential target of a very good cancer treatment drug.
At present, the PBK/TOPK inhibitors synthesized by people only have three main classes, the first class is 7-hydroxy-benzimidazole-4-methyl ketone derivatives, and the representative drug is HI-TOPK-032. The second kind is thieno [2,3-c ] quinolinone derivatives, and the representative drugs are OTS514 and OTS 964. The third major class is the new proton pump inhibitors of older drugs, such as pantoprazole and ilaprazole. Although both PBK/TOPK inhibitors were in preclinical studies, they showed good antitumor effects in both cell and transplantable tumor model experiments. The novel anti-tumor drug with high efficiency, low toxicity and strong specificity which selectively acts on a specific target point becomes an important direction for the research and development of the current anti-tumor drugs.
Disclosure of Invention
The invention provides a quinazoline derivative and a preparation method and application thereof.
The quinazoline derivative provided by the invention has the following structural formula:
in the formula, -R1One selected from the group consisting of 2-acetamido-1-methylethyl, 2-amino-1-methylethyl, 1-acetamido-ethyl, 1-aminoethyl, (R) -2-acetamido-1-methylethyl, (S) -2-acetamido-1-methylethyl, (R) -2-amino-1-methylethyl, (S) -2-amino-1-methylethyl, both structural formulas, (R) -1-acetamido-ethyl, (S) -1-acetamido-ethyl, (R) -1-aminoethyl, (S) -1-aminoethyl; -R2Is selected from one of hexahydropiperidine propyl, tetrahydropyrrole propyl, dimethylamine propyl, morpholine propyl and dibutylamine propyl.
Further, the structural formula of the quinazoline derivative is selected from one of the following structural formulas:
the invention also provides a preparation method of the quinazoline derivative, which comprises the following steps:
1) performing neutralization reaction on the compound A1 and a sodium hydroxide solution to obtain a compound A2, wherein the structural formula of the compound A1 is shown in the specification
The structural formula of the compound A2 is
-R3One selected from the group consisting of 2-amino-1-methylethyl, (R) -2-amino-1-methylethyl, (S) -2-amino-1-methylethyl, 1-aminoethyl, (R) -1-aminoethyl, and (S) -1-aminoethyl; then dissolving the compound A2 in dichloromethane, cooling to-5-0 ℃, and dropwise adding acetic anhydride solution for acylation reaction to obtain a compound A3, wherein the structural formula of the compound A3 is shown in the specification
-R1Selected from 2-acetamido-1-methylethyl, 2-amino-1-methylethyl, 1-acetamido-ethyl, 1-aminoOne of ethyl, (R) -2-acetylamino-1-methylethyl, (S) -2-acetylamino-1-methylethyl, (R) -2-amino-1-methylethyl, (S) -2-amino-1-methylethyl, (R) -1-acetylaminoethyl, (S) -1-acetylaminoethyl, (R) -1-aminoethyl, and (S) -1-aminoethyl;
2) dissolving the compound A3 in dichloromethane, cooling to-5-0 ℃, and slowly dripping mixed acid solution for nitration reaction to obtain a compound A4, wherein the structural formula of the compound A4 is shown in the specification
The mixed acid solution is preferably an acid solution formed by mixing 98% of sulfuric acid and 68% of nitric acid in a volume ratio of 1.2: 1;
3) reducing the nitro group on the benzene ring of the compound A4 into amino group to obtain a compound A5, wherein the structural formula of the compound A5 is shown in the specification
Specifically, nitro reduction is carried out on the compound A4 by adopting activated carbon, ferric trichloride hexahydrate and absolute ethyl alcohol to obtain a compound A5;
4) performing substitution reaction on a compound B3 and the compound A5 to obtain a compound A6, wherein the structural formula of the compound A6 is shown in the specification
The structural formula of the compound B3 is
5) Hydrolyzing the compound A6 with ammonia water to obtain a compound A7, wherein the structural formula of the compound A7 is shown in the specification
6) Carrying out substitution reaction on the compound A7 and a compound M to obtain a compound A8, wherein the compound M contains-R2A group of-R2Selected from the group consisting of hexahydropiperidinopropyl, tetrahydropyrrolopropyl, dimethylaminopropyl, and dimethylaminopropyl,One of morpholine propyl group and dibutylamine propyl group, and the structural formula of the compound A8 is shown in the specification
Preferably, before step 4), further comprising the preparation of said compound B3: acylating the compound B1 with acetic anhydride to obtain a compound B2, wherein the structural formula of the compound B1 is shown in the specification
The structural formula of the compound B2 is
And (3) carrying out halogenation reaction on the compound B2 and thionyl chloride to obtain the compound B3. Preferably, the compound B1 is mixed with acetic anhydride, pyridine, DMAP and 4-dimethylaminopyridine to carry out the acylation reaction to obtain the compound B2; halogenating the compound B2 with thionyl chloride to generate the compound B3.
Preferably, the molar ratio of the compound A2 to the acetic anhydride in the acetic anhydride solution in the step 1) is 1: 1.2-1.5, and the reaction time is 8-10 h.
Preferably, the mixed acid used in the nitration reaction in the step 2) is an acid solution formed by mixing 98% of sulfuric acid and 68% of nitric acid in a volume ratio of 1.2:1, and the temperature is controlled to be-5-0 ℃.
Preferably, the method for reducing the nitro group on the benzene ring of the compound a4 to amino group in the step 3) adopts one of an iron powder reduction method, a hydrazine hydrate reduction method, a sodium hydrosulfite reduction method and a stannous chloride dihydrate reduction method, preferably a hydrazine hydrate reduction method; the molar ratio of the compound A4 to 80% hydrazine hydrate is 1: 2.5-4.0, the reaction temperature is 75-88 ℃, and the reaction time is 4-6 h.
Preferably, the reaction temperature of the acylation reaction of the compound B1 and the compound B1 with acetic anhydride is 95-100 ℃, and the reaction time is 5-8 hours.
