CN116444505A - 一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法 - Google Patents
一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法 Download PDFInfo
- Publication number
- CN116444505A CN116444505A CN202310217070.1A CN202310217070A CN116444505A CN 116444505 A CN116444505 A CN 116444505A CN 202310217070 A CN202310217070 A CN 202310217070A CN 116444505 A CN116444505 A CN 116444505A
- Authority
- CN
- China
- Prior art keywords
- silybin
- derivative
- tetraacetate
- tumor activity
- compound
- 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
- 229940043175 silybin Drugs 0.000 title claims abstract description 67
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 title claims abstract description 57
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 title claims abstract description 55
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 235000014899 silybin Nutrition 0.000 title claims abstract description 55
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims abstract description 39
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 title abstract description 6
- -1 silybin ester Chemical class 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- MJOQJPYNENPSSS-XQHKEYJVSA-N [(3r,4s,5r,6s)-4,5,6-triacetyloxyoxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1CO[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O MJOQJPYNENPSSS-XQHKEYJVSA-N 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003607 modifier Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 125000000565 sulfonamide group Chemical group 0.000 abstract description 6
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 abstract description 5
- 239000005511 L01XE05 - Sorafenib Substances 0.000 abstract description 5
- 239000013641 positive control Substances 0.000 abstract description 5
- 229960003787 sorafenib Drugs 0.000 abstract description 5
- 229940124530 sulfonamide Drugs 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- 150000002611 lead compounds Chemical class 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 244000272459 Silybum marianum Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SEBFKMXJBCUCAI-WAABAYLZSA-N (2r,3r)-3,5,7-trihydroxy-2-[(2s,3s)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one Chemical compound C1=C(O)C(OC)=CC([C@H]2[C@@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-WAABAYLZSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
