CN113845485B - Amino acid derivative and preparation method and application thereof - Google Patents

Abstract

Translated fromChinese

本发明涉及氨基酸衍生物及其制备方法和应用。该氨基酸衍生物具有如下结构式中的一种：

该氨基酸衍生物具有良好的水溶性，良好的与靶标蛋白结合力，以吉非替尼为阳性对照，结果表明与吉非替尼相比具有良好的活性，为氨基酸衍生物的进一步改造并发现新的抗肿瘤药物候选物具有较高的借鉴与参考价值。本发明还提出了上述氨基酸衍生物的制备方法以及其在制备抗癌药物中的应用。

The present invention relates to amino acid derivatives and their preparation methods and applications. The amino acid derivative has one of the following structural formulas:

The amino acid derivative has good water solubility and good binding ability to the target protein. Taking gefitinib as a positive control, the results show that it has good activity compared with gefitinib. It is a further modification and discovery of amino acid derivatives. New anti-tumor drug candidates have high reference and reference value. The present invention also proposes the preparation method of the amino acid derivative and its application in the preparation of anticancer drugs.

Description

Translated fromChinese

氨基酸衍生物及其制备方法和应用Amino acid derivatives and their preparation methods and applications

技术领域technical field

本发明涉及药物化学领域，尤其涉及氨基酸衍生物及其制备方法和应用。The invention relates to the field of medicinal chemistry, in particular to amino acid derivatives and their preparation methods and applications.

背景技术Background technique

氨基酸是构成蛋白质的基本单位，具有良好的生物相容性和亲和性，将其引入药物分子，不仅可以增加药物的溶解度，加强小肠对药物的吸收速率，促进药物在体内的主动转运过程，提高生物利用度，还能提高药物对肿瘤细胞的选择性，降低对正常细胞的毒性，提高抗肿瘤活性和代谢稳定性，为寻求高效、低毒的抗肿瘤药物开辟途径。Amino acid is the basic unit of protein and has good biocompatibility and affinity. The introduction of amino acid into drug molecules can not only increase the solubility of drugs, enhance the absorption rate of drugs in the small intestine, promote the active transport of drugs in the body, and improve the The bioavailability can also improve the selectivity of the drug to tumor cells, reduce the toxicity to normal cells, improve the anti-tumor activity and metabolic stability, and open up a way for seeking highly efficient and low-toxic anti-tumor drugs.

喹唑啉一直是EGFR抑制剂的重要母核，是设计NSCLC靶向治疗药物的一种优势结构。但现有技术中，以喹唑啉环为骨架制备的抗肿瘤药物中，溶解性较差，吸收效果不如意。Quinazoline has always been an important mother core of EGFR inhibitors, and it is an advantageous structure for designing NSCLC targeted therapy drugs. However, in the prior art, antitumor drugs prepared with quinazoline rings as skeletons have poor solubility and unsatisfactory absorption effects.

发明内容Contents of the invention

基于上述存在的技术问题，本发明提出了氨基酸衍生物及其制备方法和应用。Based on the above technical problems, the present invention proposes amino acid derivatives and their preparation methods and applications.

本发明提出的氨基酸衍生物，具有如下结构式中的一种：The amino acid derivative proposed by the present invention has one of the following structural formulas:

式中，-R₁选自氢或C1-C6烷烃中的一种；-R₂选自二甲胺丙基、吗啉丙基、二丁胺丙基、二乙胺丙基、二己胺丙基、二辛胺丙基中的一种；-R₃选自氢、乙酰基、丙酰基或丁酰基中的一种。In the formula, -R₁ is selected from one of hydrogen or C1-C6 alkane; -R₂ is selected from dimethylaminopropyl, morpholinopropyl, dibutylaminopropyl, diethylaminopropyl, dihexylamine One of propyl and dioctylaminopropyl;_-R3 is selected from one of hydrogen, acetyl, propionyl or butyryl.

进一步地，所述氨基酸衍生物的结构式选自如下结构式中的一种：Further, the structural formula of the amino acid derivative is selected from one of the following structural formulas:

本发明还提出一种上述任一项所述的氨基酸衍生物的制备方法，包括以下步骤：The present invention also proposes a method for preparing the amino acid derivative described in any one of the above, comprising the following steps:

1)将化合物A1或B1溶解在氢氧化钠溶液，常温下滴加酸酐进行酰化反应，分别得到化合物A2、B2，所述化合物A1的结构式为

所述化合物B1的结构式为

所述化合物A2的结构式为

所述化合物B2的结构式为

其中，-R₃选自乙酰基、丙酰基、丁酰基中的一种；1) Dissolving compound A1 or B1 in sodium hydroxide solution, adding acid anhydride dropwise at room temperature for acylation reaction to obtain compounds A2 and B2 respectively, the structural formula of the compound A1 is

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, -R₃ is selected from the one in acetyl, propionyl, butyryl;

2)将所述化合物A2分批次加入混酸溶液中进行硝化反应，分别得化合物A3、B3，所述化合物A3的结构式为

所述化合物B3的结构式为

2) adding the compound A2 in batches into the mixed acid solution for nitration reaction to obtain compounds A3 and B3 respectively, the structural formula of the compound A3 is

The structural formula of the compound B3 is

3)将所述化合物A3或B3溶解在醇溶液中，升温，缓慢滴加硫酸溶液进行酯化反应，分别得到化合物A4、B4，所述化合物A4的结构式为

所述化合物B4的结构式为：

其中，-R₁选自C1-C6烷烃中的一种；3) Dissolving the compound A3 or B3 in the alcohol solution, heating up, slowly adding sulfuric acid solution dropwise to carry out esterification reaction, to obtain compounds A4 and B4 respectively, the structural formula of the compound A4 is

The structural formula of the compound B4 is:

Wherein, -R₁ is selected from the one in C1-C6 alkane;

4)将所述化合物A4或B4苯环上的硝基还原成氨基，分别得到化合物A5、B5，所述化合物A5的结构式为

所述B5的结构式为：

4) reducing the nitro group on the benzene ring of the compound A4 or B4 to an amino group to obtain compounds A5 and B5 respectively, and the structural formula of the compound A5 is

The structural formula of the B5 is:

5)将化合物C3与所述化合物A5或B5发生取代反应，得化合物A6或B6，所述化合物A6的结构式为

所述B6的结构式为：

所述化合物C3的结构式为

5) Compound C3 is subjected to a substitution reaction with the compound A5 or B5 to obtain the compound A6 or B6, and the structural formula of the compound A6 is

The structural formula of the B6 is:

The structural formula of the compound C3 is

6)将所述化合物A6或B6与氨水发生水解反应，得化合物A7或B7，所述化合物A7的结构式为

所述化合物B7的结构式为：

6) The compound A6 or B6 is hydrolyzed with ammonia water to obtain the compound A7 or B7, and the structural formula of the compound A7 is

The structural formula of the compound B7 is:

7)将所述化合物A7或B7与含有-R₂的化合物M发生取代反应，分别得到化合物A8、B8，所述化合物A8的结构式为

所述化合物B8的结构式为：

7) The compound A7 or B7 is subjected to a substitution reaction with the compound M containing -R₂ to obtain compounds A8 and B8 respectively, and the structural formula of the compound A8 is

The structural formula of the compound B8 is:

当-R₁为氢、-R₃为氢时，将所述化合物A8或B8与盐酸和冰醋酸发生水解反应，分别得化合物A9、B9，所述化合物A9的结构式为

所述化合物B9的结构式为

When -R₁ is hydrogen and -R₃ is hydrogen, the compound A8 or B8 is hydrolyzed with hydrochloric acid and glacial acetic acid to obtain compounds A9 and B9 respectively, and the structural formula of the compound A9 is

The structural formula of the compound B9 is

当-R₁为氢，-R₃为乙酰基、丙酰基或丁酰基中的一种，将所述化合物A8或B8与盐酸进行反应；When -R₁ is hydrogen, and -R₃ is one of acetyl, propionyl or butyryl, the compound A8 or B8 is reacted with hydrochloric acid;

当-R₁为C1-C6烷烃中的一种，-R₃为氢，将化合物A9或B9按步骤4)的方式发生酯化反应。When -R₁ is one of the C1-C6 alkanes, and -R₃ is hydrogen, the compound A9 or B9 is subjected to an esterification reaction in the manner of step 4).

优选地，在步骤5)之前，还包括所述化合物C3的制备：将化合物C1与醋酐发生酰化反应，得化合物C2，所述化合物C1的结构式为

所述化合物C2的结构式为

将所述化合物C2与氯化亚砜发生卤化反应，得所述化合物C3。优选地，将所述化合物B1与乙酸酐、吡啶及DMAP(4-二甲基氨基吡啶)发生所述酰化反应得到所述化合物C2；将所述化合物C2与氯化亚砜发生卤化反应生成所述化合物C3。Preferably, before step 5), the preparation of the compound C3 is also included: the compound C1 is acylated with acetic anhydride to obtain the compound C2, and the structural formula of the compound C1 is

The structural formula of the compound C2 is

The compound C2 is subjected to a halogenation reaction with thionyl chloride to obtain the compound C3. Preferably, the acylation reaction of the compound B1 with acetic anhydride, pyridine and DMAP (4-dimethylaminopyridine) occurs to obtain the compound C2; the halogenation reaction of the compound C2 with thionyl chloride generates The compound C3.