Preferably, the molar ratio of the substitution reaction of the compound A5 and the compound B3 in the step 4) is 1: 0.8-0.9, the reaction temperature is 90-100 ℃, and the reaction time is 4-6 h.
Preferably, in the step 5), the molar ratio of the compound A6 to the ammonia water is 1: 4-7, the reaction temperature is 60-70 ℃, and the reaction time is 3-5 h.
Preferably, the molar ratio of the compound A7 to the compound M in the substitution reaction in the step 6) is 1: 1.2-1.5; the reaction temperature is 90-95 ℃; the reaction time is 5-8 h.
In addition, the invention also provides application of the quinazoline derivative in preparation of a PBK/TOPK inhibitor.
In addition, the invention also provides application of the quinazoline derivative in preparing anti-cancer drugs.
Preferably, the anti-cancer drug includes an anti-lung cancer drug and an anti-breast cancer drug.
Compared with the prior art, the invention has the advantages that: the quinazoline derivative provided by the invention takes gefitinib as a positive control, and the result shows that the quinazoline derivative has good activity compared with gefitinib; compared with the lead compound OTS514, the activity is equivalent, and the derivative is further modified for PBK/TOPK inhibitor and has higher reference and reference value for finding new antitumor drug candidates.
The embodiment of the invention also provides a preparation method of the quinazoline derivative, which adopts a quinazoline framework and obtains a series of compounds with anti-tumor activity by introducing related groups on a quinazoline ring. The method can efficiently obtain various quinazoline derivatives with high quality, is simple and convenient to operate, has low requirements on equipment, and is suitable for large-scale production and application.
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.
This embodiment provides quinazoline derivatives having the following structural formula:
in the formula, -R1One selected from the group consisting of 2-acetamido-1-methylethyl, 2-amino-1-methylethyl, 1-acetamido-ethyl, 1-aminoethyl, (R) -2-acetamido-1-methylethyl, (S) -2-acetamido-1-methylethyl, (R) -2-amino-1-methylethyl, (S) -2-amino-1-methylethyl, both structural formulas, (R) -1-acetamido-ethyl, (S) -1-acetamido-ethyl, (R) -1-aminoethyl, (S) -1-aminoethyl; -R2Is selected from one of hexahydropiperidine propyl, tetrahydropyrrole propyl, dimethylamine propyl, morpholine propyl and dibutylamine propyl. The structural formula of the quinazoline derivative can be any one of 60 compounds in the structural formula, and in order to further illustrate the preparation method and the performance of the quinazoline derivative provided by the invention, detailed descriptions are given for the preparation method and the performance research of part of the structural formula.
The 7-methoxy-6-acetoxy-4-chloroquinazoline (i.e., Compound B3) in this example embodiment was prepared by the following method
Adding 6-hydroxy-7-methoxy-4-ketoquinazoline (20g, 0.11mol, namely compound B1), acetic anhydride (150mL, 1.6mol) and pyridine (20mL, 0.25mol) into a 500mL round-bottom flask in sequence, heating to 100 ℃, refluxing for reaction for 1h, adding 4-dimethylaminopyridine (0.9g, 0.0073mol), continuing for 5h, stopping the reaction, evaporating under reduced pressure to remove acetic anhydride, adding a cold saturated sodium carbonate solution (500mL) into the reaction liquid, stirring, carrying out suction filtration, transferring the filter cake into the round-bottom flask, adding a large amount of ice water, stirring, carrying out suction filtration, washing the filter cake with distilled water until the pH is 7, and drying to obtain an off-white solid (namely compound B2). The resulting mixture and thionyl chloride (190mL, 2.0mol) were sequentially added to a 500mL three-necked round-bottomed flask, the temperature was raised to 80 ℃ and reflux-reacted for 20min, and N, N-dimethylformamide (4.4mL, 0.52eq) was slowly added dropwise to the reaction mixture from a constant-pressure dropping funnel. After 6 hours of reaction, the reaction was stopped, the reaction was cooled, thionyl chloride was recovered under reduced pressure, an appropriate amount of toluene was added and stirred, toluene was recovered under reduced pressure, ice water (250mL) was added to the reaction product and stirred for about 1 hour, dichloromethane (120 mL. times.2) was extracted, the organic layer was separated, washed with water (80 mL. times.2), dried over anhydrous sodium sulfate, and dichloromethane was distilled off under reduced pressure to obtain 21.5g of an off-white solid with a yield of 81.9%.
Example 1
Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
(1) Preparation of N- (2-phenylpropyl) acetamide (i.e. a compound A3)
2-phenyl-1-propylamine hydrochloride (20g, 0.118mol, i.e. a compound a1) was dissolved in distilled water (20mL), a sodium hydroxide solution (5.6g, 0.140mol) was added, the reaction was stirred at normal temperature for 30min during which a yellow oil was formed, ethyl acetate (100mL x 3) was added for extraction, the organic layer was separated, washed with water (100mL x 2), dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to give a pale yellow oil (i.e. a compound a 2). Dissolving the mixture in dichloromethane (80mL), adding the mixture into a 250mL round-bottom flask, placing the round-bottom flask into a low-temperature reaction tank, dissolving acetic anhydride (12.8mL, 0.135mol) in dichloromethane (30mL), slowly dropwise adding the mixture into the round-bottom flask at the temperature of 0 ℃, continuously stirring the mixture for reaction for 30min after the dropwise adding is finished, placing the mixture at room temperature for stirring the mixture for reaction for 8h, and stopping the reaction after the TLC detection reaction is complete. Dichloromethane (70mL) and 2% NaOH solution (100mL) were added to the reaction mixture and stirred for 10min, the organic layer was separated, washed with water (100mL × 2), dried over anhydrous sodium sulfate, and dichloromethane was recovered under reduced pressure to give 18.0g of a pale yellow oily liquid with a yield of 86.9%.