- 235000019606 astringent taste Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法，涉及一种抗肿瘤衍生物及其制备方法，本发明通过对天然产物水飞蓟宾的化学结构改造及修饰，得到一系列具有抗肿瘤活性的新型水飞蓟宾磺胺衍生物。以水飞蓟宾为先导化合物，将羟基乙酰化，得到3,5,7,20,23‑五乙酸水飞蓟宾酯，得到3,5,20,23‑四乙酸水飞蓟宾磺酸酯，最后通过在C‑7位拼合磺胺基团，设计合成了15个新型水飞蓟宾磺胺衍生物I1～I15。MTT实验结果显示，水飞蓟宾磺胺衍生物对HepG‑2的抑制率均优于母体水飞蓟宾，其中化合物I1对HepG‑2有明显的抑制作用，抑制率优于阳性对照物Sorafenib。实验表明，此类化合物可增强抗肿瘤活性。
Description
技术领域
本发明涉及一种抗肿瘤衍生物及其制备方法，特别是涉及一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法。
背景技术
水飞蓟宾(Silybin)是从植物水飞蓟种子中提取的一种黄酮木脂素，由两种非对映异构体水飞蓟宾A和水飞蓟宾B构成等比例混合组成。分子式：C25H22O10，分子量：482.436。熔点：164-174℃，密度：1.527g/cm3。水飞蓟宾纯品为类白色结晶粉末，无臭、味微苦涩，有引湿性。易溶于丙酮、乙酸乙酯、甲醇、乙醇，略溶于氯仿，几乎不溶于水。水飞蓟宾具有稳定肝细胞膜、抗肝纤维化、清除氧自由基、抗肿瘤和抗病毒等生物活性，目前临床上主要用于肝胆系统疾病的治疗。最新研究表明水飞蓟宾对肺癌、前列腺癌、肝癌等具有一定的抑制活性。
水飞蓟宾的化学结构式:
发明内容
本发明的目的在于提供一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法，本发明以水飞蓟宾为先导化合物，通过在C-7位拼合磺胺基团，设计合成了15个新型水飞蓟宾磺胺衍生物I1～I15。体外抗肿瘤活性测试结果显示，水飞蓟宾拼合磺胺结构的衍生物I1、I3、I4可提高抗肿瘤活性，优于阳性对照药Sorafenib。
本发明的目的是通过以下技术方案实现的：
一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物，所述衍生物为对C-7位羟基的结构改造，得到一系列水飞蓟宾类似物I1～I15，所述水飞蓟宾化学修饰物如下：
C-7位引入基团R如下表所示：
一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物制备方法，所述方法包括以下制备过程：
(1)以水飞蓟宾为反应原料，乙酸酐作为酰化试剂，在DMAP的催化下合成3,5,7,20,23-五乙酸水飞蓟宾酯；
(2)将中间体3,5,7,20,23-五乙酸水飞蓟宾酯溶于吡啶中，与丙胺反应30s后立即淬灭反应，TLC检测反应终点，得到3,5,20,23-四乙酸水飞蓟宾酯；
(3)将化合物3,5,20,23-四乙酸水飞蓟宾酯在DCM中三乙胺的催化下与磺酰氯反应，得到3,5,20,23-四乙酸水飞蓟宾磺酸酯；
(4)将3,5,20,23-四乙酸水飞蓟宾磺酸酯与相应的胺反应得到目标化合物I1～I15。
本发明的优点与效果是：
本发明以水飞蓟宾为先导化合物，将羟基乙酰化，得到3,5,7,20,23-五乙酸水飞蓟宾酯，随后在丙胺中发生淬灭反应，将C-7位还原成羟基，产物在DCM中三乙胺的催化下与磺酰氯反应，得到3,5,20,23-四乙酸水飞蓟宾磺酸酯，最后通过在C-7位拼合磺胺基团，设计合成了15个新型水飞蓟宾磺胺衍生物I1～I15。体外抗肿瘤活性测试结果显示，水飞蓟宾拼合磺胺结构的衍生物I1、I3、I4可提高抗肿瘤活性，优于阳性对照药Sorafenib。
具体实施方式
下面结合实施例对本发明进行详细说明。
1.水飞蓟种粕以正己烷预脱脂后，以无水乙醇作为提取溶剂，加热溶解，活性炭脱色，滤液放置析出白色结晶，乙酸乙酯-甲醇重结晶得水飞蓟宾。
2.将水飞蓟宾溶解在吡啶溶液中，室温下搅拌，在乙酸酐与DMAP的条件下将反应混合物在室温下继续搅拌。反应结束后，向混合物中加入冰水，快速搅拌，抽滤并洗涤滤饼，干燥得3,5,7,20,23-五乙酸水飞蓟宾酯。
3.将3,5,7,20,23-五乙酸水飞蓟宾酯溶于吡啶溶液中，在冰浴条件下滴加丙胺溶液，搅拌30s，立即加入冰醋酸淬灭反应。将反应混合物缓慢倒入冰水中，快速搅拌，抽滤并洗涤滤饼，干燥得3,5,20,23-四乙酸水飞蓟宾酯。
