CN115160318A - 一种吴茱萸碱衍生物的制备方法 - Google Patents
一种吴茱萸碱衍生物的制备方法 Download PDFInfo
- Publication number
- CN115160318A CN115160318A CN202210997815.6A CN202210997815A CN115160318A CN 115160318 A CN115160318 A CN 115160318A CN 202210997815 A CN202210997815 A CN 202210997815A CN 115160318 A CN115160318 A CN 115160318A
- Authority
- CN
- China
- Prior art keywords
- derivative
- evodiamine
- indolylethyl
- reaction
- substituted
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- TXDUTHBFYKGSAH-SFHVURJKSA-N Evodiamine Chemical class C1=CC=C2N(C)[C@@H]3C(NC=4C5=CC=CC=4)=C5CCN3C(=O)C2=C1 TXDUTHBFYKGSAH-SFHVURJKSA-N 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical class C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- SEMDBZVZJSTQOB-UHFFFAOYSA-N N-[2-(1H-indol-2-yl)ethyl]benzamide Chemical class O=C(NCCc1cc2ccccc2[nH]1)c1ccccc1 SEMDBZVZJSTQOB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002841 Lewis acid Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000000967 suction filtration Methods 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 239000000460 chlorine Chemical group 0.000 claims description 13
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- -1 N- (2-indolylethyl) -2-anilinobenzamide derivative Chemical class 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 150000001448 anilines Chemical class 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Chemical group 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 229940112669 cuprous oxide Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 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
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 5
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 229910052802 copper Inorganic materials 0.000 abstract description 2
- 239000010949 copper Substances 0.000 abstract description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 7
- VCTPRAAYKABSJU-UHFFFAOYSA-N 2-bromo-n-[2-(1h-indol-3-yl)ethyl]benzamide Chemical compound BrC1=CC=CC=C1C(=O)NCCC1=CNC2=CC=CC=C12 VCTPRAAYKABSJU-UHFFFAOYSA-N 0.000 description 6
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- JUXTWKYSGNVPGS-UHFFFAOYSA-N 7,8-dihydro-6h-quinazolin-5-one Chemical compound C1=NC=C2C(=O)CCCC2=N1 JUXTWKYSGNVPGS-UHFFFAOYSA-N 0.000 description 4
- 241001078983 Tetradium ruticarpum Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- JTEJPPKMYBDEMY-UHFFFAOYSA-N 5-methoxytryptamine Chemical compound COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HYZIDPAMLUKNIR-UHFFFAOYSA-N 2-(3-fluoroanilino)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(F)=C1 HYZIDPAMLUKNIR-UHFFFAOYSA-N 0.000 description 1