(2) Preparation of N- [2- (4-nitrophenyl) propyl ] acetamide (i.e. a compound A4)
Placing N- (2-phenylpropyl) acetamide (18.0g, 0.101mol) in a low-temperature reaction tank at the temperature of-5 ℃, slowly adding mixed acid 98% sulfuric acid (12.2mL) and 68% nitric acid (10.1mL) from a constant-pressure dropping funnel, adjusting the dropping speed, stirring for reaction for 1h after the dropping is finished, taking out, placing at the normal temperature for stirring for 18h, and stopping the reaction after the TLC detection reaction is completed. The reaction mixture was poured into ice water, stirred, extracted with dichloromethane (30mL x 3), the organic layer was separated, dried over anhydrous sodium sulfate, and dichloromethane was distilled off under reduced pressure to give 16.0g of a yellow solid product in a yield of 70.9%.
(3) Preparation of N- [2- (4-aminophenyl) propyl ] acetamide (i.e. a compound A5)
N- [2- (4-nitrophenyl) propyl ] acetamide (6.0g, 0.027mol), activated carbon (0.50g, 0.042mol), ferric chloride hexahydrate (0.23g, 0.001mol), and absolute ethanol (60mL) were sequentially charged into a 250mL three-necked flask equipped with a constant pressure dropping funnel and drying tube apparatus. Heating to 80 ℃ for reflux reaction, slowly dropwise adding 80% hydrazine hydrate (4.1mL, 0.069mol) from a constant-pressure dropping funnel, controlling the titration speed, dropwise adding for about 30min, after 5h of reaction, carrying out suction filtration while the reaction is hot, carrying out reduced pressure evaporation to remove anhydrous ethanol, extracting dichloromethane (30mL x 3), drying anhydrous sodium sulfate, and carrying out reduced pressure evaporation to remove dichloromethane to obtain a crude product, namely, carrying out column chromatography purification (ethyl acetate: petroleum ether is 4:1) to obtain 3.8g of yellow oily matter, wherein the yield is 73.1%.
(4) Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxy-quinazoline (i.e. a compound A6)
N- [2- (4-aminophenyl) propyl ] acetamide (5.0g, 0.026mol), isopropanol (30mL) were added in that order to a 100mL round-bottomed flask, followed by 7-methoxy-6-acetoxy-4-chloroquinazoline (5.9g, 0.023 mol). Heating to 90 ℃, carrying out reflux reaction for 3h, stopping the reaction after TLC detection reaction is completed, carrying out suction filtration, washing a filter cake for a plurality of times by using isopropanol, and drying to obtain a light yellow solid 8.0g with a yield of 75.3%.
(5) Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (i.e. compound A7)
4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxy quinazoline (5.0g, 0.012mol), methanol (30mL), ammonia (3.5mL, 0.091mol) were sequentially added into a 100mL round-bottomed flask, heated to 65 ℃ for reflux reaction for 3h, after TLC detection reaction was completed, reaction was stopped, cooled, methanol was evaporated under reduced pressure to obtain a yellow oily substance, acetone (15mL) was added, heated to 65 ℃ for reflux until a white solid appeared, reaction was stopped, filtered, and the filter cake was washed with acetone and water alternately to obtain 4.0g of a yellow white solid with a yield of 88.9%.
(6) Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline
4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (1g, 0.0027mol), N-dimethylformamide (10mL), potassium carbonate (0.57g, 0.0041mol) and 1, 3-bromochloropropane (0.3mL, 0.0032mol) are sequentially added into a 100mL round-bottom flask, the temperature is raised to 75 ℃ for reflux reaction for 5h, after the TLC detection reaction is completed, the reaction is stopped, 50mL of water is added, solid is precipitated after stirring, a crude product is obtained by suction filtration, and acetone is recrystallized to obtain 1.0g of yellow solid, and the yield is 82.7%.
(7) Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline (0.8g, 0.0018mol), N-dimethylformamide (10mL), potassium carbonate (0.38g, 0.0027mol), piperidine hexahydrate (0.20mL, 0.0022mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 5h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.56g is obtained, and the yield is 62.9%. Melting point (mp) is 168.9-172.1 ℃.
In other embodiments, 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (i.e., compound A8) may also be produced by direct substitution of a compound of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline with N- (3-chloropropyl) piperidine.
Example 2
Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline
4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline (0.8g, 0.0018mol), N-dimethylformamide (10mL), potassium carbonate (0.38g, 0.0027mol), tetrahydropyrrole (0.18mL, 0.0022mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 5h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.48g is obtained, and the yield is 55.8%. mp 161.9-164.2 ℃.
In other embodiments, 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (i.e., compound A8) may also be produced by direct substitution of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline with a compound of 1- (3-chloropropyl) pyrrolidine.
Example 3
Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dimethylamino) propoxy) quinazoline
4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (0.8g, 0.0022mol), N-dimethylformamide (10mL), potassium carbonate (0.45g, 0.0032mol), N-dimethyl-3-chloropropylamine (0.34mL, 0.0026mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 5h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.62g is obtained, and the yield is 62.6%. mp 137.2-139.6 ℃.
Example 4
Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-morpholinyl) propoxy) quinazoline
4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (0.8g, 0.0022mol), N-dimethylformamide (10mL), potassium carbonate (0.45g, 0.0032mol), N- (3-chloropropyl) -morpholine (0.40mL, 0.0026mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 5h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.85g is obtained, and the yield is 76.6%. mp 199.5-212.7 ℃.
Example 5
Preparation of 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (0.8g, 0.0022mol), N-dimethylformamide (10mL), potassium carbonate (0.45g, 0.0032mol), N- (3-chloropropyl) -dibutylamine (0.60mL, 0.0026mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 5h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.93g is obtained, and the yield is 77.8%. mp 155.4-157.9 ℃.
Example 6
Preparation of 4- [4- (2-amino-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline (0.1g, 0.0002mol) and 1N HCl (3mL) were added sequentially to a 100mL round bottom flask. Heating to 95 ℃ for reflux reaction for 48h, and stopping the reaction after HPLC monitoring and detection show that the reaction is complete. Distilling under reduced pressure, washing the mother liquor with a small amount of anhydrous ethanol for multiple times, continuously distilling under reduced pressure to remove the anhydrous ethanol, and vacuum drying to obtain yellow white solid 0.07g with a yield of 77.8%. mp 120.5-123.1 ℃.
