CN108997232A - 一种组蛋白去乙酰化酶抑制剂的合成方法 - Google Patents
一种组蛋白去乙酰化酶抑制剂的合成方法 Download PDFInfo
- Publication number
- CN108997232A CN108997232A CN201810865552.7A CN201810865552A CN108997232A CN 108997232 A CN108997232 A CN 108997232A CN 201810865552 A CN201810865552 A CN 201810865552A CN 108997232 A CN108997232 A CN 108997232A
- Authority
- CN
- China
- Prior art keywords
- hdac
- enester
- synthetic method
- configuration
- histon deacetylase
- 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.)
- Granted
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 31
- -1 cinnamyl nitrine Chemical compound 0.000 claims abstract description 29
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 150000003852 triazoles Chemical class 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000003512 tertiary amines Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 238000007699 photoisomerization reaction Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 abstract description 2
- 238000005576 amination reaction Methods 0.000 abstract description 2
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- 230000021615 conjugation Effects 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 150000002240 furans Chemical class 0.000 abstract description 2
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 abstract 3
- 150000000177 1,2,3-triazoles Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- 229940096395 DNA methylase inhibitor Drugs 0.000 description 1
- 229940122964 Deacetylase inhibitor Drugs 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- IILXTLMEJJIBSG-NUXDXBQRSA-N ONC(/C=C/c1c[n](C/C=C/c2ccccc2)nn1)=O Chemical compound ONC(/C=C/c1c[n](C/C=C/c2ccccc2)nn1)=O IILXTLMEJJIBSG-NUXDXBQRSA-N 0.000 description 1
- 235000019082 Osmanthus Nutrition 0.000 description 1
- 241000333181 Osmanthus Species 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 239000003968 dna methyltransferase inhibitor Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XPFVYQJUAUNWIW-UHFFFAOYSA-N furfuryl alcohol Substances OCC1=CC=CO1 XPFVYQJUAUNWIW-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-N iodic acid Chemical compound OI(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种组蛋白去乙酰化酶抑制剂的合成方法，该化合物的结构式为
Description
技术领域
本发明涉及一种组蛋白去乙酰化酶抑制剂NSC746457(histone deacetylases，HDACi)的合成方法。
背景技术
随着药物发现、细胞信号分子探针的发展，如何快速并高效地合成杂环化合物已经成为当前该领域中的热点问题。组蛋白去乙酰化酶(histone deacetylase)是一类蛋白酶，它对染色体的结构修饰和基因的相关表达发挥着重要的作用。当前在肿瘤学的相关研究已经表明，组蛋白的乙酰化修饰对肿瘤的发生发展起重要作用。正常细胞体若出现核内组蛋白乙酰化与去乙酰化失去失衡，即会导致正常的细胞周期与细胞代谢行为的改变进而诱发形成肿瘤。组蛋白去乙酰化酶抑制剂通过增加细胞内组蛋白的乙酰化程度，提高p21等基因的表达水平等途径，抑制肿瘤细胞的增殖，诱导细胞分化和(或)凋亡。组蛋白去乙酰化酶抑制剂是一种新型有效的抗肿瘤治疗药物，具有极大的临床及社会应用价值，已成为肿瘤靶向治疗的研究新热点，其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实。