4.将3,5,20,23-四乙酸水飞蓟宾酯溶于二氯甲烷溶液中，室温下搅拌，随后加入磺酰氯与NaH，室温下反应得淡黄色液体,减压蒸发溶剂,粗品在甲醇中重结晶,过滤、干燥得3,5,20,23-四乙酸水飞蓟宾磺酸酯。
5.将3,5,20,23-四乙酸水飞蓟宾磺酸酯溶于二氯甲烷溶液中,加入正戊胺，随后加入三乙胺催化，室温下搅拌。反应结束后，过滤除去沉淀物，减压蒸发溶剂，粗品在甲醇中重结晶，过滤、干燥得I1。按照I1合成方法，引入不同基团，合成I2～I15。
其中R为正戊胺基、间硝基苯胺基、间氟苯胺基、异戊胺基、邻溴苯胺基、苯胺基、对甲氧基苯胺基、间氯苯胺基、3,4-二硝基苯胺基、4-氨基二苯甲酮基、2-碘苯胺基、3-溴苯胺基、4-氟苯胺基、对甲苯胺基、对氯苯胺基。
以Sorafenib为阳性对照物,采用四甲基偶氮唑盐法(MTT比色法)对合成的化合物进行初步的体外抗肿瘤活性测试，化合物的体外实验结果如下表:
注：a.化合物浓度分别在100μM、10μM时测得的抑制率。b.IC50表示半数有效抑制浓度。
MTT实验结果显示，药物浓度在10与100μmol·L-1时对HepG-2的抑制率均优于母体水飞蓟宾，因此在C-7位引入磺胺结构可提高化合物的抗肿瘤活性。在C-7位连接脂肪烃取代基的化合物I1、I4比芳香烃侧链化合物具有更好的抗肿瘤活性，且随着取代基碳数的增加，其抗肿瘤活性也随之增加。其中化合物I1对HepG-2的有明显的抑制作用，抑制率优于阳性对照物Sorafenib。
下面举例说明：
实例1
3,5,7,20,23-五乙酸水飞蓟宾酯的合成：
将水飞蓟宾(0.9640g,2mmol)溶解在10mL吡啶溶液中，在室温下搅拌，随后加入乙酸酐(2mL,3.5mmol)与5mgDMAP，将反应混合物在室温下继续搅拌5min，TLC检测反应终点。反应结束后，将100mL冰水倒入混合物中，快速搅拌析出白色固体，抽滤，用水洗涤滤饼，干燥得1.3650g白色粉末状固体即化合物3,5,7,20,23-五乙酸水飞蓟宾酯。产率99％,mp 111～117℃。
实例2
3,5,20,23-四乙酸水飞蓟宾酯的合成：
将化合物3,5,7,20,23-五乙酸水飞蓟宾酯(1.3840g,2mmol)溶于10mL吡啶溶液中，在冰浴条件下滴加丙胺溶液(0.33mL,4mmol)，搅拌30s，立即加入冰醋酸(0.23mL,4mmol)淬灭反应。将反应混合物缓慢倒入200mL冰水中，快速搅拌析出白色固体，抽滤，用水洗涤滤饼，干燥得1.2790g白色粉末状固体即化合物3,5,20,23-四乙酸水飞蓟宾酯。产率98％，mp 132～135℃。
实例3
3,5,20,23-四乙酸水飞蓟宾磺酸酯：
将化合物3,5,20,23-四乙酸水飞蓟宾酯(0.3250g,0.5mmol)溶于5mL二氯甲烷溶液中，在室温下搅拌，随后加入磺酰氯(0.0525mL,0.6mmol)与NaH(0.024g,0.5mmol)室温反应1h。得淡黄色液体，减压蒸发溶剂(DCM)，粗品在15mL甲醇中重结晶，过滤、干燥得0.2656g淡黄色片状固体即化合物3,5,20,23-四乙酸水飞蓟宾磺酸酯。产率:71％，mp 125～128℃。1HNMR(600MHz,DMSO-d6):δ7.91(dd,J＝3.5,0.8Hz),7.28,7.24(d,J＝0.6Hz),6.99,6.91–6.90(m),6.88(d,J＝1.0Hz,1H),6.82,6.70(t,J＝3.0Hz),6.10,5.32(d,J＝0.7Hz),5.14,4.65(d,J＝4.1Hz),4.33(dd,J＝3.9,1.4Hz,1H),4.24(d,J＝1.7Hz),3.78,2.21(s,3H),2.17(s,3H),2.10(s,3H),2.03(s,3H).；ESI-MS m/z[M+Na]+:771.12.
实例4
化合物I1：7-N-戊基磺酰胺基-3,5,20,23-四乙酸水飞蓟宾酯的合成：
将化合物3,5,20,23-四乙酸水飞蓟宾磺酸酯(0.7481g，0.5mmol)溶于5mL二氯甲烷溶液中，加入正戊胺(0.0580mL，0.5mmol)，随后加入三乙胺(0.2770mL，1.5mmol)催化，室温下搅拌1.5h，TLC检测反应终点。反应结束后，过滤除去沉淀物(三乙胺盐酸盐)，减压蒸发溶剂(THF)，残余物在15mL甲醇中重结晶，过滤、干燥得0.2558g黄色粉末状固体I1。产率：64％，mp 110-127℃。1HNMR(600MHz,DMSO-d6):δ7.35–6.89(m,6H),6.31(d,J＝2.3Hz,1H),6.26(d,J＝2.2Hz,1H),5.76(t,J＝12.1Hz,1H),5.50(d,J＝12.2Hz,1H),5.14(t,1H),4.66–4.59(m,1H),4.20(s,1H),4.14(d,J＝11.8Hz,1H),3.88(dd,J＝12.7,5.1Hz,1H),3.79(s,3H),2.87(t,2H),2.28(s,3H),2.26(s,3H),2.01(s,3H),1.96(s,3H),1.52(m,J＝7.0Hz,2H),1.29(m,J＝7.4Hz,2H),1.28(m,J＝7.1Hz,2H),0.88(t,J＝7.5Hz,3H)；ESI-MSm/z[M+Na]+:799.18.