Example 7
Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
(1) Preparation of (R) -N- (2-phenylpropyl) acetamide
The 2-phenyl-1-propylamine hydrochloride of step (1) in example 1 was replaced with (R) -2-phenyl-1-propylamine hydrochloride, and the other reaction conditions of this step were the same as in step (1) in example 1, to give a pale yellow oily liquid in a yield of 85.2%.
(2) Preparation of (R) -N- [2- (4-nitrophenyl) propyl ] acetamide
The reaction conditions for the step (2) of example 1 in which N- (2-phenylpropyl) acetamide was replaced with (R) -N- (2-phenylpropyl) acetamide were otherwise the same as in the step (2) of example 1, to give a yellow solid product in a yield of 73.1%.
(3) Preparation of (R) -N- [2- (4-aminophenyl) propyl ] acetamide
The reaction conditions for the step (3) of example 1 in which N- [2- (4-nitrophenyl) propyl ] acetamide was replaced with (R) -N- [2- (4-nitrophenyl) propyl ] acetamide were otherwise the same as in the step (3) of example 1 gave a yellow oil with a yield of 69.9%.
(4) Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxy quinazoline
The reaction conditions for the step (4) of example 1 in which N- [2- (4-aminophenyl) propyl ] acetamide was replaced with (R) -N- [2- (4-aminophenyl) propyl ] acetamide were otherwise the same as in the step (4) of example 1 gave a pale yellow solid with a yield of 78.8%.
(5) Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline of step (5) in example 1 was replaced with (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline, and the other reaction conditions for this step were the same as in step (5) in example 1, to give a yellowish white solid in a yield of 92.5%.
(6) Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline
The 4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline of step (6) in example 1 was replaced with (R) -4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline, and the other reaction conditions of this step were the same as in step (6) in example 1, to give a yellow solid in a yield of 80.5%.
(7) Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
The (7)4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in example 1 was replaced with (R) -4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline, and the other reaction conditions of this step were the same as in step (7) of example 1, to give a pale yellow solid in a yield of 60.8%. mp 177.9-179.1 ℃.
Example 8
Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in example 2 was replaced with (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in the same manner as in example 2 under the same reaction conditions and by the same procedure, a pale yellow solid was obtained in a yield of 53.2%. mp 164.0-165.2 ℃.
Example 9
Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dimethylamino) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 3 was replaced with (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 3 to give a pale yellow oil in a yield of 60.0%.
Example 10
Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-morpholinyl) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 4 was replaced with (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 4 to give an off-white solid in 73.5% yield. mp 169.0-171.0 ℃.
Example 11
Preparation of (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 5 was replaced with (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 5 to give an off-white solid in a yield of 75.5%. mp 148.0-149.0 ℃.
Example 12
Preparation of (R) -4- [4- (2-amino-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline in example 6 was replaced with (R) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline and the other reaction conditions and procedures were the same as in example 6 to give a pale yellow solid with a yield of 73.8%. mp is 121.4-122.9 ℃.
Example 13
Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
(1) Preparation of (S) -N- (2-phenylpropyl) acetamide
The reaction conditions were otherwise the same as in step (1) of example 1 except for replacing (1) 2-phenyl-1-propylamine hydrochloride in example 1 with (S) -2-phenyl-1-propylamine hydrochloride, to give a pale yellow oily liquid in a yield of 82.5%.
(2) Preparation of (S) -N- [2- (4-nitrophenyl) propyl ] acetamide
The reaction conditions were otherwise the same as in step (2) of example 1 except that (2) N- (2-phenylpropyl) acetamide in example 1 was replaced with (S) -N- (2-phenylpropyl) acetamide to give a yellow solid product with a yield of 69.9%.
(3) Preparation of (S) -N- [2- (4-aminophenyl) propyl ] acetamide
The procedure of step (3) of example 1 was repeated except for replacing (3) N- [2- (4-nitrophenyl) propyl ] acetamide with (S) -N- [2- (4-nitrophenyl) propyl ] acetamide in example 1 to obtain a yellow oily substance with a yield of 65.0%.
(4) Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxy quinazoline
The reaction conditions were otherwise the same as in the step (4) in example 1 except for replacing (4) N- [2- (4-aminophenyl) propyl ] acetamide with (S) -N- [2- (4-aminophenyl) propyl ] acetamide in example 1, to obtain a pale yellow solid with a yield of 73.8%.
(5) Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline
By substituting (5)4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline in example 1 with (S) -4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline and other reaction conditions and step (5) of example 1, a yellowish white solid was obtained with a yield of 87.0%.
(6) Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline
By substituting (6)4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 1 with (S) -4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in step (6) of example 1, a yellow solid was obtained in a yield of 83.5%.
(7) Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
The reaction conditions were otherwise the same as in (7) in example 1 except that (7)4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in example 1 was replaced with (S) -4- [4- (2-acetylamino-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline, whereby a pale yellow solid was obtained in a yield of 58.0%. mp is 160.2-163.3 ℃.
Example 14
Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in example 2 was replaced with (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline and the other reaction conditions and procedures were the same as in example 2 to give a pale yellow solid in a yield of 57.0%. mp 153.1-154.3 ℃.
Example 15
Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dimethylamino) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 3 was replaced with (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 3 to give a pale yellow oil in a yield of 65%.
Example 16
Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (1-morpholinyl) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 4 was replaced with (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 4 to give a white solid in a yield of 70.2%. mp 168.4-170.0 ℃.
Example 17
Preparation of (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 5 was replaced with (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 5 to give an off-white solid in 76.0% yield. mp 155.4-156.8 ℃.
Example 18
Preparation of (S) -4- [4- (2-amino-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline in example 6 was replaced with (S) -4- [4- (2-acetamido-1-methylethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline and the other reaction conditions and procedures were the same as in example 6 to give a pale yellow solid in a yield of 70.0%. mp 119.9-120.1 ℃.