优选地，步骤1)中所述化合物A1或B1与所述醋酐溶液中的醋酐的用量摩尔比为1:1.5～1.8，反应时间为3～4h。Preferably, the molar ratio of the compound A1 or B1 to the acetic anhydride in the acetic anhydride solution in step 1) is 1:1.5-1.8, and the reaction time is 3-4 hours.

优选地，步骤2)中所述硝化反应所用的混酸为98％硫酸与68％硝酸以体积比例1.2:1相混合的酸液，控温-20℃。Preferably, the mixed acid used in the nitration reaction in step 2) is an acid solution in which 98% sulfuric acid and 68% nitric acid are mixed at a volume ratio of 1.2:1, and the temperature is controlled at -20°C.

优选地，步骤3)中将所述化合物A3或B3用甲醇做溶剂，硫酸催化进行酯化，所述化合物A3或B3与甲醇用量摩尔比为1:0.65～0.8，反应温90～95℃，反应时间7～8h。Preferably, in step 3), the compound A3 or B3 is esterified with methanol as a solvent, catalyzed by sulfuric acid, the molar ratio of the compound A3 or B3 to methanol is 1:0.65-0.8, and the reaction temperature is 90-95°C. The reaction time is 7-8 hours.

优选地，步骤4)中将所述化合物A4或B4苯环上的硝基还原成氨基的方法采用铁粉还原法，具体为：将铁粉、氯化铵、无水乙醇、水和冰醋酸与化合物A4或B4混合进行还原反应；所述化合物A4或B4与铁粉用量摩尔比为1:10～11，反应温度90～95℃，反应时间4～6h。Preferably, in step 4), the method for reducing the nitro group on the benzene ring of the compound A4 or B4 to an amino group adopts an iron powder reduction method, specifically: iron powder, ammonium chloride, absolute ethanol, water and glacial acetic acid Mixing with compound A4 or B4 for reduction reaction; the molar ratio of compound A4 or B4 to iron powder is 1:10-11, the reaction temperature is 90-95°C, and the reaction time is 4-6h.

优选地，所述化合物C1与醋酐发生酰化反应的反应温度为95～100℃，时间为4～5h。Preferably, the reaction temperature of the acylation reaction between the compound C1 and acetic anhydride is 95-100° C., and the time is 4-5 hours.

优选地，步骤5)中所述化合物A5或B5与所述化合物B3发生取代反应的用量摩尔比为1:1.2～1.5，反应温度为90℃～100℃，反应时间4～6h。Preferably, in step 5), the molar ratio of compound A5 or B5 to the compound B3 for the substitution reaction is 1:1.2-1.5, the reaction temperature is 90°C-100°C, and the reaction time is 4-6h.

优选地，在步骤6)中所述化合物A6或B6与所述氨水的摩尔比为1:4～7，反应温度为70℃～75℃，反应时间5～6h。Preferably, in step 6), the molar ratio of the compound A6 or B6 to the ammonia water is 1:4-7, the reaction temperature is 70°C-75°C, and the reaction time is 5-6h.

优选地，步骤7)中所述化合物A7或B7与所述化合物M发生取代反应的用量摩尔比为1:1.2～1.5；反应温度90～95℃；反应时间6～8h。Preferably, the molar ratio of compound A7 or B7 and compound M for the substitution reaction in step 7) is 1:1.2-1.5; the reaction temperature is 90-95° C.; the reaction time is 6-8 hours.

优选地，步骤8)中所述化合物A8或B8与冰醋酸发生水解反应的用量摩尔比为1:30～38；反应温度110℃；反应时间6～8h。Preferably, the molar ratio of compound A8 or B8 and glacial acetic acid for the hydrolysis reaction in step 8) is 1:30-38; the reaction temperature is 110° C.; the reaction time is 6-8 hours.

此外，本发明还提出了上述所述的氨基酸衍生物在制备抗癌药物中的应用。In addition, the present invention also proposes the application of the above-mentioned amino acid derivatives in the preparation of anticancer drugs.

优选地，所述为抗肺癌药物。Preferably, the drug is an anti-lung cancer drug.

本发明与现有技术对比的有益效果包括：The beneficial effect of the present invention compared with prior art comprises:

本发明提出的氨基酸衍生物，采用喹唑啉骨架，通过在喹唑啉环上引入不同氨基酸衍生物及其它相关基团，得到一系列具有抗肿瘤活性的化合物，以吉非替尼为阳性对照，结果表明与吉非替尼相比具有良好的活性，为发现新的抗肿瘤药物候选物具有较高的借鉴与参考价值。本发明的氨基酸衍生物还具有溶解性好、易被吸收的优点。The amino acid derivative proposed by the present invention adopts a quinazoline skeleton and introduces different amino acid derivatives and other related groups on the quinazoline ring to obtain a series of compounds with antitumor activity. Gefitinib is used as a positive control , the results show that it has good activity compared with gefitinib, which has a high reference and reference value for the discovery of new anti-tumor drug candidates. The amino acid derivatives of the present invention also have the advantages of good solubility and easy absorption.

本发明实施例还提供了一种氨基酸衍生物的制备方法，其采用喹唑啉骨架，通过在喹唑啉环上引入不同氨基酸衍生物及其它相关基团，得到一系列具有抗肿瘤活性的化合物。该方法可高效高品质地得到多种氨基酸衍生物，操作简单方便，对设备要求不高，适合规模化生产与应用。The embodiment of the present invention also provides a preparation method of amino acid derivatives, which uses a quinazoline skeleton and introduces different amino acid derivatives and other related groups on the quinazoline ring to obtain a series of compounds with antitumor activity . The method can obtain various amino acid derivatives with high efficiency and high quality, is simple and convenient to operate, does not require high equipment, and is suitable for large-scale production and application.

附图说明Description of drawings

图1为实施例19制备的化合物与2ITY靶蛋白对接示意图及对接结果。Figure 1 is a schematic diagram of the docking of the compound prepared in Example 19 and the 2ITY target protein and the docking results.

具体实施方式Detailed ways

为使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。In order to make the above objects, features and advantages of the present invention more obvious and comprehensible, specific implementations of the present invention will be described in detail below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention can be implemented in many other ways different from those described here, and those skilled in the art can make similar improvements without departing from the connotation of the present invention, so the present invention is not limited by the specific implementations disclosed below.

除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field of the invention. The terms used herein in the description of the present invention are for the purpose of describing specific embodiments only, and are not intended to limit the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

本具体实施方式提出氨基酸衍生物，具有如下结构式中的一种：This specific embodiment proposes amino acid derivatives, which have one of the following structural formulas:

式中，-R₁选自氢或C1-C6烷烃中的一种；-R₂选自二甲胺丙基、吗啉丙基、二丁胺丙基、二乙胺丙基、二己胺丙基、二辛胺丙基中的一种；-R₃选自氢、乙酰基、丙酰基或丁酰基中的一种。氨基酸衍生物的结构式可选取上述结构式中的任意一种，为进一步说明本发明提出的氨基酸衍生物的制备方法和性能，现列举其中的部分结构式的制备方法和性能研究进行详细说明。In the formula, -R₁ is selected from one of hydrogen or C1-C6 alkane; -R₂ is selected from dimethylaminopropyl, morpholinopropyl, dibutylaminopropyl, diethylaminopropyl, dihexylamine One of propyl and dioctylaminopropyl;_-R3 is selected from one of hydrogen, acetyl, propionyl or butyryl. The structural formula of the amino acid derivative can be any one of the above structural formulas. In order to further illustrate the preparation method and performance of the amino acid derivative proposed by the present invention, the preparation method and performance research of some of the structural formulas are listed for detailed description.

本具体实施例方式中的7-甲氧基-6-乙酰氧基-4-氯喹唑啉(即化合物C3)通过以下方法制备The 7-methoxy-6-acetoxy-4-chloroquinazoline (i.e. compound C3) in this specific embodiment is prepared by the following method

将6-羟基-7-甲氧基-4-酮喹唑啉(10g，0.052mol，即化合物C1)、乙酸酐(108mL，1.14mol)和吡啶(22.4mL，0.278mol)依次加入到500mL的圆底烧瓶中，升温至100℃回流反应1h后，加入4-二甲氨基吡啶(1.4g，0.0115mol)，继续反应4h，停止反应，将滤液倒入大量冰水搅拌，抽滤，滤饼烘干，得黄白色固体(即化合物C2)。将其与氯化亚砜(107mL，1.47mol)依次加入到500mL的三口圆底烧瓶中，升温至80℃回流反应30min，自恒压滴液漏斗缓慢将N,N-二甲基甲酰胺(4.6mL，0.059mol)滴加到反应液中。反应4h，停止反应，冷却，减压回收氯化亚砜，向反应物中加入冰水(250mL)搅拌约1h后，抽滤，烘干滤饼，得灰白色固体10.5g，收率:80.0％。6-Hydroxy-7-methoxy-4-ketoquinazoline (10g, 0.052mol, compound C1), acetic anhydride (108mL, 1.14mol) and pyridine (22.4mL, 0.278mol) were added to a 500mL In a round-bottomed flask, heat up to 100°C for reflux reaction for 1 hour, add 4-dimethylaminopyridine (1.4 g, 0.0115 mol), continue the reaction for 4 hours, stop the reaction, pour the filtrate into a large amount of ice water and stir, suction filter, and filter cake After drying, a yellow-white solid (namely compound C2) was obtained. Add it and thionyl chloride (107mL, 1.47mol) into a 500mL three-necked round-bottomed flask in turn, heat up to 80°C for 30min under reflux, and slowly add N,N-dimethylformamide ( 4.6mL, 0.059mol) was added dropwise to the reaction solution. React for 4h, stop the reaction, cool down, recover thionyl chloride under reduced pressure, add ice water (250mL) to the reactant and stir for about 1h, filter with suction, and dry the filter cake to obtain 10.5g of off-white solid, yield: 80.0% .