- OQBMJMJZMDBQSM-UHFFFAOYSA-N 2-bromo-5-fluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC=C1Br OQBMJMJZMDBQSM-UHFFFAOYSA-N 0.000 description 1
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 229940097276 5-methoxytryptamine Drugs 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- HMXRXBIGGYUEAX-SFHVURJKSA-N Evodiamine Natural products CN1[C@H]2N(CCc3[nH]c4ccccc4c23)C(=O)c5ccccc15 HMXRXBIGGYUEAX-SFHVURJKSA-N 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种吴茱萸碱衍生物的制备方法,是以邻卤苯甲酸衍生物和取代色胺为起始原料,在缩合剂的催化下得到中间体N‑(2‑吲哚乙基)‑苯甲酰胺衍生物,进一步在铜催化剂的作用下与取代苯胺进行偶联反应,然后在路易斯酸的催化下,环合得到吴茱萸碱衍生物。本发明的方法具有反应条件温和、路线简短以及生产成本低的优点,解决了现有制备方法中难以大量生产的问题。
Description
技术领域
本发明属于制药领域,涉及一种吴茱萸碱衍生物的制备方法。
背景技术
吴茱萸碱来源于芸香科植物吴茱萸的近成熟果实,属于生物碱类,具有镇痛、止干呕、抗肿瘤、抗菌等药理作用(Journal of Ethnopharmacology 262 (2020) 113164、Eur JMed Chem. 2022;228:113960)。
尽管吴茱萸碱衍生物药理学作用广泛而显著,但尚无适宜工业化生产的路线被报道。专利CN109734714、CN202111134080、文献(Bioorganic and Medicinal Chemistry,2022, 55, 116595)已经报道了吴茱萸衍生物及其合成方法,并对吴茱萸碱衍生物药理活性进行了研究,发现其具有很好的药理活性,可以被应用于抗肿瘤、抗菌、抗炎。但其起始原料不易得、缩合剂和催化剂用量较大,制备工艺、纯化方法复杂,不适合工业化生产,生产成本较高,不能进行大量制备。
发明内容
基于上述技术问题,本发明的目的在于提供一种吴茱萸碱衍生物的制备方法,具有反应条件温和、路线简短以及生产成本低的优点,解决了现有制备方法中较难大量制备的问题。
为实现上述目的,本发明吴茱萸衍生物采用的制备方法如下:
(1)以邻卤苯甲酸衍生物和取代色胺为原料,在缩合剂的作用下,在DMF中发生缩合反应,反应温度为-10 ~ 35℃,反应时间为2~24 h,反应完成后加水搅拌后抽滤,固体于乙酸乙酯-石油醚体系中重结晶,得到取代N-(2-吲哚乙基)-苯甲酰胺;
邻卤苯甲酸衍生物的结构为,取代色胺的结构式为,取代N-(2-吲哚乙基)-苯甲酰胺衍生物的结构式为,其中X为溴、氯、碘;R1、R2为氢、甲基、甲氧基、氯、溴、氟中的一种;其中,当R1或R2为溴时,X为碘;
所述邻卤苯甲酸衍生物、取代色胺、缩合剂的摩尔比为1:(0.8~1.2):(1 ~ 10);所述缩合剂为草酰氯、氯化亚砜、二环己基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯或苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯。
(2)以步骤(1)中的取代N-(2-吲哚乙基)-苯甲酰胺衍生物和取代苯胺为原料,在催化剂和碱存在下,于溶剂水中发生偶联反应,反应温度为60~ 120℃,反应时间为2 ~ 12h,反应完成后加入活性炭搅拌,抽滤干燥后用二氯甲烷-石油醚体系重结晶,得到N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物;
所述N-(2-吲哚乙基)-苯甲酰胺衍生物、取代苯胺、催化剂的摩尔比为1:(0.8 ~1.5):(0.05 ~ 0.3);所述催化剂为铜粉、氯化亚铜、溴化亚铜、碘化亚铜、氧化亚铜、五水硫酸铜中的至少一种;所述碱为碳酸钾。
(3)将步骤(2)得到的N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物加入有机溶液中,在原甲酸三甲酯或原甲酸三乙酯和路易斯酸存在下,发生环合反应,反应温度为100~130 ℃,反应时间为1.5 ~ 12 h,反应完成后,加入饱和碳酸氢钠水溶液搅拌,抽滤干燥后,用乙腈或甲醇打浆纯化,干燥得到吴茱萸碱衍生物;
N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸的摩尔比为1:(1~3):(0.5~3);所述路易斯酸为氯化铝、氯化锌、溴化锌、四氯化锡、氯化钛中的一种;所述有机溶剂为二甲基甲酰胺、N-甲基吡咯烷酮或二甲基亚砜。
合成路线如下:
其中,R1、R2为氢、甲基、甲氧基、氯、溴、氟中的一种;R3为氢、甲基、甲氧基、氯、氟中的一种。