Example 19
Preparation of 4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
(1) Preparation of N- [1- (4-nitrophenyl) ethyl ] acetamide
Adding 1-phenylethylamine (20g, 0.165mol) and dichloromethane (80mL) into a 250mL round-bottom flask in sequence, placing the flask in a low-temperature reaction tank, dissolving acetic anhydride (20mL, 0.196mol) in dichloromethane (30mL), slowly dropwise adding the mixture into the round-bottom flask at the temperature of 0 ℃, continuously stirring for reaction for 30min after dropwise adding, placing the mixture at room temperature for stirring for reaction for 8h, and stopping the reaction after the TLC detection reaction is completed. Dichloromethane (70mL) and 2% NaOH solution (100mL) were added to the reaction solution and stirred for 10min, the organic layer was separated, washed with water (100mL × 2), dried over anhydrous sodium sulfate, and dichloromethane was recovered under reduced pressure to obtain 24g of a white solid. Preparing 98% sulfuric acid (17.8mL) and 68% nitric acid (15.0mL) in a low-temperature reaction tank at-5 ℃, slowly adding a white solid, stirring for reaction for 1h, taking out, stirring at normal temperature for reaction for 18h, and stopping the reaction after TLC detection reaction is completed. Pouring the reaction solution into ice water, carrying out suction filtration, and washing a filter cake with a large amount of water to obtain 23.5g of a yellowish white solid product, wherein the yield is 68.3%.
(2) Preparation of N- [1- (4-aminophenyl) ethyl ] acetamide
N- [1- (4-nitrophenyl) ethyl ] acetamide (6.0g, 0.029mol), activated carbon (1.16g, 0.097mol), ferric chloride hexahydrate (0.20g, 0.001mol), and absolute ethanol (60mL) were sequentially charged into a 250mL three-necked flask equipped with a constant-pressure dropping funnel and a drying tube apparatus. Heating to 80 ℃ for reflux reaction, slowly dropwise adding 80% hydrazine hydrate (5.4mL, 0.108mol) from a constant-pressure dropping funnel, controlling the titration speed, completing dropping for about 30min, after 5h of reaction, carrying out suction filtration while the solution is hot, carrying out reduced pressure evaporation to remove absolute ethyl alcohol, extracting dichloromethane (30mL x 3), separating an organic layer, drying anhydrous sodium sulfate, and carrying out reduced pressure evaporation to remove dichloromethane to obtain 4.2g of yellow oily matter, wherein the yield is 82.4%.
(3) Preparation of 4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6-acetoxy quinazoline
N- [1- (4-aminophenyl) ethyl ] acetamide (4.2g, 0.024mol), isopropanol (40mL) were added in that order to a 100mL round bottom flask, and 7-methoxy-6-acetoxy-4-chloroquinazoline (5.3g, 0.021mol) was added. Heating to 90 ℃, carrying out reflux reaction for 3h, stopping the reaction after TLC detection reaction is completed, carrying out suction filtration, washing a filter cake for a plurality of times by using isopropanol, and drying to obtain a light yellow solid 6.8g with the yield of 73.1%.
(4) Preparation of 4- [4- (1-acetamido ethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline
4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6-acetoxy quinazoline (4g, 0.010mol), methanol (30mL) and ammonia (2.8mL, 0.073mol) were sequentially added to a 100mL round bottom flask, heated to 65 ℃ for reflux reaction for 3h, after the reaction was detected by TLC, the reaction was stopped, cooled, filtered, and the filter cake was washed with isopropanol to give 3.1g of a white solid with a yield of 86.1%.
(5) Preparation of 4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline
4- [4- (1-acetamido ethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (1g, 0.0028mol), N-dimethylformamide (10mL), potassium carbonate (0.57g, 0.0041mol) and 1, 3-bromochloropropane (0.3mL, 0.0032mol) are sequentially added into a 100mL round-bottom flask, the temperature is raised to 75 ℃ for reflux reaction for 5h, the reaction is stopped after the TLC detection reaction is completed, 50mL of water is added, solid is stirred to be precipitated, a crude product is obtained by suction filtration, acetone is recrystallized to obtain 0.9g of yellow solid, and the yield is 75%.
(6) Preparation of 4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
4- [4- (1-Acylaminoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline (0.8g, 0.002mol), N-dimethylformamide (10mL), potassium carbonate (0.39g, 0.0028mol), piperidine hexahydro (0.22mL, 0.0024mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 6h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.52g is obtained, and the yield is 58.4%. mp 129.1-130.9 ℃.
Example 20
Preparation of 4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline
4- [4- (1-Acylaminoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline (0.8g, 0.002mol), N-dimethylformamide (10mL), potassium carbonate (0.39g, 0.0028mol), tetrahydropyrrole (0.19mL, 0.0022mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 6h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow solid 0.42g is obtained, and the yield is 48.3%. mp 132.5-134.7 ℃.
Example 21
Preparation of 4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6- (3- (dimethylamino) propoxy) quinazoline
4- [4- (1-Acylaminoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (0.8g, 0.0023mol), N-dimethylformamide (10mL), potassium carbonate (0.47g, 0.0034mol), N-dimethyl-3-chloropropylamine (0.34mL, 0.0026mol) were added sequentially to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 6h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and light yellow oily matter 0.65g is obtained, and the yield is 65.7%.
Example 22
Preparation of 4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6- (3- (1-morpholinyl) propoxy) quinazoline
4- [4- (1-Acylaminoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (0.8g, 0.0023mol), N-dimethylformamide (10mL), potassium carbonate (0.47g, 0.0034mol), N- (3-chloropropyl) -morpholine (0.43mL, 0.0025mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 6h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and 0.79g of off-white solid is obtained with the yield of 71.8 percent. mp 185.0-188.5 ℃.