实施例1Example 1

(S)-2-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(S)-2-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propane Preparation of methyl ester

(1)(S)-2-乙酰氨基-3-苯基丙酸(即一种化合物A2)的制备(1) Preparation of (S)-2-acetylamino-3-phenylpropionic acid (i.e. a compound A2)

将L-苯丙氨酸(15g,0.091mol，即一种化合物A1)和水(200mL)室温搅拌10min，缓慢滴加饱和NaOH水溶液，调节溶液的pH值至苯丙氨酸全溶，缓慢滴加乙酸酐(15mL,0.159mol)；乙酸酐滴加过程中，由于pH值的改变，L-苯丙氨酸析出，滴加饱和NaOH水溶液维持反应液的弱碱性环境(pH＝8.0)；室温反应3h，TLC检测反应完全后，滴加盐酸调节反应液的pH值至2，产物完全析出，抽滤，干燥得白色固体16.6g，收率:88.2％。Stir L-phenylalanine (15g, 0.091mol, a compound A1) and water (200mL) at room temperature for 10min, slowly add saturated NaOH aqueous solution dropwise, adjust the pH value of the solution until the phenylalanine is completely dissolved, slowly drop Add acetic anhydride (15mL, 0.159mol); during the dropwise addition of acetic anhydride, L-phenylalanine is precipitated due to the change of pH value, and saturated NaOH aqueous solution is added dropwise to maintain the weak alkaline environment of the reaction solution (pH=8.0); After reacting at room temperature for 3 hours, after the reaction was complete as detected by TLC, hydrochloric acid was added dropwise to adjust the pH value of the reaction solution to 2, the product was completely precipitated, filtered by suction, and dried to obtain 16.6 g of white solid, yield: 88.2%.

(2)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸(即一种化合物A3)的制备(2) Preparation of (S)-2-acetylamino-3-(4-nitrophenyl) propionic acid (i.e. a compound A3)

在250mL烧瓶中缓慢加入98％硫酸(9.6mL)和硝酸(8.0mL)，控温-20℃搅拌0.5h，取出，置于室温冰浴搅拌，分批加(S)-2-乙酰氨基-3-苯基丙酸(10g,0.048mol)；搅拌反18h，TLC检测反应完全后，停止反应；将反应液倒入200mL冰水中，搅拌，产物析出，抽滤，干燥得白色固体6.9g，收率:56.7％。Slowly add 98% sulfuric acid (9.6mL) and nitric acid (8.0mL) into a 250mL flask, stir at -20°C for 0.5h, take it out, stir in an ice bath at room temperature, add (S)-2-acetamido- 3-Phenylpropanoic acid (10g, 0.048mol); Stir for 18h, stop the reaction after TLC detects that the reaction is complete; pour the reaction solution into 200mL of ice water, stir, the product is precipitated, suction filtered, and dried to obtain 6.9g of white solid, Yield: 56.7%.

(3)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯(即一种化合物A4)的制备(3) Preparation of (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester (i.e. a compound A4)

将(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸(6g，0.024mol)溶于甲醇(60mL)85℃搅拌0.5h，缓慢滴加98％浓硫酸(0.843mL)，回流反应7h，停止反应，冷却至室温；减压蒸除甲醇，加乙酸乙酯(100mL)提取，滴加饱和Na₂CO₃溶液，调节pH值至7，水相用乙酸乙酯(50mL×2)萃取，合并有机相，加水(50mL×2)洗涤，无水硫酸镁干燥有机相4h；过滤，滤液减压浓缩，得黄色固体5.8g，收率:91.6％。Dissolve (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid (6g, 0.024mol) in methanol (60mL) and stir at 85°C for 0.5h, then slowly add 98% concentrated sulfuric acid (0.843mL ), reflux reaction for 7h, stop the reaction, and cool to room temperature; evaporate methanol under reduced pressure, add ethyl acetate (100mL) for extraction, add saturated Na₂ CO₃ solution dropwise, adjust the pH value to 7, and use ethyl acetate ( 50mL×2) extraction, combined the organic phases, washed with water (50mL×2), dried the organic phase with anhydrous magnesium sulfate for 4h; filtered, and concentrated the filtrate under reduced pressure to obtain 5.8g of yellow solid, yield: 91.6%.

(4)(S)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯(即一种化合物A5)的制备(4) Preparation of (S)-2-acetylamino-3-(4-aminophenyl)propionic acid methyl ester (i.e. a compound A5)

将还原铁粉(11.1g，0.199mol)、氯化铵(0.68g，0.013mol)、乙醇(56mL)、水(14mL)和冰醋酸(3.4mL)，依次加入装有干燥管装置的250mL三口瓶中，升温至90℃回流反应，机械搅拌1.5h，加入(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯(5.1g，0.019mol)继续反应3h，趁热抽滤，滤液减压浓缩，加二氯甲烷(150mL)提取，加水(50mL×2)洗涤，无水硫酸镁干燥有机相4h；过滤，滤液减压浓缩，得黄白色固体3.4g，收率:75.2％。Add reduced iron powder (11.1g, 0.199mol), ammonium chloride (0.68g, 0.013mol), ethanol (56mL), water (14mL) and glacial acetic acid (3.4mL) into a 250mL three-port tube equipped with a drying tube device in sequence In the bottle, heat up to 90°C for reflux reaction, mechanically stir for 1.5h, add (S)-2-acetamido-3-(4-nitrophenyl)propionic acid methyl ester (5.1g, 0.019mol) to continue the reaction for 3h, Suction filtration while hot, concentrate the filtrate under reduced pressure, add dichloromethane (150mL) for extraction, add water (50mL×2) to wash, dry the organic phase with anhydrous magnesium sulfate for 4h; filter, and concentrate the filtrate under reduced pressure to obtain 3.4g of yellow-white solid, Yield: 75.2%.

(5)(S)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(即一种化合物A6)的制备(5) (S)-methyl 2-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate (i.e. a Preparation of a compound A6)

将(S)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯(3.7g,0.016mol)溶于异丙醇(37mL)，95℃搅拌0.5h，加入7-甲氧基-6-乙酰氧基-4-氯喹唑啉(4.8g，0.014mol)；继续回流反应4h，TLC检测反应完全后，停止反应，趁热抽滤，烘干滤饼，得白色固体5.0g，收率:70.6％。Dissolve (S)-methyl 2-acetylamino-3-(4-aminophenyl)propionate (3.7g, 0.016mol) in isopropanol (37mL), stir at 95°C for 0.5h, add 7-methoxy Base-6-acetoxy-4-chloroquinazoline (4.8g, 0.014mol); continue to reflux reaction for 4h, after TLC detects that the reaction is complete, stop the reaction, suction filter while it is hot, and dry the filter cake to obtain 5.0g of white solid , Yield: 70.6%.

(6)(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(即一种化合物A7)的制备(6) Methyl (S)-2-acetylamino-3-(4-((6-hydroxy-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate (a compound A7) Preparation

将(S)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(3g,0.007mol)溶于甲醇(20mL)，升温至65℃回流反应0.5h，加入氨水(5.2mL)。继续反应5h，TLC检测反应完全后，停止反应，冷却至室温，反应液减压浓缩，得黄色油状物；加入乙酸乙酯(30mL)搅拌，出现黄色固体，抽滤，烘干滤饼，得黄色固体2.5g，收率:91.9％。(S)-methyl 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° C. for reflux reaction for 0.5 h, and ammonia water (5.2 mL) was added. Continue the reaction for 5h, after the reaction is complete as detected by TLC, stop the reaction, cool to room temperature, and concentrate the reaction solution under reduced pressure to obtain a yellow oil; add ethyl acetate (30mL) and stir, a yellow solid appears, suction filter, and dry the filter cake to obtain Yellow solid 2.5g, yield: 91.9%.