组蛋白去乙酰化酶抑制剂NSC746457的结构式如下所示：
其合成方法的关键是对1,2,3-三氮唑的合成。在之前的相关报道中1,2,3-三氮唑的合成主要是通过1,3-偶极子叠氮-炔环加成反应(AAC)，但反应前体的多步合成限制了它的进一步应用。对于该抑制剂，已报道的合成方法需要以丙炔酸作为原料，通过对其氢碘化构筑反式碘代双键；Sonogashira偶联构筑共轭的炔；click反应构筑三唑。显而易见，多步合成非常繁琐。没有以廉价易得的化合物为起始原料，通过简单并直接的办法去合成该抑制剂。
发明内容
本发明所要解决的技术问题在于克服现有合成组蛋白去乙酰化酶抑制剂NSC746457的起始原料复杂、合成路线长、反应产率低、反应条件苛刻等缺点，提供一种简单高效的合成组蛋白去乙酰化酶抑制剂NSC746457的方法。
解决上述技术问题所采用的技术方案由下述步骤组成：
1、合成(Z)-构型的烯酯三唑
以二氯甲烷为溶剂，将5-溴代-2-糠醇、肉桂基叠氮、甲醇在路易斯酸和叔胺的作用下，-20℃～室温反应，反应结束后经减压浓缩、分离纯化，得到式I所示的(Z)-构型的烯酯三唑化合物。
2、合成(E)-构型的烯酯三唑化合物
将式I所示的(Z)-构型的烯酯三唑化合物溶于氯仿，在紫外光照下使(Z)-构型的烯酯三唑化合物发生光异构化反应，得到式II所示的(E)-构型的烯酯三唑化合物。
3、将式II所示的(E)-构型的烯酯三唑化合物溶于甲醇与四氢呋喃体积比为1:1的混合溶剂中，加入盐酸羟胺和氢氧化钠水溶液，将反应物倒入冰水混合物中，再加入酸析出白色固体，过滤、洗涤，得到组蛋白去乙酰化酶抑制剂。
上述步骤1中，所述的路易斯酸为SnCl4，所述的叔胺为吡啶、三乙胺或N,N-二异丙基乙胺。
上述步骤1中，优选5-溴代-2-糠醇、肉桂基叠氮、甲醇的摩尔比为1:1.1～1.5:1.3～2.0，SnCl4的加入量为5-溴代-2-糠醇摩尔量的1～1.3倍，叔胺的加入量为5-溴代-2-糠醇摩尔量的1.3～2.0倍。
上述步骤2中，所述的紫外光照波段为385～395nm，光照时间为3～5h。
上述步骤3中，优选(E)-构型的烯酯三唑化合物与盐酸羟胺、氢氧化钠的摩尔比为1:7～10:5～7，所述酸为浓盐酸。
本发明的有益效果如下：
本发明以肉桂基叠氮、5-溴-2-糠醇和甲醇为反应原料，在路易斯酸的作用下，通过一锅三组分反应合成高度官能团化的(Z)-构型的烯酯三唑。在这个新骨架生成反应中，涉及到一个[3+2]环加成/呋喃开环/酯化串联反应。在紫外光照条件下(Z)-构型的烯酯三唑发生光反应异构化生成(E)-构型的烯酯三唑，接下来用盐酸羟胺对(E)-构型的烯酯三唑进行取代胺化，即可得到组蛋白去乙酰化酶抑制剂NSC746457。本发明方法具有合成路线短、原料易得、合成过程用时短、目标化合物产率高、成本低廉等优点。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施例。
实施例1
1、合成(Z)-构型的烯酯三唑
向25mL的圆底烧瓶里加入176mg(1.0mmol)5-溴-2-呋喃甲醇、191mg(1.2mmol)肉桂基叠氮、48mg(1.5mmol)甲醇、152mg(1.5mmol)三乙胺、5mL干燥的二氯甲烷，搅拌1min使混合均匀，然后将反应液置于冰水浴中，加入1.1mL1mol/L SnCl4的二氯甲烷溶液，再将反应液转移至室温下反应，并用薄层色谱法进行监测。待反应完全后，将反应物用饱和碳酸氢钠水溶液淬灭，然后用20mL二氯甲烷稀释，分离出有机相，将水相转移到分液漏斗中用二氯甲烷萃取(10mL×2次)，合并有机层。有机相用10mL饱和食盐水清洗两次，分离有机相，用无水硫酸钠干燥2h。过滤、浓缩后得到(Z)-构型的烯酯三唑化合物粗品，该粗品用硅胶柱色谱法纯化(石油醚:乙酸乙酯＝10:1作为洗脱剂)，得到式I所示的纯净的(Z)-构型的烯酯三唑化合物145mg，其收率为54％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.73(s,1H),7.66(d,J＝16.0Hz,1H),7.39(d,J＝7.2Hz,2H),7.35(t,J＝7.4Hz,2H),7.31(d,J＝7.1Hz,1H),6.68(t,J＝15.6Hz,2H),6.37-6.30(m,1H),5.16(dd,J＝6.7,1.1Hz,2H),3.79(s,3H)；13CNMR(151MHz,CDCl3)δ167.12,143.78,135.95,135.25,132.56,128.79,128.73,126.74,122.95,121.27,119.62,52.47,51.77；HRMS(ESI)C15H15N3NaO2[M+Na]+:理论值292.1062,实测值292.1066。
2、合成(E)-构型的烯酯三唑化合物
将纯净的(Z)-构型的烯酯三唑化合物置于20mL反应管中，加入4mL氯仿作为反应溶剂，在50W紫色LED(λem＝385～395nm)灯光下持续照射4h，并采用薄层色谱法进行监测，待反应完全后，用旋转蒸发仪蒸除溶剂氯仿，浓缩得到(E)-构型的烯酯三唑化合物粗品，该粗品用硅胶柱色谱法纯化(石油醚:乙酸乙酯＝100:1作为洗脱剂)，得到式II所示的纯净的(E)-构型的烯酯三唑化合物85.2mg，其产率为59％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.73(s,1H),7.66(d,J＝16.0Hz,1H),7.39(d,J＝7.2Hz,2H),7.35(t,J＝7.4Hz,2H),7.31(d,J＝7.1Hz,1H),6.68(t,J＝15.6Hz,2H),6.37-6.30(m,1H),5.16(dd,J＝6.7,1.1Hz,2H),3.79(s,3H)；13C NMR(151MHz,CDCl3)δ167.12,143.78,135.95,135.25,132.56,128.79,128.73,126.74,122.95,121.27,119.62,52.47,51.77；HRMS(ESI)C15H15N3NaO2[M+Na]+:理论值292.1062,实测值292.1066。