Example 23
Preparation of 4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
4- [4- (1-Acylaminoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline (0.8g, 0.0023mol), N-dimethylformamide (10mL), potassium carbonate (0.47g, 0.0034mol), N- (3-chloropropyl) -dibutylamine (0.63mL, 0.0028mol) were added in that order to a 100mL round bottom flask. Heating to 90 ℃, refluxing and reacting for 6h, and stopping the reaction after the TLC detection shows that the reaction is complete. Adding 50mL of water, stirring to separate out a solid, and performing suction filtration to obtain a crude product. At room temperature, the crude product is dissolved in acetone, hydrochloric acid is slowly dropped and stirred until solid appears, the filtration is carried out, a filter cake is washed by a small amount of acetone, and 0.72g of off-white solid is obtained with the yield of 60%. mp 165.4-167.7 ℃.
Example 24
Preparation of 4- [4- (1-aminoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
4- [4- (1-Acetaminoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline (0.1g, 0.0002mol) and 1N HCl (3mL) were added in that order to a 100mL round bottom flask. Heating to 95 ℃ for reflux reaction for 48h, and stopping the reaction after HPLC monitoring and detection show that the reaction is complete. Vacuum distilling, washing the mother liquid with small amount of anhydrous alcohol for several times, evaporating under reduced pressure to remove anhydrous alcohol, and vacuum drying to obtain yellow white solid 0.06g with yield of 66.7%. mp is 126.7-127.9 ℃.
Example 25
Preparation of (R) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
(1) Preparation of (R) -N- [1- (4-nitrophenyl) ethyl ] acetamide
1-phenethylamine in step (1) in example 19 was replaced with R- (+) -1-phenethylamine, and the other reaction conditions were the same as in step (1) in example 19, to give a yellow-white solid in a yield of 71.2%.
(2) Preparation of (R) -N- [1- (4-aminophenyl) ethyl ] acetamide
The procedure in example 19 was repeated except for replacing N- [1- (4-nitrophenyl) ethyl ] acetamide by (R) -N- [1- (4-nitrophenyl) ethyl ] acetamide in step (2) of example 19, to obtain a yellow oil in a yield of 81.0%.
(3) Preparation of (R) -4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6-acetoxy quinazoline
The reaction conditions were otherwise the same as in the step (3) of example 19 except that N- [1- (4-aminophenyl) ethyl ] acetamide used in the step (3) of example 19 was replaced with (R) -N- [1- (4-aminophenyl) ethyl ] acetamide, whereby a pale yellow solid was obtained in a yield of 75.0%.
(4) Preparation of (R) -4- [4- (1-acetamido ethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline
The reaction conditions were the same as in step (4) of example 19 except that 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline in step (4) of example 19, whereby a white solid was obtained in a yield of 82.8%.
(5) Preparation of (R) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline prepared in example 19 in step (5) was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline prepared in the same manner as in example 19 in step (5), giving a yellow solid in 73.2% yield.
(6) Preparation of (R) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline of step (6) in example 19 was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline, and the other reaction conditions were the same as in step (6) in example 19, giving a pale yellow solid in a yield of 60.2%. mp is 122.1-125.6 ℃.
Example 26
Preparation of (R) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in example 20 was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline and the other reaction conditions and procedures were the same as in example 20 to give a pale yellow solid with a yield of 52.5%. mp is 124.6-125.7 ℃.
Example 27
Preparation of (R) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (dimethylamino) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 21 was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 21 to give a pale yellow oil in a yield of 60.8%.
Example 28
Preparation of (R) -4- [4- (1-acetamido ethyl) phenylamino ] -7-methoxy-6- (3- (1-morpholinyl) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 22 was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 22 to give an off-white solid in a yield of 75.6%. mp 176.3-178.1 ℃.
Example 29
Preparation of (R) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 23 was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 23 to give a pale yellow solid with a yield of 76.0%. mp 155.4-157.9 ℃.
Example 30
Preparation of (R) -4- [4- (1-aminoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline in example 24 was replaced with (R) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline in the same manner as in example 24 under the same reaction conditions and by the same procedure, to give a pale yellow solid in a yield of 72.8%. mp 127.4-130.6 ℃.
Example 31
Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
Preparation of (S) -N- [1- (4-nitrophenyl) ethyl ] acetamide
(1) The 1-phenethylamine (1) in example 19 was replaced with S- (-) -1-phenethylamine, and the other reaction conditions were the same as in the step (1) in example 19, to obtain a yellow-white solid with a yield of 73.1%.
(2) Preparation of (S) -N- [1- (4-aminophenyl) ethyl ] acetamide
The procedure in example 19 was repeated except for replacing N- [1- (4-nitrophenyl) ethyl ] acetamide by (S) -N- [1- (4-nitrophenyl) ethyl ] acetamide in step (2) of example 19, to obtain a yellow oil in a yield of 79.2%.
(3) Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6-acetoxy-quinazoline
The N- [1- (4-aminophenyl) ethyl ] acetamide obtained in step (3) of example 19 was replaced with (S) -N- [1- (4-aminophenyl) ethyl ] acetamide under the same reaction conditions as in step (3) of example 19, to give a pale yellow solid in a yield of 70.8%
(4) Preparation of (S) -4- [4- (1-acetamido ethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline
The reaction conditions were the same as in step (4) of example 19 except that 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6-acetoxyquinazoline in step (4) of example 19, whereby a white solid was obtained in a yield of 78.0%.
(5) Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline prepared in example 19 in step (5) was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline prepared in the same manner as in example 19 in step (5), giving a yellow solid in a yield of 74.0%.
(6) Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-hexahydropiperidinyl) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline of step (6) in example 19 was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline, and the other reaction conditions were the same as in step (6) in example 19, giving a pale yellow solid in a yield of 57.0%. mp is 121.4-123.8 ℃.
Example 32
Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-tetrahydropyrrolyl) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline in example 20 was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3-chloropropoxy) quinazoline and the other reaction conditions and procedures were the same as in example 20 to give a pale yellow solid with a yield of 56.3%. mp 125.7-127.2 ℃.
Example 33
Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (dimethylamino) propoxy) quinazoline
The procedure used in example 21 was carried out in which 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline, and a pale yellow solid was obtained in a yield of 67.6%. mp is 146.3-149.6 ℃.
Example 34
Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (1-morpholinyl) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 22 was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 22 to give a pale yellow solid with a yield of 73.2%. mp 189.3-192.4 ℃.