(7)(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(7) (S)-2-Acetamido-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid Preparation of methyl esters

将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.5g,0.006mol)溶于DMF(10mL)，升温至75℃回流反应0.5h后，加入碳酸钾(1.0g，0.017mol)、碘化钾(0.02g)和1,3-溴氯丙烷(0.78mL，0.008mol)；继续反应8h，TLC检测反应完全后，停止反应。冷却至室温，加冰水(50mL)，搅拌2h，抽滤得粗产品，加丙酮洗涤，烘干滤饼，得黄色固体2.3g，收率:77.4％。(S)-methyl 2-acetylamino-3-(4-((6-hydroxy-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate (2.5g, 0.006mol) Dissolve in DMF (10mL), heat up to 75°C and reflux for 0.5h, then add potassium carbonate (1.0g, 0.017mol), potassium iodide (0.02g) and 1,3-bromochloropropane (0.78mL, 0.008mol); continue After 8 hours of reaction, the reaction was stopped after TLC detected that the reaction was complete. Cool to room temperature, add ice water (50 mL), stir for 2 h, suction filter to obtain a crude product, add acetone to wash, and dry the filter cake to obtain 2.3 g of yellow solid, yield: 77.4%.

(8)(S)-2-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(8) (S)-2-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)benzene base) preparation of methyl propionate

将(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.3g,0.005mol)溶于DMF(10mL)，升温至95℃回流反应0.5h后，加入碳酸钾(1.2g,0.0085mol)、碘化钾(0.02g)和二乙胺(0.8mL，0.007mol)；继续反应8h，TLC检测反应完全后，停止反应；冷却至室温，加冰水(50mL)，搅拌2h，抽滤得粗产品；将粗产品溶于甲醇(10mL)，缓慢滴加盐酸，有白色固体产生，抽滤，烘干滤饼，得黄白色固体1.0g，收率:40.4％。m.p.176.3～177.9℃。Methyl (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate (2.3g, 0.005mol) was dissolved in DMF (10mL), heated to 95°C and refluxed for 0.5h, then potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02g) and diethylamine (0.8mL, 0.007mol ); continue to react for 8h, after TLC detects that the reaction is complete, stop the reaction; cool to room temperature, add ice water (50mL), stir for 2h, and suction filter to obtain the crude product; dissolve the crude product in methanol (10mL), slowly add hydrochloric acid dropwise, A white solid was produced, suction filtered, and the filter cake was dried to obtain 1.0 g of a yellow-white solid, yield: 40.4%. m.p.176.3～177.9℃.

在其他实施例中，也可通过将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯与N,N-二乙基-3-氯丙胺化合物直接发生取代反应生成(S)-2-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(即一种化合物A8)。In other embodiments, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid Direct substitution reaction between methyl ester and N,N-diethyl-3-chloropropylamine compound to generate (S)-2-acetylamino-3-(4-((6-(3-(diethylamino)propoxy )-methyl 7-methoxyquinazolin-4-yl)amino)phenyl)propionate (ie a compound A8).

实施例2Example 2

(S)-2-乙酰氨基-3-(4-((6-(3-(二己基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(S)-2-Acetamido-3-(4-((6-(3-(dihexylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propane Preparation of methyl ester

将(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.3g,0.005mol)溶于DMF(10mL)，升温至95℃回流反应0.5h后，加入碳酸钾(1.2g,0.0085mol)、碘化钾(0.02g)和二己胺(1.53mL，0.007mol)。继续反应8h，TLC检测反应完全后，停止反应；冷却至室温，加冰水(50mL)，搅拌2h，抽滤得粗产品；将粗产品溶于甲醇(10mL)，缓慢滴加盐酸，有白色固体产生，抽滤，烘干滤饼，得黄白色固体1.4g，收率:45.4％。m.p.186.3～188.9℃。Methyl (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate (2.3g, 0.005mol) was dissolved in DMF (10mL), heated to 95°C and refluxed for 0.5h, then potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02g) and dihexylamine (1.53mL, 0.007mol ). Continue to react for 8h, stop the reaction after TLC detects that the reaction is complete; cool to room temperature, add ice water (50mL), stir for 2h, and filter with suction to obtain the crude product; dissolve the crude product in methanol (10mL), slowly add hydrochloric acid dropwise, white A solid was formed, suction filtered, and the filter cake was dried to obtain 1.4 g of a yellow-white solid, yield: 45.4%. m.p.186.3～188.9℃.

在其他实施例中，也可通过将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯与N-(3-氯丙基)-二己基胺化合物直接发生取代反应生成(S)-2-乙酰氨基-3-(4-((6-(3-(二己基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(即一种化合物A8)。In other embodiments, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid The direct substitution reaction between methyl ester and N-(3-chloropropyl)-dihexylamine compound produces (S)-2-acetylamino-3-(4-((6-(3-(dihexylamino)propoxy yl)-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester (ie a compound A8).

实施例3Example 3

(S)-2-乙酰氨基-3-(4-((6-(3-(二辛基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(S)-2-Acetamido-3-(4-((6-(3-(dioctylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Preparation of methyl propionate

将(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.3g,0.005mol)溶于DMF(10mL)，升温至95℃回流反应0.5h后，加入碳酸钾(1.2g,0.0085mol)、碘化钾(0.02g)和二辛胺(1.5g，0.006mol)。继续反应8h，TLC检测反应完全后，停止反应；冷却至室温，加冰水(50mL)，搅拌2h，抽滤得粗产品；将粗产品溶于甲醇(10mL)，缓慢滴加盐酸，有白色固体产生，抽滤，烘干滤饼，得黄白色固体1.4g，收率:43.3％。m.p.202.6～204.1℃。Methyl (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate (2.3g, 0.005mol) was dissolved in DMF (10mL), heated to 95°C and refluxed for 0.5h, then potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02g) and dioctylamine (1.5g, 0.006mol) were added ). Continue to react for 8h, stop the reaction after TLC detects that the reaction is complete; cool to room temperature, add ice water (50mL), stir for 2h, and filter with suction to obtain the crude product; dissolve the crude product in methanol (10mL), slowly add hydrochloric acid dropwise, white A solid was formed, suction filtered, and the filter cake was dried to obtain 1.4 g of a yellow-white solid, yield: 43.3%. m.p.202.6～204.1℃.

在其他实施例中，也可通过将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯与N-(3-氯丙基)-二辛基胺化合物直接发生取代反应生成(S)-2-乙酰氨基-3-(4-((6-(3-(二辛基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(即一种化合物A8)。In other embodiments, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid The direct substitution reaction between methyl ester and N-(3-chloropropyl)-dioctylamine compound produces (S)-2-acetylamino-3-(4-((6-(3-(dioctylamino) propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester (ie a compound A8).

实施例4Example 4

(S)-2-乙酰氨基-3-(4-((6-(3-(二甲基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(S)-2-Acetamido-3-(4-((6-(3-(dimethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate

将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.8g,0.007mol)溶于DMF(14mL)，升温至95℃回流反应0.5h后，加入碳酸钾(1.2g,0.0085mol)、碘化钾(0.02g)和N,N-二甲基-3-氯丙胺(1.5mL，0.011mol)；继续反应8h，TLC检测反应完全后，停止反应；冷却至室温，加入冰水(70mL)，搅拌2h，抽滤得粗产品；将粗产品溶于甲醇(10mL)搅拌，缓慢滴加盐酸，有白色固体产生，抽滤，烘干滤饼，得白色固体1.4g，收率:41.6％。m.p.165.1～167.5℃。(S)-methyl 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionate (2.8g, 0.007mol) Dissolve in DMF (14mL), heat up to 95°C and reflux for 0.5h, then add potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02g) and N,N-dimethyl-3-chloropropylamine (1.5mL, 0.011mol); continue to react for 8h, stop the reaction after TLC detects that the reaction is complete; cool to room temperature, add ice water (70mL), stir for 2h, and suction filter to obtain the crude product; dissolve the crude product in methanol (10mL) and stir, slowly drop Adding hydrochloric acid, a white solid was produced, suction filtered, and the filter cake was dried to obtain 1.4 g of a white solid, yield: 41.6%. m.p.165.1～167.5℃.

实施例5Example 5

(S)-2-乙酰氨基-3-(4-((6-(3-吗啉代丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(S)-2-Acetamido-3-(4-((6-(3-morpholinopropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl Preparation of esters

将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.8g,0.007mol)溶于DMF(14mL)，升温至95℃回流反应0.5h后，加入碳酸钾(1.2g,0.0085mol)、碘化钾(0.02g)和N-(3-氯丙基)-吗啉(1.3mL，0.008mol)；继续反应8h，TLC检测反应完全后，停止反应；冷却至室温，加入冰水(70mL)，搅拌2h，抽滤得粗产品；将粗产品溶于甲醇(10mL)搅拌，缓慢滴加盐酸，有白色固体产生，抽滤，烘干滤饼，得白色固体1.4g，收率:36.7％。m.p.168.0～170.2℃。(S)-methyl 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionate (2.8g, 0.007mol) Dissolve in DMF (14mL), heat up to 95°C and reflux for 0.5h, then add potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02g) and N-(3-chloropropyl)-morpholine (1.3mL, 0.008mol); continue to react for 8h, stop the reaction after TLC detects that the reaction is complete; cool to room temperature, add ice water (70mL), stir for 2h, and suction filter to obtain the crude product; dissolve the crude product in methanol (10mL) and stir, slowly drop Adding hydrochloric acid, a white solid was produced, suction filtered, and the filter cake was dried to obtain 1.4 g of a white solid, yield: 36.7%. m.p.168.0～170.2℃.