3、合成组蛋白去乙酰化酶抑制剂
向25mL的圆底烧瓶里加入80.7mg(0.3mmol)(E)-构型的烯酯三唑化合物、5mL甲醇与四氢呋喃体积比为1:1的混合液、0.3mL质量分数为50％的盐酸羟胺水溶液和0.3mL5mol/L氢氧化钠水溶液，在冰盐浴中反应2min后，将反应液倒入3mL冰水，再加入0.6mL浓盐酸，将会有白色固体析出，过滤出白色固体，并用甲醇进行洗涤，即得到式III所示的纯净的组蛋白去乙酰化酶抑制剂NSC74645768mg，其产率为84.4％，结构表征数据为：1H NMR(600MHz,DMSO)δ10.25(s,1H),8.59(s,1H),7.63(d,J＝16.0Hz,1H),7.48(d,J＝7.4Hz,2H),7.35(t,J＝7.3Hz,2H),7.28(t,J＝7.1Hz,1H),6.70(d,J＝15.8Hz,1H),6.63(d,J＝16.0Hz,1H),6.56-6.48(m,1H),5.22(d,J＝6.3Hz,2H)；13C NMR(151MHz,DMSO)δ166.44,142.65,135.73,134.15,133.50,128.73,128.25,126.67,125.55,123.25,118.15,51.59；HRMS(ESI)C14H14N4NaO2[M+Na]+:理论值293.1014,实测值293.1011。
Claims (9)
1.一种组蛋白去乙酰化酶抑制剂的合成方法，该化合物的结构式如下所示：
其特征在于：
(1)合成(Z)-构型的烯酯三唑
以二氯甲烷为溶剂，将5-溴代-2-糠醇、肉桂基叠氮、甲醇在路易斯酸和叔胺的作用下，-20℃～室温反应，反应结束后经减压浓缩、分离纯化，得到式I所示的(Z)-构型的烯酯三唑化合物；
(2)合成(E)-构型的烯酯三唑化合物
将式I所示的(Z)-构型的烯酯三唑化合物溶于氯仿，在紫外光照下使(Z)-构型的烯酯三唑化合物发生光异构化反应，得到式II所示的(E)-构型的烯酯三唑化合物；
(3)将式II所示的(E)-构型的烯酯三唑化合物溶于甲醇与四氢呋喃体积比为1:1的混合溶剂中，加入盐酸羟胺和氢氧化钠水溶液，将反应物倒入冰水混合物中，再加入酸析出白色固体，过滤、洗涤，得到组蛋白去乙酰化酶抑制剂。
2.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(1)中，所述的路易斯酸为SnCl4。
3.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(1)中，所述的叔胺为吡啶、三乙胺或N,N-二异丙基乙胺。
4.根据权利要求1～3任意一项所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(1)中，所述的5-溴代-2-糠醇、肉桂基叠氮、甲醇的摩尔比为1:1.1～1.5:1.3～2.0。
5.根据权利要求1～3任意一项所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(1)中，所述的SnCl4的加入量为5-溴代-2-糠醇摩尔量的1～1.3倍。
6.根据权利要求1～3任意一项所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(1)中，所述的叔胺的加入量为5-溴代-2-糠醇摩尔量的1.3～2.0倍。
7.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(2)中，所述的紫外光照波段为385～395nm，光照时间为3～5h。
8.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(3)中，所述(E)-构型的烯酯三唑化合物与盐酸羟胺、氢氧化钠的摩尔比为1:7～10:5～7。
9.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法，其特征在于：步骤(3)中，所述酸为浓盐酸。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810865552.7A CN108997232B (zh) | 2018-08-01 | 2018-08-01 | 一种组蛋白去乙酰化酶抑制剂的合成方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810865552.7A CN108997232B (zh) | 2018-08-01 | 2018-08-01 | 一种组蛋白去乙酰化酶抑制剂的合成方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108997232A true CN108997232A (zh) | 2018-12-14 |
| CN108997232B CN108997232B (zh) | 2021-09-28 |
Family
ID=64594822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810865552.7A Expired - Fee Related CN108997232B (zh) | 2018-08-01 | 2018-08-01 | 一种组蛋白去乙酰化酶抑制剂的合成方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108997232B (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674079A (zh) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | 一种帕比司他的合成方法 |
-
2018
- 2018-08-01 CN CN201810865552.7A patent/CN108997232B/zh not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674079A (zh) * | 2015-11-10 | 2017-05-17 | 南京卡文迪许生物工程技术有限公司 | 一种帕比司他的合成方法 |
Non-Patent Citations (3)
| Title |
|---|
| ELENA GARCI´A-EXPO´SITO，等: "On the Z-E Photoisomerization of Chiral 2-Pentenoate Esters: Stationary Irradiations, Laser-Flash Photolysis Studies, and Theoretical Calculations", 《J. ORG. CHEM》 * |
| HENGTUO YANG,等: "Bifunctional Furfuryl Cations Strategy: Three-Component Synthesis of Enamidyl Triazoles", 《CHEM. EUR. J.》 * |
| JIE SHEN，等: "Histone Deacetylase Inhibitors through Click Chemistry", 《J. MED. CHEM.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108997232B (zh) | 2021-09-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NZ539095A (en) | Acetyl 2-hydroxy-1,3 diaminoalkanes | |
| KR102041154B1 (ko) | 칼슘 감지 수용체 조절자로서의 치환 크로만 화합물 | |
| CN105440020B (zh) | 具有抗肿瘤活性的1,2,3-三唑类化合物及其制备方法 | |
| CN106573904A (zh) | 用于产生贝前列素及其衍生物的方法 | |
| CA2959437A1 (en) | Cannabinoid type 1 receptor modulators | |
| CN110041333A (zh) | 溴结构域抑制剂化合物及其用途 | |
| Wang et al. | Synthesis and biological evaluation of new 4β-anilino-4′-O-demethyl-4-desoxypodophyllotoxin derivatives as potential antitumor agents | |
| CN107698521B (zh) | 一种5-氟尿嘧啶取代羧酸衍生物的制备及用途 | |
| Gao et al. | Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors | |
| CN102336686A (zh) | 2-(7-甲氧基-1-萘基)乙氰的制备方法 | |
| RU2722441C2 (ru) | Замещённые индольные соединения в качестве понижающих регуляторов рецепторов эстрогена | |
| CN105753795B (zh) | 一种具有1,2,3‑三氮唑结构片段的生物碱化合物及其用途 | |
| JPS58965A (ja) | キノリン誘導体、その製造法及び該化合物を含有する、５―ヒドロキシトリプタミン拮抗質として使用する医薬組成物 | |
| CN102249921A (zh) | 2-(2,3-二甲基苯基)丙二酸二酯,其制备方法和用途 | |
| US20030149038A1 (en) | Alpha-helix mimicry by a class of organic molecules | |
| CN110240539B (zh) | 一种氟取代二苯乙烷类化合物及制备方法和应用 | |
| CN108997232A (zh) | 一种组蛋白去乙酰化酶抑制剂的合成方法 | |
| CN107021886A (zh) | 一类季铵类手性离子液体及其制备方法 | |
| CN112110897A (zh) | 一种氘代克里唑蒂尼及其衍生物的制备方法 | |
| CN106957237B (zh) | 一种合成溴芬酸钠的方法 | |
| CN103864877B (zh) | 一种醋酸阿比特龙的制备方法 | |
| CN105693632A (zh) | 一种多取代喹喔啉衍生物的制备方法 | |
| JP2021509685A (ja) | クリサボロールおよびその中間体を調製するためのプロセス | |
| CN100522965C (zh) | 8-芳胺基-3H-咪唑[4,5-g]喹唑啉类衍生物及其固相合成方法 | |
| CN103896889B (zh) | 拉帕替尼中间体及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210928 |