Example 35
Preparation of (S) -4- [4- (1-acetamido-ethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in example 23 was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -6-hydroxy-7-methoxyquinazoline in the same reaction conditions and procedure as in example 23 to give a pale yellow solid with a yield of 77.0%. mp 158.4-160.9 ℃.
Example 36
Preparation of (S) -4- [4- (1-aminoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline
The 4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline in example 24 was replaced with (S) -4- [4- (1-acetamidoethyl) phenylamino ] -7-methoxy-6- (3- (dibutylamino) propoxy) quinazoline in the same manner and under the same reaction conditions and in the same procedure as in example 24, to give a pale yellow solid in a yield of 76.5%. mp 127.8-129.5 ℃.
The target compound is synthesized by adopting a nuclear magnetic resonance hydrogen spectrum to determine the structure or a high-resolution mass spectrum to determine the structure, and the structure is shown in table 1.
TABLE 1 structural formula of the compound synthesized in each example and the results of the structural determination thereof
Preliminary evaluation test of antitumor bioactivity
To further verify the antitumor biological activities of the above examples, the test was conducted by selecting the target compounds prepared in examples 5, 6, 11, 12, 17, 18, 23, 24, 29, 30, 35 and 36, and performing pharmacological tests using MTT assay using commercially available gefitinib (Gifitinib) and OTS514 as a comparison, wherein the cell lines and culture media used in the test are shown in table 2.
TABLE 2 cell lines and media used for the experiments
| Cell lines | Cell type | Culture medium |
| A549 | Lung cancer cell | RPMI-1640+10％FBS |
| MDA-MB-231 | Breast cancer cell | DMEM+10％FBS |
The specific operation method comprises the following steps:
the cancer cells in logarithmic growth phase were digested in 96-well plates (8X 104 cells/mL) at 37 ℃ in 5% CO2The culture was performed overnight in adherent culture in an incubator under the following conditions, and the supernatant was discarded, as follows: 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: OTS514, 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 duplicate wells per drug concentration), 100 μ L were dosed, placed at 37 ℃ in 5% CO2An incubator; after culturing the cells for 48h/72h, removing the original culture medium by suction, adding 100 mu L of MTT (0.5 mg. mL < -1 >) culture medium into each hole, placing the holes in an incubator for continuous culture for 4h to generate purple crystals, discarding MTT solution, adding 150 mu L DMSO into each hole, and placing the holes in a shaking table for 10 min; the absorbance (OD value) was measured at a wavelength of 490nm with a microplate reader, and the survival rate was calculated.
Statistical software SPSS Statistics21 was used to calculate IC50 and the results are shown in Table 3.
Table 3 antitumor Activity test Structure of Compounds
As can be seen from table 3, for the a549 cell line, the target compounds prepared in examples 6, 11, 12, 18, 24, 29, 30 and 36 of the present invention have higher activity than the positive control Gefitinib; the biological activities of examples 5, 17, 23 and 35 are comparable to Gefitinib, indicating that the synthesized target compound can be a candidate for antitumor drugs. The biological activity of examples 6, 12, 24, 30 and 36 is comparable to OTS514, indicating that it can be a new chiral PBK/TOPK inhibitor candidate, providing possibility for searching compounds with better activity. For MDA-MB-231 cell lines, the bioactivity of the cells in the invention in the examples 5, 6, 11, 12, 17, 18, 23, 24, 29, 30, 35 and 36 is higher than that of the positive control Gefitinib. Therefore, the target compounds prepared in the above embodiments can be used for preparing anticancer drugs, especially for preparing anti-lung cancer drugs or anti-breast cancer drugs.
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 (9)
1. A quinazoline derivative selected from one of the following structural formulae:
2. a method for producing a quinazoline derivative according to claim 1, comprising the steps of:
1) performing neutralization reaction on the compound A1 and a sodium hydroxide solution to obtain a compound A2, wherein the structural formula of the compound A1 is shown in the specification
The structural formula of the compound A2 is
-R3One selected from the group consisting of 2-amino-1-methylethyl, (R) -2-amino-1-methylethyl, (S) -2-amino-1-methylethyl, 1-aminoethyl, (R) -1-aminoethyl, and (S) -1-aminoethyl; then dissolving the compound A2 in dichloromethane, cooling to-5-0 ℃, and dropwise adding acetic anhydride solution for acylation reaction to obtain a compound A3, wherein the structural formula of the compound A3 is shown in the specification
-R1One selected from the group consisting of 2-acetamido-1-methylethyl, 2-amino-1-methylethyl, 1-acetamido-ethyl, 1-aminoethyl, (R) -2-acetamido-1-methylethyl, (S) -2-acetamido-1-methylethyl, (R) -2-amino-1-methylethyl, (S) -2-amino-1-methylethyl, (R) -1-acetamido-ethyl, (S) -1-acetamido-ethyl, (R) -1-aminoethyl, (S) -1-aminoethyl;
2) dissolving the compound A3 in dichloromethane, cooling to-5-0 ℃, and slowly dripping mixed acid solution for nitration reaction to obtain a compound A4, wherein the structural formula of the compound A4 is shown in the specification
3) Reducing the nitro group on the benzene ring of the compound A4 into amino group to obtain a compound A5, wherein the structural formula of the compound A5 is shown in the specification
4) Performing substitution reaction on a compound B3 and the compound A5 to obtain a compound A6, wherein the structural formula of the compound A6 is shown in the specification
The structural formula of the compound B3 is
5) Hydrolyzing the compound A6 with ammonia water to obtain a compound A7, wherein the structural formula of the compound A7 is shown in the specification
6) Carrying out substitution reaction on the compound A7 and a compound M to obtain a compound A8, wherein the compound M contains-R2A group of-R2Is dibutylamine propyl group, and the structural formula of the compound A8 is shown in the specification
3. The method of claim 2, further comprising, prior to step 4), the preparation of compound B3: acylating the compound B1 with acetic anhydride to obtain a compound B2, wherein the structural formula of the compound B1 is shown in the specification
The structural formula of the compound B2 is
And (3) carrying out halogenation reaction on the compound B2 and thionyl chloride to obtain the compound B3.