本发明相对于现有合成方法的有益效果:以含卤取代苯甲酸衍生物和取代色胺为起始原料,经缩合反应得到中间体N-(2-吲哚乙基)-苯甲酰胺衍生物,进一步在铜催化剂的作用下与取代苯胺得到中间体N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物,最后在路易斯酸的催化下,环合得到吴茱萸衍生物。本发明的方法具有反应条件温和、路线简短以及生产成本低的优点。本制备方法中,解决了现有制备方法中两性物质较难提取完全的缺点;第二步使用了水作溶剂,催化剂用量少,环境友好。本制备方法适宜大量生产,解决了现有制备方法中难以大量生产的问题。
具体实施方式
下面通过具体实施例对本发明吴茱萸衍生物的制备方法做进一步说明。
实施例1
(1)N-(2-(吲哚-3-基)乙基)-2-溴-苯甲酰胺的制备
称取100 g (0. 497mol)的邻溴苯甲酸,2-(3-吲哚)-乙胺70.4 g(0.44 mol),1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(EDCI)101.2 g(0.528 mol),1-羟基苯并三唑(HOBt,活化剂)89.1 g(0.66 mol)于2 L圆底烧瓶中,加入300 ml DMF常温下磁力搅拌。12 h反应完全。加水搅拌2 h,抽滤,固体于乙酸乙酯-石油醚体系中重结晶,得固体140.7g,收率82.5 %。
(2)N-(2-吲哚-3-基)乙基)-2-间甲苯甲酰胺的制备
将100 g (0. 291mol)的N-(2-(吲哚-3-基)乙基)-2-溴-苯甲酰胺,1.89 g(0.03mol)的铜粉,70 g(0.5 mol)的碳酸钾置于干燥的3 L单颈瓶中,加入500 ml的水,磁力搅拌,加入32.2 ml(0.3mol)的3-甲基苯胺,在80 ℃加热3h。将反应液温度降至60 ℃,加入活性炭搅拌2 h,趁热抽滤得滤液,调pH至3,抽滤得固体,干燥后用二氯甲烷-石油醚体系重结晶,得80 g固体,收率为74 %。
(3)14-间甲苯基-8, 13, 13b, 14-四氢茚苷[2', 1': 3, 4]吡啶并[2, 1-b]喹唑啉-5(7H)-酮的制备
称取N-(2-吲哚-3-基)乙基)-2-间甲苯甲酰胺50.00 g(0.135 mol)于1L 圆底烧瓶中,加入200 ml的DMF,加入原甲酸三甲酯48.4 ml(0.406 mol),加入氯化锌18.4 g(0.135 mol),120℃下加热回流12h,加水淬灭后冷却,加入饱和碳酸氢钠水溶液搅拌4 h,抽滤,滤饼干燥后用甲醇打浆,干燥后得固体35 g,收率为70 %。 1H NMR (500 MHz, DMSO)δ 11.25 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.39 (d,J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.08(dd, J = 19.7, 7.7 Hz, 4H), 7.02 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.6 Hz,2H), 6.60 (s, 1H), 4.60 (dd, J = 13.2, 5.8 Hz, 1H), 3.50 – 3.39 (m, 1H), 2.99– 2.80 (m, 1H), 2.64 (dd, J = 15.4, 4.3 Hz, 1H), 2.27 (s, 3H).
实施例2
(1)N-(2-(吲哚-3-基)乙基)-2-溴-苯甲酰胺的制备
称取50 g (0.248mol)的邻溴苯甲酸,加入90ml氯化亚砜,回流下反应2 h,浓缩旋去过量溶剂后缓慢滴入含有2-(3-吲哚)-乙胺48 g(0.3mol)的DMF(250ml)溶液中,冰浴下反应。2 h反应完全,加1L水搅拌2 h,用1M的NaOH调节pH至弱碱性,抽滤得到固体,固体于乙酸乙酯-石油醚体系中重结晶,得固体68 g,收率80 %。
(2)N-(2-吲哚-3-基)乙基)-2-间甲苯甲酰胺的制备
将100 g (0. 291mol)的N-(2-(吲哚-3-基)乙基)-2-溴-苯甲酰胺,1.89 g(0.03mol)的铜粉,70 g(0.5 mol)的碳酸钾置于干燥的3 L单颈瓶中,加入300 ml的DMF,磁力搅拌,加入32.2 ml(0.3mol)的3-甲基苯胺,在80 ℃加热3h。将反应液温度降至60 ℃,加入活性炭搅拌2 h,趁热抽滤得滤液,调pH至3,抽滤得固体,干燥后用二氯甲烷-石油醚体系重结晶,得75 g固体,收率为70 %。
(3)14-间甲苯基-8, 13, 13b, 14-四氢茚苷[2', 1': 3, 4]吡啶并[2, 1-b]喹唑啉-5(7H)-酮的制备
称取N-(2-吲哚-3-基)乙基)-2-间甲苯甲酰胺25.0 g(0.067mol)于500 ml圆底烧瓶中,加入100 ml的DMF,加入原甲酸三甲酯24.2 ml(0.203mol),加入氯化锌9.2 g(0.067mol),120 ℃下加热回流12 h,加水淬灭后冷却,加入饱和碳酸氢钠水溶液搅拌4 h,抽滤,滤饼干燥后用乙腈打浆,干燥后得固体17 g,收率为68 %。 1H NMR (500 MHz, DMSO)δ 11.25 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.39 (d,J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.08(dd, J = 19.7, 7.7 Hz, 4H), 7.02 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.6 Hz,2H), 6.60 (s, 1H), 4.60 (dd, J = 13.2, 5.8 Hz, 1H), 3.50 – 3.39 (m, 1H), 2.99– 2.80 (m, 1H), 2.64 (dd, J = 15.4, 4.3 Hz, 1H), 2.27 (s, 3H).