实例5
化合物I4：7-N-(3-硝基苯基)磺酰胺基-3,5,20,23-四乙酸水飞蓟宾酯的合成：
将化合物3,5,20,23-四乙酸水飞蓟宾磺酸酯(0.7481g，0.5mmol)溶于5mL二氯甲烷溶液中，加入异戊胺(0.0580mL，0.5mmol)，随后加入三乙胺(0.2770mL，1.5mmol)催化，室温下搅拌1.5h，TLC检测反应终点。反应结束后，过滤除去沉淀物(三乙胺盐酸盐)，减压蒸发溶剂(THF)，残余物在15mL甲醇中重结晶，过滤、干燥得0.1839g黄色片状固体化合物I4。产率：46％，mp 120-124℃。1HNMR(600MHz,DMSO-d6):δ7.35–6.89(m,6H),6.31(d,J＝2.3Hz,1H),6.26(d,J＝2.2Hz,1H),5.76(t,J＝12.1Hz,1H),5.52(d,J＝12.1Hz,1H),5.11(t,1H),4.94–4.69(m,1H),4.20(s,1H),4.14(d,J＝11.6Hz,1H),3.98(dd,J＝12.4,5.1Hz,1H),3.79(s,3H),2.87(t,,J＝6.8Hz,2H),2.27(s,3H),2.26(s,3H),2.01(s,3H),1.96(s,3H),1.59(m,J＝7.3Hz,2H)1.53(m,J＝7.0Hz,2H),0.91(d,J＝2.3Hz,6H)。
Claims (2)
1.一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物，其特征在于，所述衍生物为对C-7位羟基的结构改造，得到一系列水飞蓟宾类似物I1～I15，所述水飞蓟宾化学修饰物如下：
C-7位引入基团R如下表所示：
2.一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物制备方法，其特征在于，所述方法包括以下制备过程：
(1)以水飞蓟宾为反应原料，乙酸酐作为酰化试剂，在DMAP的催化下合成3,5,7,20,23-五乙酸水飞蓟宾酯；
(2)将中间体3,5,7,20,23-五乙酸水飞蓟宾酯溶于吡啶中，与丙胺反应30s后立即淬灭反应，TLC检测反应终点，得到3,5,20,23-四乙酸水飞蓟宾酯；
(3)将化合物3,5,20,23-四乙酸水飞蓟宾酯在DCM中三乙胺的催化下与磺酰氯反应，得到3,5,20,23-四乙酸水飞蓟宾磺酸酯；
(4)将3,5,20,23-四乙酸水飞蓟宾磺酸酯与相应的胺反应得到目标化合物I1～I15。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310217070.1A CN116444505A (zh) | 2023-03-08 | 2023-03-08 | 一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310217070.1A CN116444505A (zh) | 2023-03-08 | 2023-03-08 | 一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116444505A true CN116444505A (zh) | 2023-07-18 |
Family
ID=87131066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310217070.1A Pending CN116444505A (zh) | 2023-03-08 | 2023-03-08 | 一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116444505A (zh) |
-
2023
- 2023-03-08 CN CN202310217070.1A patent/CN116444505A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP4212509A1 (en) | Method for preparing water-soluble magnolol derivative and honokiol derivative, methods for preparing intermediates of water-soluble magnolol derivative and honokiol derivative, and related monohydroxy protected intermediate | |
| CN106977415B (zh) | 一种沙库必曲的中间体及其制备方法 | |
| CN113416189B (zh) | 一类β-卡波林氮芥衍生物、制备方法和抗肿瘤用途 | |
| KR100346672B1 (ko) | 3-o-치환 아스코르브산의 제조방법 | |
| CN113173857B (zh) | 一种大麻二酚衍生物及其制备方法与应用 | |
| CN107722101A (zh) | 甾体吡啶类衍生物及其制备方法和应用 | |
| CN116444505A (zh) | 一种具有抗肿瘤活性的水飞蓟宾磺胺衍生物及其制备方法 | |
| CN114057710B (zh) | 一种具有抗肿瘤活性的水飞蓟宾化学修饰物及其制备方法 | |
| CN114315813B (zh) | 一种抗糖尿病活性的水飞蓟宾化学修饰物及其制备方法 | |
| CN112645863B (zh) | 二吡咯甲烯-1-酮类化合物及其制备方法 | |
| CN113845485A (zh) | 氨基酸衍生物及其制备方法和应用 | |
| CN108101892B (zh) | 一种白杨素非天然氨基酸衍生物及其制备方法和应用 | |
| EP4083045B1 (en) | Novel method for synthesizing decursin derivative | |
| CN113788809B (zh) | 一类色原酮的3位拼合氮芥衍生物与应用 | |
| CN114805168B (zh) | 吡咯啉酮类化合物及其合成方法 | |
| CN111333513B (zh) | 一种2,4-二氟-3-硝基苯甲酸的制备方法 | |
| CN114560845B (zh) | 喹啉化合物的晶型ɑ及其制备方法和应用 | |
| CN113956267B (zh) | 一种抗肿瘤药物依喜替康甲磺酸盐的制备方法 | |
| CN112480026B (zh) | Ae-活性酯的制备方法 | |
| KR101794970B1 (ko) | 신규한 뉴클레오시드 유도체 | |
| CN111253323A (zh) | 去氢枞酸嘧啶衍生物及其制备方法和应用 | |
| KR100966027B1 (ko) | 데커신 및 데커신 유사체의 신규한 제조방법 | |
| CN116425731A (zh) | 一种具有抗前列腺癌活性水飞蓟宾衍生物及其制备方法 | |
| CN116478160A (zh) | 恶唑酮类苦参碱衍生物及其制备方法与应用 | |
| CN116283853A (zh) | 一种合成立他司特的有关物质的中间体及其制备方法及立他司特的有关物质的制备方法 |
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 |