实施例6Example 6

(S)-2-乙酰氨基-3-(4-((6-(3-(二丁基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(S)-2-Acetamido-3-(4-((6-(3-(dibutylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Preparation of methyl propionate

将(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(2.8g,0.007mol)溶于DMF(14mL)，升温至95℃回流反应0.5h后，加入碳酸钾(1.2g,0.0085mol)、碘化钾(0.02g)和N-(3-氯丙基)-二丁基胺(1.9mL，0.008mol)；继续反应8h，TLC检测反应完全后，停止反应；冷却至室温，加入冰水(70mL)，搅拌2h，抽滤得粗产品。将粗产品溶于甲醇(10mL)搅拌，缓慢滴加盐酸，有白色固体产生，抽滤，烘干滤饼，得白色固体1.8g，收率:46.2％。m.p.180.4～182.1℃。(S)-methyl 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionate (2.8g, 0.007mol) Dissolve in DMF (14mL), heat up to 95°C and reflux for 0.5h, then add potassium carbonate (1.2g, 0.0085mol), potassium iodide (0.02g) and N-(3-chloropropyl)-dibutylamine (1.9 mL, 0.008mol); continue to react for 8h, stop the reaction after TLC detects that the reaction is complete; cool to room temperature, add ice water (70mL), stir for 2h, and filter with suction to obtain the crude product. Dissolve the crude product in methanol (10 mL) and stir, slowly add hydrochloric acid dropwise, a white solid is produced, filter with suction, and dry the filter cake to obtain 1.8 g of white solid, yield: 46.2%. m.p.180.4～182.1℃.

实施例7Example 7

(S)-2-氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸的制备(S)-2-Amino-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid preparation of

将(S)-2-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(1g,0.002mol)溶于冰醋酸(4mL,0.07mol)，并加入HCl(12mL)，升温至110℃回流反应7h后，TLC检测反应完全后，停止反应；冷却至室温，反应液减压浓缩后，加乙酸乙酯(50mL)，搅拌2h，抽滤，烘干滤饼，得黄白色固体0.4g，收率:44.9％。m.p.156.5～157.3℃。(S)-2-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate (1g, 0.002mol) was dissolved in glacial acetic acid (4mL, 0.07mol), and HCl (12mL) was added, heated to 110°C and refluxed for 7 hours. After the reaction was complete by TLC, the reaction was stopped; cooled to room temperature, After the reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added, stirred for 2 h, filtered with suction, and the filter cake was dried to obtain 0.4 g of a yellow-white solid, yield: 44.9%. m.p.156.5-157.3°C.

实施例8Example 8

(R)-2-乙酰氨基-3-(4-((6-(3-(二甲基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(R)-2-Acetamido-3-(4-((6-(3-(dimethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Preparation of methyl propionate

(1)(R)-2-乙酰氨基-3-苯基丙酸的制备(1) Preparation of (R)-2-acetylamino-3-phenylpropionic acid

将实施例1中步骤(2)L-苯丙氨酸替换为D-苯丙氨酸，该步骤的其他反应条件与实施例1的步骤(2)相同，得黄色固体产物，收率:85.1％。Step (2) L-phenylalanine is replaced by D-phenylalanine in embodiment 1, other reaction conditions of this step are identical with the step (2) of embodiment 1, obtain yellow solid product, yield: 85.1 %.

(2)(R)-2-乙酰氨基-3-(4-硝基苯基)丙酸的制备(2) Preparation of (R)-2-acetylamino-3-(4-nitrophenyl)propionic acid

将实施例1中步骤(2)(S)-2-乙酰氨基-3-苯基丙酸替换为(R)-2-乙酰氨基-3-苯基丙酸，该步骤的其他反应条件与实施例1的步骤(2)相同，得黄色固体产物，收率:60.1％。Step (2) (S)-2-acetylamino-3-phenylpropionic acid in Example 1 is replaced by (R)-2-acetylamino-3-phenylpropionic acid, other reaction conditions and implementation of this step The step (2) of Example 1 is the same to obtain a yellow solid product, yield: 60.1%.

(3)(R)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯的制备(3) Preparation of (R)-2-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester

将实施例1中步骤(3)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸替换为(R)-2-乙酰氨基-3-(4-硝基苯基)丙酸，该步骤的其他反应条件与实施例1的步骤(3)相同，得黄色固体，收率:90.9％。Step (3) (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid in Example 1 was replaced by (R)-2-acetylamino-3-(4-nitrophenyl ) propionic acid, other reaction conditions of this step are identical with the step (3) of embodiment 1, obtain yellow solid, yield: 90.9%.

(4)(R)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯的制备(4) Preparation of (R)-2-acetylamino-3-(4-aminophenyl)propionic acid methyl ester

将实施例1中步骤(4)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(4)相同，得黄白色固体，收率:78.8％。In Example 1, step (4) (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester was replaced by (R)-2-acetylamino-3-(4-nitro Phenyl) methyl propionate, the other reaction conditions of this step are identical with the step (4) of embodiment 1, obtain yellow-white solid, yield: 78.8%.

(5)(R)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(5) Preparation of (R)-2-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中步骤(5)(S)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(5)相同，得白色固体，收率:72.5％。In Example 1, step (5) (S)-2-acetylamino-3-(4-aminophenyl)propionic acid methyl ester was replaced by (R)-2-acetylamino-3-(4-aminophenyl ) methyl propionate, other reaction conditions of this step are identical with the step (5) of embodiment 1, obtain white solid, yield: 72.5%.

(6)(R)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(6) Preparation of (R)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中步骤(6)(S)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(6)相同，得黄色固体，收率:89.5％。Step (6) (S)-2-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propane in Example 1 acid methyl ester was replaced by (R)-methyl 2-acetamido-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate, Other reaction conditions of this step are the same as step (6) of Example 1 to obtain a yellow solid, yield: 89.5%.

(7)(R)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(7)(R)-2-Acetamido-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid Preparation of methyl esters

将实施例1中(7)(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(7)相同，得淡黄色固体，收率:70.8％。(7)(S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester in Example 1 Substituting (R)-methyl 2-acetylamino-3-(4-((6-hydroxy-7-methoxyquinazolin-4-yl)amino)phenyl)propanoate, other reactions of this step The conditions were the same as step (7) of Example 1 to obtain a light yellow solid, yield: 70.8%.

(R)-2-乙酰氨基-3-(4-((6-(3-(二甲基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯(R)-2-Acetamido-3-(4-((6-(3-(dimethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate

将实施例4中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例4相同，得白色固体，收率:38.9％。m.p.153.3～154.5℃。In Example 4 (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by ( R)-methyl 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionate, other reaction conditions and steps and examples 4 is the same, a white solid is obtained, yield: 38.9%. m.p.153.3～154.5℃.

实施例9Example 9

(R)-2-乙酰氨基-3-(4-((6-(3-吗啉代丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(R)-2-Acetamido-3-(4-((6-(3-morpholinopropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl Preparation of esters

将实施例5中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例5相同，得白色固体，收率:41.6％。m.p.153.0～155.2℃。In Example 5, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl) amino) phenyl) propionic acid methyl ester is replaced by ( R)-methyl 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionate, other reaction conditions and steps and examples 5 was the same, and a white solid was obtained, yield: 41.6%. m.p.153.0～155.2℃.

实施例10Example 10

(R)-2-乙酰氨基-3-(4-((6-(3-(二丁基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(R)-2-Acetamido-3-(4-((6-(3-(dibutylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Preparation of methyl propionate

将实施例6中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为(R)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例6相同，得白色固体，收率:46.2％。m.p.171.9～173.8℃。(S)-2-acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl) amino) phenyl) methyl propionate in Example 6 is replaced by ( R)-methyl 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionate, other reaction conditions and steps and examples 6 is the same, to obtain a white solid, yield: 46.2%. m.p.171.9～173.8℃.

实施例11Example 11

2-乙酰氨基-3-(4-((6-(3-(二乙基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备2-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation of

(1)2-乙酰氨基-3-苯基丙酸的制备(1) Preparation of 2-acetylamino-3-phenylpropionic acid

将实施例1中步骤(1)L-苯丙氨酸替换为DL-苯丙氨酸，该步骤的其他反应条件与实施例1的步骤(1)相同，得黄色固体产物，收率:84.0％。Step (1) L-phenylalanine is replaced by DL-phenylalanine in Example 1, other reaction conditions of this step are identical with the step (1) of Example 1, obtain yellow solid product, yield: 84.0 %.

(2)2-乙酰氨基-3-(4-硝基苯基)丙酸的制备(2) Preparation of 2-acetylamino-3-(4-nitrophenyl)propionic acid

将实施例1中步骤(2)(S)-2-乙酰氨基-3-苯基丙酸替换为2-乙酰氨基-3-苯基丙酸，该步骤的其他反应条件与实施例1的步骤(2)相同，得黄色固体产物，收率:64.3％。Step (2) (S)-2-acetylamino-3-phenylpropionic acid in Example 1 is replaced by 2-acetylamino-3-phenylpropionic acid, other reaction conditions of this step are the same as those of Example 1 (2) the same, to obtain a yellow solid product, yield: 64.3%.

(3)2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯的制备(3) Preparation of 2-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester

将实施例1中步骤(3)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸替换为2-乙酰氨基-3-(4-硝基苯基)丙酸，该步骤的其他反应条件与实施例1的步骤(3)相同，得黄色固体，收率:92.0％。Step (3) (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid in Example 1 was replaced by 2-acetylamino-3-(4-nitrophenyl)propionic acid, The other reaction conditions of this step are the same as step (3) of Example 1 to obtain a yellow solid, yield: 92.0%.

(4)2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯的制备(4) Preparation of 2-acetylamino-3-(4-aminophenyl)propionic acid methyl ester

将实施例1中步骤(4)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(4)相同，得黄白色固体，收率:76.7％。Step (4) (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester in Example 1 is replaced by 2-acetylamino-3-(4-nitrophenyl)propane Acid methyl ester, other reaction conditions of this step are identical with the step (4) of embodiment 1, obtain yellow-white solid, yield: 76.7%.

(5)2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(5) Preparation of methyl 2-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propionate

将实施例1中步骤(5)(S)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(5)相同，得白色固体，收率:70.5％。In Example 1, step (5) (S)-2-acetylamino-3-(4-aminophenyl)propionic acid methyl ester is replaced by 2-acetylamino-3-(4-aminophenyl)propionic acid methyl Ester, other reaction conditions of this step are identical with the step (5) of embodiment 1, obtain white solid, yield: 70.5%.

(6)2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(6) Preparation of 2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中步骤(6)(S)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(6)相同，得黄色固体，收率:90.5％。Step (6) (S)-2-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propane in Example 1 Acid methyl ester is replaced with 2-acetamido-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid methyl ester, the rest of this step The reaction conditions were the same as step (6) of Example 1 to obtain a yellow solid with a yield of 90.5%.

(7)2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(7) Preparation of 2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中(7)(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(7)相同，得淡黄色固体，收率:72.5％。(7)(S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester in Example 1 Replaced with 2-acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl) amino) phenyl) propionic acid methyl ester, other reaction conditions and examples of this step Step (7) of 1 is the same to obtain a light yellow solid, yield: 72.5%.

(8)2-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(8) 2-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid Preparation of methyl esters

将实施例1中(8)(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(8)相同，得黄白色固体，收率:48.8％。m.p.179.9～181.8℃。(8)(S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino) in Example 1 Phenyl)propanoic acid methyl ester is replaced by 2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate, other reaction conditions of this step are identical with the step (8) of embodiment 1, obtain yellow-white solid, yield: 48.8%. m.p.179.9～181.8℃.

实施例12Example 12

2-乙酰氨基-3-(4-((6-(3-(二己氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备2-Acetamido-3-(4-((6-(3-(dihexylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation

将实施例2中(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例2相同，得白色固体，收率:40.5％。m.p191.1～193.6℃。In Example 2 (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate was replaced by methyl 2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionate Ester, other reaction conditions and steps are the same as in Example 2 to obtain a white solid, yield: 40.5%. m.p191.1～193.6℃.

实施例13Example 13

2-乙酰氨基-3-(4-((6-(3-(二辛基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备2-Acetamido-3-(4-((6-(3-(dioctylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation of

将实施例2中(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例3相同，得白色固体，收率:44.5％。m.p.206.0～208.9℃。In Example 2 (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate was replaced by methyl 2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionate Ester, other reaction conditions and steps are the same as in Example 3 to obtain a white solid, yield: 44.5%. m.p.206.0～208.9℃.

实施例14Example 14

2-乙酰氨基-3-(4-((6-(3-(二甲基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯2-Acetamido-3-(4-((6-(3-(dimethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester

将实施例4中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例4相同，得白色固体，收率:47.3％。m.p.171.7～174.6℃。In Example 4, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by 2 -Acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester, other reaction conditions and steps are the same as in Example 4, to obtain White solid, yield: 47.3%. m.p.171.7～174.6℃.

实施例15Example 15

2-乙酰氨基-3-(4-((6-(3-吗啉代丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备Preparation of methyl 2-acetylamino-3-(4-((6-(3-morpholinopropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionate

将实施例5中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例5相同，得白色固体，收率:33.7％。m.p.171.0～172.9℃。In Example 5, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by 2 -Acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester, other reaction conditions and steps are the same as in Example 5, to obtain White solid, yield: 33.7%. m.p.171.0～172.9℃.

实施例16Example 16

2-乙酰氨基-3-(4-((6-(3-(二丁基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备2-Acetamido-3-(4-((6-(3-(dibutylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation of

将实施例6中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例6相同，得白色固体，收率:51.2％。m.p.184.2～186.6℃。In Example 6, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by 2 -Acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester, other reaction conditions and steps are the same as in Example 6, to obtain White solid, yield: 51.2%. m.p.184.2～186.6℃.

实施例17Example 17

3-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备3-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation

(1)3-乙酰氨基-3-苯基丙酸的制备(1) Preparation of 3-acetylamino-3-phenylpropionic acid

将实施例1中步骤(2)L-苯丙氨酸替换为3-氨基-3-苯基丙酸，该步骤的其他反应条件与实施例1的步骤(2)相同，得黄色固体产物，收率:79.0％。Step (2) L-phenylalanine in Example 1 is replaced by 3-amino-3-phenylpropionic acid, other reaction conditions of this step are the same as step (2) of Example 1 to obtain a yellow solid product, Yield: 79.0%.

(2)3-乙酰氨基-3-(4-硝基苯基)丙酸的制备(2) Preparation of 3-acetylamino-3-(4-nitrophenyl)propionic acid

将实施例1中步骤(2)(S)-2-乙酰氨基-3-苯基丙酸替换为3-乙酰氨基-3-苯基丙酸，该步骤的其他反应条件与实施例1的步骤(2)相同，得黄色固体产物，收率:60.9％。Step (2) (S)-2-acetylamino-3-phenylpropionic acid in Example 1 is replaced by 3-acetylamino-3-phenylpropionic acid, other reaction conditions of this step are the same as those of Example 1 (2) the same, to obtain a yellow solid product, yield: 60.9%.

(3)3-乙酰氨基-3-(4-硝基苯基)丙酸甲酯的制备(3) Preparation of 3-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester

将实施例1中步骤(3)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸替换为3-乙酰氨基-3-(4-硝基苯基)丙酸，该步骤的其他反应条件与实施例1的步骤(3)相同，得黄色固体，收率:90.0％。Step (3) (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid in Example 1 was replaced by 3-acetylamino-3-(4-nitrophenyl)propionic acid, The other reaction conditions of this step are the same as step (3) of Example 1 to obtain a yellow solid, yield: 90.0%.

(4)3-乙酰氨基-3-(4-氨基苯基)丙酸甲酯的制备(4) Preparation of 3-acetylamino-3-(4-aminophenyl)propionic acid methyl ester

将实施例1中步骤(4)(S)-2-乙酰氨基-3-(4-硝基苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-硝基苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(4)相同，得黄白色固体，收率:77.0％。Step (4) (S)-2-acetylamino-3-(4-nitrophenyl)propionic acid methyl ester in Example 1 is replaced by 3-acetylamino-3-(4-nitrophenyl)propane Acid methyl ester, other reaction conditions of this step are identical with the step (4) of embodiment 1, obtain yellow-white solid, yield: 77.0%.

(5)3-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(5) Preparation of 3-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中步骤(5)(S)-2-乙酰氨基-3-(4-氨基苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-氨基苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(5)相同，得白色固体，收率:74.5％。In Example 1, step (5) (S)-2-acetylamino-3-(4-aminophenyl)propionic acid methyl ester is replaced by 3-acetylamino-3-(4-aminophenyl)propionic acid methyl Ester, other reaction conditions of this step are identical with the step (5) of embodiment 1, obtain white solid, yield: 74.5%.

(6)3-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(6) Preparation of 3-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中步骤(6)(S)-2-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-乙酰氧基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(6)相同，得黄色固体，收率:89.5％。Step (6) (S)-2-acetylamino-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl)amino)phenyl)propane in Example 1 Acid methyl ester is replaced with 3-acetamido-3-(4-((6-acetoxy-7-methoxyquinazolin-4-yl) amino) phenyl) propanoic acid methyl ester, the rest of this step The reaction conditions were the same as step (6) of Example 1 to obtain a yellow solid with a yield of 89.5%.

(7)3-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(7) Preparation of 3-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester

将实施例1中(7)(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(7)相同，得淡黄色固体，收率:70.5％。(7)(S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester in Example 1 Replaced with 3-acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl) amino) phenyl) propionic acid methyl ester, other reaction conditions and examples of this step Step (7) of 1 is the same to obtain a light yellow solid, yield: 70.5%.

(8)3-乙酰氨基-3-(4-((6-(3-(二乙氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备(8) 3-Acetamido-3-(4-((6-(3-(diethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid Preparation of methyl esters

将实施例1中(8)(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，该步骤的其他反应条件与实施例1的步骤(8)相同，得白色固体，收率:40.4％。m.p.166.6～168.3℃。(8)(S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino) in Example 1 Phenyl)propanoic acid methyl ester is replaced by 3-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate, other reaction conditions of this step are identical with the step (8) of embodiment 1, obtain white solid, yield: 40.4%. m.p.166.6～168.3℃.

实施例18Example 18

3-乙酰氨基-3-(4-((6-(3-(二己氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备3-Acetamido-3-(4-((6-(3-(dihexylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation

将实施例2中(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例2相同，得白色固体，收率:48.5％。m.p.191.3～192.9℃。In Example 2 (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate was replaced by methyl 3-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionate Ester, other reaction conditions and steps are the same as in Example 2 to obtain a white solid, yield: 48.5%. m.p.191.3～192.9℃.

实施例19Example 19

3-乙酰氨基-3-(4-((6-(3-(二辛基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备3-Acetamido-3-(4-((6-(3-(dioctylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation of

将实施例2中(S)-2-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-(3-氯丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例3相同，得白色固体，收率:43.2％。m.p.199.7～201.4℃。In Example 2 (S)-2-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl) Methyl propionate was replaced by methyl 3-acetylamino-3-(4-((6-(3-chloropropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionate Ester, other reaction conditions and steps were the same as in Example 3 to obtain a white solid, yield: 43.2%. m.p.199.7～201.4℃.

实施例20Example 20

3-乙酰氨基-3-(4-((6-(3-(二甲基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯3-Acetamido-3-(4-((6-(3-(dimethylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester

将实施例4中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例4相同，得白色固体，收率:47.3％。m.p.145.7～146.6℃。In Example 4, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by 3 -Acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester, other reaction conditions and steps are the same as in Example 4, to obtain White solid, yield: 47.3%. m.p.145.7～146.6℃.

实施例21Example 21

3-乙酰氨基-3-(4-((6-(3-吗啉代丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备Preparation of methyl 3-acetylamino-3-(4-((6-(3-morpholinopropoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propionate

将实施例5中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例5相同，得白色固体，收率:41.6％。m.p.148.5～150.1℃。In Example 5, (S)-2-acetylamino-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by 3 -Acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester, other reaction conditions and steps are the same as in Example 5, to obtain White solid, yield: 41.6%. m.p.148.5～150.1℃.

实施例22Example 22

3-乙酰氨基-3-(4-((6-(3-(二丁基氨基)丙氧基)-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯的制备3-Acetamido-3-(4-((6-(3-(dibutylamino)propoxy)-7-methoxyquinazolin-4-yl)amino)phenyl)propanoic acid methyl ester preparation of

将实施例6中(S)-2-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯替换为3-乙酰氨基-3-(4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)丙酸甲酯，其他反应条件及步骤与实施例6相同，得白色固体，收率:43.3％。m.p.152.6～153.9℃。In Example 6, (S)-2-acetylamino-3-(4-((6-hydroxy-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester was replaced by 3 -Acetamido-3-(4-((6-hydroxyl-7-methoxyquinazolin-4-yl)amino)phenyl)propionic acid methyl ester, other reaction conditions and steps are the same as in Example 6, to obtain White solid, yield: 43.3%. m.p.152.6～153.9℃.

将上述实施例合成的终化合物采用核磁共振氢谱测定结构，或高分辨质谱测定结构，结构如表1所示。The structures of the final compounds synthesized in the above examples were determined by proton nuclear magnetic resonance spectroscopy or high-resolution mass spectrometry, and the structures are shown in Table 1.

表1各个实施例合成的化合物的结构式及其结构测定结果The structural formula of the compound synthesized by each embodiment of table 1 and the structural determination result thereof

初步抗肿瘤生物活性评价试验Preliminary anti-tumor biological activity evaluation test

为进一步验证上述实施例的抗肿瘤生物活性，本试验选取实施例7、17、19制备的化合物，以市售吉非替尼(Gifitinib)作为对比，采用CCK-8检测法进行药理实验，其中，试验所用细胞株和培养基如表2所示。In order to further verify the antitumor biological activity of the above-mentioned examples, the compounds prepared in Examples 7, 17, and 19 were selected in this test, and compared with commercially available gefitinib (Gifitinib), the CCK-8 detection method was used to carry out pharmacological experiments, wherein , the cell lines and medium used in the test are shown in Table 2.

表2试验所用细胞株和培养基Table 2 The cell lines and medium used in the test

具体操作方法如下：The specific operation method is as follows:

将处于对数生长期的A549癌细胞消化种于96孔板中(8×104个·mL^-1)，置于37℃，5％CO₂条件下的培养箱中贴壁培养24h，弃去原培养基，按照如下组：正常组：不做任何处理；A549 cancer cells in the logarithmic growth phase were digested into 96-well plates (8×104 cells·mL^-1 ), placed in an incubator at 37°C and 5% CO₂ for 24 hours, and discarded. The original medium, according to the following groups: normal group: without any treatment;

溶剂对照组(若药物易溶于培养基无需设溶剂对照)：细胞培养基中加入DMSO使其浓度为0.2％；阳性药对照组：吉非替尼(0.5μM；1μM；5μM；10μM；25μM；50μM；100μM)；Solvent control group (if the drug is easily soluble in the culture medium, no solvent control is required): add DMSO to the cell culture medium to make the concentration 0.2%; positive drug control group: gefitinib (0.5 μM; 1 μM; 5 μM; 10 μM; 25 μM ; 50 μM; 100 μM);

给药组：药物按照浓度梯度0.5μM；1μM；5μM；10μM；25μM；50μM；100μM(每个药物浓度设6个复孔)，给药100μL，置于37℃，5％CO₂培养箱中；细胞培养48h/72h后，每孔加入CCK-8 10μL培养基置于培养箱中继续培养1h后，用酶标仪在450nm波长下测其OD值，计算存活率。Dosing group: drug according to the concentration gradient of 0.5 μM; 1 μM; 5 μM; 10 μM; 25_μM ; ; After the cells were cultured for 48h/72h, add 10 μL of CCK-8 culture medium to each well and place them in the incubator to continue to culture for 1h. Measure the OD value with a microplate reader at a wavelength of 450nm to calculate the survival rate.

使用统计学软件SPSS Statistics21处理，用其计算IC₅₀，检测结果如表3所示。The statistical software SPSS Statistics 21 was used for processing and IC₅₀ was calculated, and the detection results are shown in Table 3.

表3本发明的化合物对人A549肺癌细胞的生长抑制作用Table 3 Compounds of the present invention have growth inhibitory effect on human A549 lung cancer cells

由表3可以看出，对于A549细胞系，本发明实施例7、17、19制备的目标化合物的活性明显优于或相当于阳性对照Gefitinib，表明合成的目标化合物可成为抗肿瘤药物候选物。It can be seen from Table 3 that for the A549 cell line, the activity of the target compounds prepared in Examples 7, 17, and 19 of the present invention is significantly better than or equivalent to the positive control Gefitinib, indicating that the synthesized target compounds can become antitumor drug candidates.

本发明还对化合物7进行了溶解性测试，结果显示，化合物7易溶于水，且易溶于0.1mol/L HCl。The present invention also carried out a solubility test on compound 7, and the results showed that compound 7 was easily soluble in water, and easily soluble in 0.1mol/L HCl.

除此之外，还对化合物进行分子对接测试，分子对接结果显示，本发明的化合物与2ITY靶蛋白有良好的结合力。大部分目标化合物都是与氨基酸残基ASP-855和LYS-745形成氢键，少部分与氨基酸残基ASP-800、LYS-716和LYS-728形成氢键。L构型的目标化合物的最低结合自由能△G(kcal·mol^-1)普遍比DL构型和D构型的目标化合物高。例如：目标化合物19能很好地插入蛋白的结合口袋并与不同的氨基酸发生相互作用，主要为疏水作用和氢键作用(如图1中的A图和B图)。化合物19中乙酰氨基部分的氮和氧分别与ASP-855和LYS-745形成氢键，碳链和苯环部分与VAL-726、LEU-718和LEU-792形成疏水作用。Ledock软件对接结果与体外抗肿瘤活性实验结果基本符合，推测目标化合物的作用靶点为EGFR蛋白。In addition, a molecular docking test was also carried out on the compound, and the molecular docking results showed that the compound of the present invention has a good binding force with the 2ITY target protein. Most of the target compounds form hydrogen bonds with amino acid residues ASP-855 and LYS-745, and a small part form hydrogen bonds with amino acid residues ASP-800, LYS-716 and LYS-728. The minimum binding free energy △G(kcal·mol^-1 ) of the target compounds of L configuration is generally higher than that of the target compounds of DL configuration and D configuration. For example: the target compound 19 can be well inserted into the binding pocket of the protein and interact with different amino acids, mainly due to hydrophobic interactions and hydrogen bond interactions (Figures A and B in Figure 1). The nitrogen and oxygen of the acetamido part in compound 19 formed hydrogen bonds with ASP-855 and LYS-745, respectively, and the carbon chain and benzene ring formed hydrophobic interactions with VAL-726, LEU-718 and LEU-792. The docking results of the Ledock software were basically consistent with the results of the anti-tumor activity experiments in vitro, and it was speculated that the target compound was EGFR protein.

除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field of the invention. The terms used herein in the description of the present invention are for the purpose of describing specific embodiments only, and are not intended to limit the present invention. The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.

Claims (10)

Translated fromChinese

1.氨基酸衍生物，其特征在于，具有如下结构式中的一种：1. Amino acid derivatives, characterized in that they have one of the following structural formulas:

式中，-R₁选自氢或C1-C6烷烃中的一种；-R₂选自二甲氨丙基、N-吗啉丙基、二丁氨丙基、二乙氨丙基、二己氨丙基、二辛氨丙基中的一种；-R₃选自氢、乙酰基、丙酰基或丁酰基中的一种。In the formula, -R₁ is selected from one of hydrogen or C1-C6 alkane; -R₂ is selected from dimethylaminopropyl, N-morpholine propyl, dibutylaminopropyl, diethylaminopropyl, di One of hexylaminopropyl and dioctylaminopropyl;_-R3 is selected from one of hydrogen, acetyl, propionyl or butyryl.2.根据权利要求1所述的氨基酸衍生物，其特征在于，所述氨基酸衍生物选自如下结构式中的一种：2. The amino acid derivative according to claim 1, wherein the amino acid derivative is selected from one of the following structural formulas:

3.一种权利要求1-2任一项所述的氨基酸衍生物的制备方法，其特征在于，包括以下步骤：3. A method for preparing the amino acid derivative according to any one of claims 1-2, comprising the following steps:1)将化合物A1或B1溶解在氢氧化钠溶液中，常温下滴加酸酐进行酰化反应，分别得到化合物A2、B2，所述化合物A1的结构式为

所述化合物B1的结构式为

所述化合物A2的结构式为

所述化合物B2的结构式为

其中，-R₃选自乙酰基、丙酰基、丁酰基中的一种；1) Dissolving compound A1 or B1 in sodium hydroxide solution, adding acid anhydride dropwise at room temperature to carry out acylation reaction to obtain compounds A2 and B2 respectively, the structural formula of the compound A1 is

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, -R₃ is selected from the one in acetyl, propionyl, butyryl;2)将所述化合物A2、B2分别分批次加入混酸溶液中进行硝化反应，分别得化合物A3、B3，所述化合物A3的结构式为

所述化合物B3的结构式为

2) adding the compounds A2 and B2 in batches into the mixed acid solution for nitration reaction to obtain compounds A3 and B3 respectively, the structural formula of the compound A3 is

The structural formula of the compound B3 is

3)将所述化合物A3或B3溶解在醇溶液中，升温，缓慢滴加硫酸溶液进行酯化反应，分别得到化合物A4、B4，所述化合物A4的结构式为

所述化合物B4的结构式为：

其中，-R₁选自C1-C6烷烃中的一种；3) Dissolving the compound A3 or B3 in the alcohol solution, heating up, slowly adding sulfuric acid solution dropwise to carry out esterification reaction, to obtain compounds A4 and B4 respectively, the structural formula of the compound A4 is

The structural formula of the compound B4 is:

Wherein, -R₁ is selected from the one in C1-C6 alkane;4)将所述化合物A4或B4苯环上的硝基还原成氨基，分别得到化合物A5、B5，所述化合物A5的结构式为

所述B5的结构式为：

4) reducing the nitro group on the benzene ring of the compound A4 or B4 to an amino group to obtain compounds A5 and B5 respectively, and the structural formula of the compound A5 is

The structural formula of the B5 is:

5)将化合物C3与所述化合物A5或B5发生取代反应，得化合物A6或B6，所述化合物A6的结构式为

所述B6的结构式为：

所述化合物C3的结构式为

5) Compound C3 is subjected to a substitution reaction with the compound A5 or B5 to obtain the compound A6 or B6, and the structural formula of the compound A6 is

The structural formula of the B6 is:

The structural formula of the compound C3 is

6)将所述化合物A6或B6与氨水发生水解反应，得化合物A7或B7，所述化合物A7的结构式为

所述化合物B7的结构式为：

6) The compound A6 or B6 is hydrolyzed with ammonia water to obtain the compound A7 or B7, and the structural formula of the compound A7 is

The structural formula of the compound B7 is:

7)将所述化合物A7或B7与含有-R₂的化合物M发生取代反应，分别得到化合物A8、B8，所述化合物A8的结构式为

所述化合物B8的结构式为：

7) The compound A7 or B7 is subjected to a substitution reaction with the compound M containing -R₂ to obtain compounds A8 and B8 respectively, and the structural formula of the compound A8 is

The structural formula of the compound B8 is:

当-R₁为氢、-R₃为氢时，将所述化合物A8或B8与盐酸和冰醋酸发生水解反应，分别得化合物A9、B9，所述化合物A9的结构式为

所述化合物B9的结构式为

When -R₁ is hydrogen and -R₃ is hydrogen, the compound A8 or B8 is hydrolyzed with hydrochloric acid and glacial acetic acid to obtain compounds A9 and B9 respectively, and the structural formula of the compound A9 is

The structural formula of the compound B9 is

当-R₁为氢，-R₃为乙酰基、丙酰基或丁酰基中的一种，将所述化合物A8或B8与盐酸进行反应；When -R₁ is hydrogen, and -R₃ is one of acetyl, propionyl or butyryl, the compound A8 or B8 is reacted with hydrochloric acid;当-R₁为C1-C6烷烃中的一种，-R₃为氢，将化合物A9或B9按步骤4)的方式发生酯化反应。When -R₁ is one of the C1-C6 alkanes, and -R₃ is hydrogen, the compound A9 or B9 is subjected to an esterification reaction in the manner of step 4).4.根据权利要求3所述的制备方法，其特征在于，在步骤5)之前，还包括所述化合物C3的制备：将化合物C1与醋酐发生酰化反应，得化合物C2，所述化合物C1的结构式为

所述化合物C2的结构式为

将所述化合物C2与氯化亚砜发生卤化反应，得所述化合物C3。4. the preparation method according to claim 3, is characterized in that, before step 5), also comprises the preparation of described compound C3: acylation reaction occurs with compound C1 and acetic anhydride, obtains compound C2, and described compound C1 The structural formula is

The structural formula of the compound C2 is

The compound C2 is subjected to a halogenation reaction with thionyl chloride to obtain the compound C3.5.根据权利要求4所述的制备方法，其特征在于，所述化合物C1与醋酐发生酰化反应的反应温度为95～100℃，时间为4～5h。5 . The preparation method according to claim 4 , characterized in that, the reaction temperature of the acylation reaction between the compound C1 and acetic anhydride is 95-100° C. and the time is 4-5 hours.6.根据权利要求3所述的制备方法，其特征在于，步骤1)中所述化合物A1或B1与所述酸酐的用量摩尔比为1:1.5～1.8，反应时间为3～4h。6. The preparation method according to claim 3, characterized in that the molar ratio of the compound A1 or B1 to the acid anhydride in step 1) is 1:1.5-1.8, and the reaction time is 3-4h.7.根据权利要求3所述的制备方法，其特征在于，步骤2)中，所述混酸溶液为98％硫酸和68％硝酸按体积比为1.2：1相混合的酸液；和/或，步骤4)中，采用铁粉、氯化铵、无水乙醇、水和冰醋酸与所述化合物A4或B4进行硝基还原得到所述化合物A5或B5。7. The preparation method according to claim 3, characterized in that, in step 2), the mixed acid solution is an acid solution in which 98% sulfuric acid and 68% nitric acid are mixed in a volume ratio of 1.2:1; and/or, In step 4), use iron powder, ammonium chloride, absolute ethanol, water and glacial acetic acid to carry out nitro reduction with the compound A4 or B4 to obtain the compound A5 or B5.8.根据权利要求3所述的制备方法，其特征在于，步骤5)中所述化合物A5或B5与所述化合物C3发生取代反应的用量摩尔比为1:1.2～1.5，反应温度为90℃～100℃，反应时间为4～6h。8. The preparation method according to claim 3, characterized in that, the molar ratio of the compound A5 or B5 and the compound C3 in the substitution reaction of the compound A5 or B5 in step 5) is 1:1.2～1.5, and the reaction temperature is 90°C ~100°C, the reaction time is 4~6h.9.权利要求1-2任一项所述的氨基酸衍生物在制备抗癌药物中的应用。9. Use of the amino acid derivative according to any one of claims 1-2 in the preparation of anticancer drugs.10.根据权利要求9所述的应用，其特征在于，所述抗癌药物为抗肺癌药物。10. The application according to claim 9, characterized in that the anticancer drug is an anti-lung cancer drug.

Images