实施例3
(1)N-(2-(吲哚-3-基)乙基)-2-溴-苯甲酰胺的制备
称取100 g (0. 497mol)的邻溴苯甲酸,2-(3-吲哚)-乙胺70.4 g(0.44 mol),EDCI 101.2 g(0.528 mol),HOBt 89.1 g(0.66 mol)于2 L圆底烧瓶中,加入300 ml DMF常温下磁力搅拌。12 h反应完全。加水搅拌2 h,抽滤,固体于乙酸乙酯-石油醚体系中重结晶,得固体138 g,收率80 %。
(2)N-(2-吲哚-3-基)乙基)-2-间甲苯甲酰胺的制备
将100 g (0. 291mol)的N-(2-(吲哚-3-基)乙基)-2-溴-苯甲酰胺, 1.8 g(0.03mol)的铜粉,1.43 g(0.01mol)的溴化亚铜,70 g(0.5 mol)的碳酸钾置于干燥的3 L单颈瓶中,加入500 ml的水,磁力搅拌,加入32.2 ml(0.3mol)的3-甲基苯胺,在80 ℃加热3h。将反应液温度降至60 ℃,加入活性炭搅拌2 h,趁热抽滤得滤液,调pH至3,抽滤得固体,干燥后用二氯甲烷-石油醚体系重结晶,得82 g固体,收率为76 %。
(3)14-间甲苯基-8, 13, 13b, 14-四氢茚苷[2', 1': 3, 4]吡啶并[2, 1-b]喹唑啉-5(7H)-酮的制备
称取N-(2-吲哚-3-基)乙基)-2-间甲苯甲酰胺50.00 g(0.135 mol)于1L 圆底烧瓶中,加入200 ml的DMF,加入原甲酸三乙酯67.4 ml(0.406 mol),加入氯化锌18.4 g(0.135 mol),120 ℃下加热回流12 h,加水淬灭后冷却,加入饱和碳酸氢钠水溶液搅拌4h,抽滤,滤饼干燥后用甲醇打浆,干燥后得固体30 g,收率为60 %。 1H NMR (500 MHz,DMSO) δ 11.25 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H),7.39 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H),7.08 (dd, J = 19.7, 7.7 Hz, 4H), 7.02 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.6Hz, 2H), 6.60 (s, 1H), 4.60 (dd, J = 13.2, 5.8 Hz, 1H), 3.50 – 3.39 (m, 1H),2.99 – 2.80 (m, 1H), 2.64 (dd, J = 15.4, 4.3 Hz, 1H), 2.27 (s, 3H).