4. The preparation method according to claim 2, wherein the molar ratio of the compound A2 to the acetic anhydride in the acetic anhydride solution in the step 1) is 1: 1.2-1.5, and the reaction time is 8-10 h.
5. The preparation method according to claim 3, wherein the acylation reaction of the compound B1 and acetic anhydride is carried out at a temperature of 95-100 ℃ for 5-8 h.
6. The preparation method of claim 2, wherein the compound A5 and the compound B3 are subjected to substitution reaction in the step 4) at a molar ratio of 1: 0.8-0.9, a reaction temperature of 90-100 ℃ and a reaction time of 4-6 h.
7. Use of a quinazoline derivative according to claim 1 in the preparation of a PBK/TOPK inhibitor.
8. Use of a quinazoline derivative according to claim 1 in the manufacture of an anti-cancer medicament.
9. The use of claim 8, wherein the anti-cancer drug comprises an anti-lung cancer drug and an anti-breast cancer drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910249262.4A CN109942499B (en) | 2019-03-29 | 2019-03-29 | Quinazoline derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910249262.4A CN109942499B (en) | 2019-03-29 | 2019-03-29 | Quinazoline derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109942499A CN109942499A (en) | 2019-06-28 |
| CN109942499B true CN109942499B (en) | 2022-03-22 |
Family
ID=67013192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910249262.4A Active CN109942499B (en) | 2019-03-29 | 2019-03-29 | Quinazoline derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109942499B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113845485B (en) * | 2021-10-22 | 2023-03-14 | 湖南中医药大学 | Amino acid derivative and preparation method and application thereof |
| CN114907261B (en) * | 2022-04-01 | 2023-10-27 | 湖南中医药大学 | 2-phenylaminoquinoline derivative, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775356A (en) * | 2011-05-13 | 2012-11-14 | 江苏恒谊药业有限公司 | 4-aminoquinazoline derivative and application thereof |
| CN103254142A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-subtituted amino acetylamino)phenylamino] quinazoline derivative as well as preparation method and application thereof |
| CN106045980A (en) * | 2016-06-03 | 2016-10-26 | 江苏开放大学 | Quinazoline derivative and preparation method thereof |
-
2019
- 2019-03-29 CN CN201910249262.4A patent/CN109942499B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775356A (en) * | 2011-05-13 | 2012-11-14 | 江苏恒谊药业有限公司 | 4-aminoquinazoline derivative and application thereof |
| CN103254142A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-subtituted amino acetylamino)phenylamino] quinazoline derivative as well as preparation method and application thereof |
| CN106045980A (en) * | 2016-06-03 | 2016-10-26 | 江苏开放大学 | Quinazoline derivative and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| 喹唑啉类化合物的合成及抗肿瘤活性;崔智勇 等;《北京医科大学学报》;19990218;第31卷(第01期);第27-31页 * |
| 喹唑啉类抗癌药物的合成研究进展;李付刚等;《精细与专用化学品》;20100221;第18卷(第02期);第45-54、60页 * |
| 新型TOPK抑制剂的设计、合成及抗肿瘤活性研究;黄珍等;《湖南中医药大学学报》;20200325;第40卷(第03期);第298-304页 * |
| 新型喹唑啉类衍生物的合成与抗肿瘤活性的研究;邵薇等;《华西药学杂志》;20130615;第28卷(第03期);第232-234页 * |
| 新型氨基喹唑啉化合物的合成及其抗肿瘤活性;黄晴菲等;《合成化学》;20150120;第23卷(第01期);第40-43页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109942499A (en) | 2019-06-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA3056712A1 (en) | Synthesis of mcl-1 inhibitor | |
| CN109438365B (en) | N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide derivative | |
| CN109942499B (en) | Quinazoline derivative and preparation method and application thereof | |
| CN110698461A (en) | Preparation method of third-generation EGFR inhibitor | |
| WO2018126898A1 (en) | Thienopyrimidine derivative, preparation method therefor, and application thereof in manufacturing of antitumor drugs | |
| WO2009060282A2 (en) | Stilbene derivatives as pstat3/il-6 inhibitors | |
| CN111704646B (en) | Steroid compound and preparation method and application thereof | |
| CN114751891B (en) | (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound and application thereof | |
| CN109280032B (en) | Pyridazinone mother nucleus structure histone deacetylase inhibitor and preparation method and application thereof | |
| CN110437156B (en) | Paeonol dihydropyrimidinone derivative, preparation method and application thereof | |
| CN110156817B (en) | Anti-tumor derivative of bi-evodiamine molecule and preparation and application thereof | |
| CN114436918B (en) | Cyclobut-1-enamine compound, preparation method thereof and application thereof in medicines | |
| CN112174958B (en) | Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof | |
| CN112679458B (en) | Sulfonic ester-containing myricetin derivative and preparation method and application thereof | |
| CN112745237B (en) | 2-arylamine compound and preparation method and application thereof | |
| CN108033913A (en) | A kind of pyrazoline quinoline derivant and its preparation method and application | |
| CN110872263B (en) | Compound, preparation method and application | |
| CN109180583B (en) | Synthesis and application of naphthalimide derivative containing heterocyclic sulfone group and N-oxide | |
| CN108530453B (en) | 2(3) -p-methylthio styryl benzofuran quinoline derivative and preparation method and application thereof | |
| AU2018298154B2 (en) | Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof | |
| CN113061117B (en) | 2- ((5-chloro-2- (4-morpholine methylanilino) pyrimidine-4-yl) amino) benzamide derivative | |
| CN111808031A (en) | Ferulic acid derivative and preparation method and application thereof | |
| CN111138413B (en) | Preparation method of cyclin-dependent kinase inhibitor and intermediate thereof | |
| CN112441970A (en) | 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof | |
| CN115109083B (en) | Pyridostatin compound, preparation method and application thereof, and pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |