CN105884653A - 一种埃罗替尼衍生物及其制备方法 - Google Patents
一种埃罗替尼衍生物及其制备方法 Download PDFInfo
- Publication number
- CN105884653A CN105884653A CN201610404877.6A CN201610404877A CN105884653A CN 105884653 A CN105884653 A CN 105884653A CN 201610404877 A CN201610404877 A CN 201610404877A CN 105884653 A CN105884653 A CN 105884653A
- Authority
- CN
- China
- Prior art keywords
- isopropanol
- quinazoline
- bis
- chloro
- methoxy ethoxy
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 5
- 150000004923 Erlotinib derivatives Chemical class 0.000 title abstract 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims description 12
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 9
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 9
- 229960001433 erlotinib Drugs 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 241001597008 Nomeidae Species 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- FQQRNBROXUGYPQ-UHFFFAOYSA-N 2-(2-methoxyethoxy)quinazoline Chemical compound C1=CC=CC2=NC(OCCOC)=NC=C21 FQQRNBROXUGYPQ-UHFFFAOYSA-N 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 4
- 230000008685 targeting Effects 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract 2
- 239000012065 filter cake Substances 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 201000005202 lung cancer Diseases 0.000 abstract 1
- 208000020816 lung neoplasm Diseases 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- ZPJLDMNVDPGZIU-UHFFFAOYSA-N 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline Chemical compound C1=NC(Cl)=C2C=C(OCCOC)C(OCCOC)=CC2=N1 ZPJLDMNVDPGZIU-UHFFFAOYSA-N 0.000 description 5
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 4
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- YGKAANSUCZGMFU-UHFFFAOYSA-N 6,7-bis(2-methoxyethoxy)-n-(4-methoxyphenyl)quinazolin-4-amine Chemical group C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=C(OC)C=C1 YGKAANSUCZGMFU-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 1
- -1 6,7-bis-(2-methoxy ethoxy)-N-(4-methoxyphenyl) quinoline azoles Chemical class 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种埃罗替尼衍生物，结构式如式(Ⅰ)所示，化学名称为6,7‑二(2‑甲氧基乙氧基)‑N‑(4‑甲氧基苯基)喹唑啉‑4‑胺。该化合物的制备方法为：将4‑甲氧基苯胺和异丙醇混合，搅拌至完全溶解；在另一反应容器中加入4‑氯‑6,7‑二(2‑甲氧基乙氧基)喹唑啉和异丙醇，60‑80℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌20‑40min，冷却，抽滤，滤饼用冷的异丙醇洗两次，烘干得到成品，产品纯度高达98％以上，收率高达96％以上。本发明所提供的埃罗替尼衍生物，对肿瘤细胞具有良好的靶向性，尤其是对肺癌具有良好的抑制效果，且对人体的毒副作用更小。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种埃罗替尼衍生物及其制备方法。
背景技术
埃罗替尼为酪氨酸激酶的抑制剂，而酪氨酸激酶是治疗非小细胞肺癌所用药物的一个新靶点。埃罗替尼能够穿过细胞膜并和细胞内的三磷酸腺苷结合，从而遏制了细胞内酪氨酸激酶自磷酸化过程的进行和信号的传输，它能够选择性地遏制与EGFR相关的酪氨酸激酶的活性，使肿瘤细胞的黏附能力得以降低，并阻碍肿瘤细胞的侵袭、增殖和转移，阻止肿瘤细胞的生长，从而诱导肿瘤细胞走向凋亡。
埃罗替尼的衍生物同样对肿瘤细胞具有良好的靶向性，尤其是对肺癌具有良好的抑制效果，且对人体的毒副作用更小。
发明内容
本发明提供了一种埃罗替尼衍生物，对肿瘤细胞具有良好的靶向性，尤其是对肺癌具有良好的抑制效果，且对人体的毒副作用更小。
本发明所述埃罗替尼衍生物的分子结构式如式(Ⅰ)所示：
其化学名称为6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺。
本发明同时提供了式(Ⅰ)所示化合物的制备方法，包括如下步骤：
(1)在反应容器中加入4-甲氧基苯胺和异丙醇，搅拌至其完全溶解；
(2)在另一反应容器中加入4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉和异丙醇，60-80℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌20-40min,有大量白色固体析出，冷却，抽滤，固体用冷的异丙醇洗两次，烘干得到白色产物即为6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺。
作为优选，步骤(1)中所述异丙醇的投料体积为0.3-0.5L/mol 4-甲氧基苯胺。
作为优选，步骤(2)中所述4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉与4-甲氧基苯胺的投料摩尔比为1:1-1.5。
作为优选，步骤(2)中所述加料过程中异丙醇的投料体积为0.6-0.9L/mol 4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉。
本发明所述6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺的合成路线为：
本发明的有益效果为：
1.本发明所述的6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺对肿瘤细胞具有良好的靶向性，尤其是对肺癌具有良好的抑制效果，且对人体的毒副作用更小。
2、本发明所提供的制备方法，所得产品纯度高达98％以上，收率高达96％以上。
3、本发明的制备方法具有操作简单，反应时间短，反应收率高，环境污染小等优点。
具体实施方式
以下结合实施例来进一步解释本发明，但实施例并不对本发明做任何形式的限定。
实施例1
在反应容器中加入1mol 4-甲氧基苯胺，并用0.3L的异丙醇溶解，在另一反应容器中加入1mol 4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉和0.6L的异丙醇，60℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌20min,有大量白色固体析出，冷却，抽滤，固体用冷的异丙醇洗两次，烘干得到白色产物6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺，HPLC纯度为98.23％，收率为96.14％。
实施例2
在反应容器中加入1mol 4-甲氧基苯胺，并用0.4L的异丙醇溶解，在另一反应容器中加入1mol 4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉和0.9L的异丙醇，70℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌30min,有大量白色固体析出，冷却，抽滤，固体用冷的异丙醇洗两次，烘干得到白色产物6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺，HPLC纯度为98.45％，收率为96.35％
实施例3
在反应容器中加入1mol 4-甲氧基苯胺，并用0.3L的异丙醇溶解，在另一反应容器中加入1mol 4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉和0.8L的异丙醇，80℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌30min,有大量白色固体析出，冷却，抽滤，固体用冷的异丙醇洗两次，烘干得到白色产物6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺，HPLC纯度为98.56％，收率为97.15％。
实施例4
在反应容器中加入1mol 4-甲氧基苯胺，并用0.5L的异丙醇溶解，在另一反应容器中加入1mol 4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉和0.6L的异丙醇，80℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌40min,有大量白色固体析出，冷却，抽滤，固体用冷的异丙醇洗两次，烘干得到白色产物6,7-二(2-甲氧基乙氧基)-N-(4-甲氧基苯基)喹唑啉-4-胺，HPLC纯度为98.72％，收率为97.21％
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (5)
1.一种埃罗替尼衍生物，其分子结构式如式(Ⅰ)所示：
2.一种制备如权利要求1所述埃罗替尼衍生物的方法，其特征在于，所述制备方法包括如下步骤：
(1)在反应容器中加入4-甲氧基苯胺和异丙醇，搅拌至其完全溶解；
(2)在另一反应容器中加入4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉和异丙醇，60-80℃下搅拌溶解，待原料全部溶解后，缓慢滴加步骤(1)所得溶液，加毕继续搅拌20-40min,有大量白色固体析出，冷却，抽滤，固体用冷的异丙醇洗两次，烘干得到白色产物即为式(Ⅰ)所示化合物。
3.如权利要求2所述的制备方法，其特征在于，步骤(1)中所述异丙醇的投料体积为0.3-0.5L/mol 4-甲氧基苯胺。
4.如权利要求2所述的制备方法，其特征在于，步骤(2)中所述4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉与4-甲氧基苯胺的投料摩尔比为1:1-1.5。
5.如权利要求2所述的制备方法，其特征在于，步骤(2)中所述加料过程中异丙醇的投料体积为0.6-0.9L/mol 4-氯-6,7-二(2-甲氧基乙氧基)喹唑啉。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610404877.6A CN105884653A (zh) | 2016-06-08 | 2016-06-08 | 一种埃罗替尼衍生物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610404877.6A CN105884653A (zh) | 2016-06-08 | 2016-06-08 | 一种埃罗替尼衍生物及其制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105884653A true CN105884653A (zh) | 2016-08-24 |
Family
ID=56729117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610404877.6A Pending CN105884653A (zh) | 2016-06-08 | 2016-06-08 | 一种埃罗替尼衍生物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105884653A (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100351242C (zh) * | 1999-03-31 | 2007-11-28 | 辉瑞产品公司 | 制备抗癌化合物的方法和中间体 |
-
2016
- 2016-06-08 CN CN201610404877.6A patent/CN105884653A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100351242C (zh) * | 1999-03-31 | 2007-11-28 | 辉瑞产品公司 | 制备抗癌化合物的方法和中间体 |
Non-Patent Citations (3)
| Title |
|---|
| CHERNYAK, D.ETAL: "Employment of the TiCl4-Anisole-Pyridine System in the Condensation of Amides with Aromatic Amines", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS (NEW YORK, NY, UNITED STATES)》 * |
| SHEN, CHAO ETAL: "Synthesis of Benzimidazo[1,2-c]quinazolines via Metal-Free Intramolecular C-H Amination Reaction", 《INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH》 * |
| 徐浩等: "埃罗替尼衍生物的合成及抗肿瘤活性", 《中国药科大学学报》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108299422B (zh) | 一种帕泊昔利布中间体的制备方法 | |
| Mallela et al. | Zn (II), Cd (II) and Hg (II) metal complexes of 2-aminonicotinaldehyde: Synthesis, crystal structure, biological evaluation and molecular docking study | |
| CN105601635B (zh) | 巴瑞克替尼磷酸盐的a晶型、h晶型和i晶型及其制备方法 | |
| Mahmoud et al. | Synthesis, characterization, antimicrobial, and MOE evaluation of nano 1, 2, 4‐triazole‐based Schiff base ligand with some d‐block metal ions | |
| CN104326979A (zh) | 2-甲基-9-吖啶(对甲氧基苯甲酰胺基)硫脲及其制备方法和用途 | |
| CN109336866A (zh) | 一种多取代吡啶环类化合物其制备方法及应用 | |
| Santu et al. | An all-rounder aminoguanidine based ligand, its unusual anionic zinc (ii) and cadmium (ii) coordination complexes and their biological implications | |
| CN105884653A (zh) | 一种埃罗替尼衍生物及其制备方法 | |
| Ramesh et al. | Synthesis, characterization, crystal structure determination, computational modelling and biological studies of a new tetrakis-(2-hydroxy-5-methylphenyl)(1H-pyrazol-4-yl) methanonezinc (II) complex | |
| CN104910212A (zh) | 一种席夫碱铂配合物及其制备方法和应用 | |
| El-Kardocy et al. | Aryl azide-sulfonamide hybrids induce cellular apoptosis: synthesis and preliminary screening of their cytotoxicity in human HCT116 and A549 cancer cell lines | |
| CN115626936B (zh) | 一种精细调控发光波长配合物发光材料的合成方法 | |
| CN106045980A (zh) | 一种喹唑啉衍生物及其制备方法 | |
| CN108191920B (zh) | 一种具有荧光特性的罗丹明b修饰的半三明治铱配合物及其制备方法、应用 | |
| CN101502503B (zh) | 氟苯水杨酰胺类化合物在制备抗肿瘤药物中的应用 | |
| CN103992303B (zh) | 制备2-三氮唑-喹啉-4-羧酸化合物的方法 | |
| CN106083740B (zh) | 一种含1,2,3-三氮唑的4-苯胺基喹唑啉衍生物及制备方法 | |
| Debnath et al. | Study of an efficient conversion of 1, 3-dimethyl-5-(Arylazo)-6-Amino-Uracils to 1, 3-dimethyl-8-(Aryl)-Azapurin-2, 6-Diones | |
| CN107304187A (zh) | 一种奥拉帕尼的重结晶方法 | |
| CN106518941B (zh) | 糖基β-榄香烯衍生物及其制备方法和应用 | |
| CN107162880A (zh) | 一种4‑甲氧基苄氯的制备方法 | |
| CN105061317B (zh) | 一类吲唑盐类化合物及其制备方法和应用 | |
| CN111718327B (zh) | 一种含多个配位点的氮杂环嘧啶腙Zn(II)配合物及其制备方法和应用 | |
| Takimoto et al. | Simple Synthesis of a Heterocyclophane Exhibiting Anti‐c‐Met Activity by Acting as a Hatch Blocking Access to the Active Site | |
| CN102731376B (zh) | 一种吉美嘧啶晶型及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160824 |
|
| RJ01 | Rejection of invention patent application after publication |