实施例4
(1)2-溴-5-氟-N-(2-(5-甲氧基-1H-吲哚-3-基)乙基)苯甲酰胺的制备
称取2-溴-5-氟苯甲酸21.9 g(0.1mol),5-甲氧基色胺19 g(0.1mol),EDCI 23 g(0.12mol),HOBt16.2 g(0.12mol)于250 ml圆底烧瓶中,加入100 ml DMF常温下磁力搅拌。10 h反应完全。加水搅拌2 h,抽滤,固体于乙酸乙酯-石油醚体系中重结晶,得固体35 g,收率为90 %。
(2)2-(间氟苯基氨基)苯甲酸的制备
将18g(0.05mol)的2-溴-5-氟-N-(2-(5-甲氧基-1H-吲哚-3-基)乙基)苯甲酰胺,0.31 g(0.005mol)的铜粉,13.8 g(0.1mol)的碳酸钾置于干燥的250ml圆底烧瓶中,加入80ml的水,磁力搅拌,加入6.088 g(0.0548 mol)的3-氟苯胺,在105 ℃加热回流4 h。将反应液温度降至80 ℃左右,加入活性炭搅拌2 h,抽滤,滤液用盐酸调pH至2~3,抽滤得固体,干燥后用二氯甲烷-石油醚体系重结晶,得14.60 g固体,收率69.5%。
(3)3-氟-14-(3-氟苯基)-10-甲氧基-8,13,13b,14-四氢吲哚[2',3':3,4]吡啶[2,1-b]喹唑啉-5(7H)-酮的制备
称取5-氟-2-((3-氟苯基)氨基)-N-(2-(5-甲氧基-1H-吲哚-3-基)乙基)苯甲酰胺10.9 g(0.026 mol)于250 ml 圆底烧瓶中,加入35 ml的DMF,加入原甲酸三甲酯8.536 ml(0.078 mol),加入三氟化硼乙醚3.21 ml(0.026 mol),120 ℃下加热回流12 h,加水淬灭后冷却,加入饱和碳酸氢钠水溶液搅拌4 h,抽滤,滤饼干燥后用乙腈打浆,干燥后得固体8.95 g,收率为79.8 %。1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.75 (dd, J =8.6, 2.5 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.14 – 7.01 (m, 2H), 6.85 (ddd, J =20.9, 10.8, 4.6 Hz, 5H), 6.35 (s, 1H), 4.86 (dd, J = 13.2, 5.6 Hz, 1H), 3.83(s, 3H), 3.26 (td, J = 12.4, 4.7 Hz, 1H), 3.05 – 2.91 (m, 1H), 2.70 (dd, J =15.6, 4.3 Hz, 1H)。
Claims (8)
1.一种吴茱萸碱衍生物的制备方法,包括以下步骤:
(1)以邻卤苯甲酸衍生物和取代色胺为原料,在缩合剂的作用下,在DMF中发生缩合反应,反应温度为-10 °C~ 35 °C,反应时间为2~24 h,反应完成后加水搅拌后抽滤,固体于乙酸乙酯-石油醚体系中重结晶,得到取代N-(2-吲哚乙基)-苯甲酰胺;邻卤苯甲酸衍生物的结构为,取代色胺的结构式为,取代N-(2-吲哚乙基)-苯甲酰胺衍生物的结构式为,其中X为溴、氯、碘;R1、R2为氢、甲基、甲氧基、氯、溴、氟中的一种;其中,当R1或R2为溴时,X为碘;
(2)以步骤(1)中的取代N-(2-吲哚乙基)-苯甲酰胺衍生物和取代苯胺为原料,在催化剂和碱存在下,于溶剂水中发生偶联反应,反应温度为60 °C~ 120 °C,反应时间为2 ~ 12h,反应完成后加入活性炭搅拌,抽滤干燥后用二氯甲烷-石油醚体系重结晶,得到N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物;
(3)将步骤(2)得到的N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物加入有机溶液中,在原甲酸三甲酯或原甲酸三乙酯和路易斯酸存在下,发生环合反应,反应温度为100 °C~130 °C,反应时间为1.5 ~ 12 h,反应完成后,加入饱和碳酸氢钠水溶液搅拌,抽滤干燥后,用乙腈或甲醇打浆纯化,干燥得到吴茱萸碱衍生物;
2.根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(1)中,所述邻卤苯甲酸衍生物、取代色胺、缩合剂的摩尔比为1:(0.8~1.2):(1 ~ 10)。
3.根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(1)中,所述缩合剂为草酰氯、氯化亚砜、二环己基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯或苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯。
4. 根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(2)中,所述N-(2-吲哚乙基)-苯甲酰胺衍生物、取代苯胺、催化剂的摩尔比为1:(0.8 ~ 1.5):(0.05 ~0.3)。
5.根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(2)中,所述催化剂为铜粉、氯化亚铜、溴化亚铜、碘化亚铜、氧化亚铜、五水硫酸铜中的至少一种;所述碱为碳酸钾。
6.根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(3)中,N-(2-吲哚乙基)-2-苯胺基苯甲酰胺衍生物、原甲酸三甲酯或原甲酸三乙酯、路易斯酸的摩尔比为1:(1~3):(0.5~3)。
7.根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(3)中,所述路易斯酸为氯化铝、氯化锌、溴化锌、四氯化锡、氯化钛中的一种。
8.根据权利要求1所述的吴茱萸碱衍生物的制备方法,其特征在于:步骤(3)中,所述有机溶剂为二甲基甲酰胺、N-甲基吡咯烷酮或二甲基亚砜。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210997815.6A CN115160318B (zh) | 2022-08-19 | 2022-08-19 | 一种吴茱萸碱衍生物的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210997815.6A CN115160318B (zh) | 2022-08-19 | 2022-08-19 | 一种吴茱萸碱衍生物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115160318A true CN115160318A (zh) | 2022-10-11 |
CN115160318B CN115160318B (zh) | 2024-08-13 |
Family
ID=83481053
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210997815.6A Active CN115160318B (zh) | 2022-08-19 | 2022-08-19 | 一种吴茱萸碱衍生物的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115160318B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109734714A (zh) * | 2019-01-29 | 2019-05-10 | 兰州大学 | 一种吴茱萸生物碱衍生物及其合成方法和应用 |
CN113683615A (zh) * | 2021-09-27 | 2021-11-23 | 南华大学 | 一种吴茱萸碱衍生物及其制备和应用 |
CN113768936A (zh) * | 2021-09-27 | 2021-12-10 | 南华大学 | 一种吴茱萸碱衍生物在制备治疗浅表真菌感染药物中的应用 |
-
2022
- 2022-08-19 CN CN202210997815.6A patent/CN115160318B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109734714A (zh) * | 2019-01-29 | 2019-05-10 | 兰州大学 | 一种吴茱萸生物碱衍生物及其合成方法和应用 |
CN113683615A (zh) * | 2021-09-27 | 2021-11-23 | 南华大学 | 一种吴茱萸碱衍生物及其制备和应用 |
CN113768936A (zh) * | 2021-09-27 | 2021-12-10 | 南华大学 | 一种吴茱萸碱衍生物在制备治疗浅表真菌感染药物中的应用 |
Non-Patent Citations (2)
Title |
---|
FANG LEI等: "Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 65, pages 7976 * |
YAN LIANG等: "Discovery of evodiamine derivatives as potential lead antifungal agents for the treatment of superficial fungal infections", 《BIOORGANIC CHEMISTRY》, vol. 127, pages 105981 * |
Also Published As
Publication number | Publication date |
---|---|
CN115160318B (zh) | 2024-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2581835C (en) | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide | |
AU2006239569B2 (en) | Method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide | |
CA2711645C (en) | Process for the preparation of 8-methoxy-quinolone-carboxylic acids | |
CN102050791B (zh) | 替米沙坦的关键中间体及其合成方法及由该中间体合成替米沙坦的方法 | |
CN108623567A (zh) | 奥斯替尼的制备方法 | |
CN106188062A (zh) | 依鲁替尼的制备方法、依鲁替尼的中间体及中间体的制备方法 | |
CN1915976B (zh) | 5-氯-4-羟基-2(1h)-吡啶酮的制备方法及中间体 | |
WO2023143630A1 (zh) | 一种核苷类似物vv116的制备方法 | |
CN101717359A (zh) | 吲达帕胺的合成方法 | |
CN109748902B (zh) | 一种盐酸安罗替尼的制备方法 | |
CN115160318B (zh) | 一种吴茱萸碱衍生物的制备方法 | |
CN113698317A (zh) | 阿帕他胺的合成方法、其中间体及合成方法 | |
CN115160312B (zh) | 一种维立西呱关键中间体及其制备方法 | |
CN113896732B (zh) | 抗癌药物卡马替尼的制备方法及其应用 | |
CN107935909B (zh) | 一种尼达尼布(nintedanib)及其中间体的合成方法 | |
JP5315337B2 (ja) | トポテカン塩酸塩の結晶形およびその製造方法 | |
CN111423437B (zh) | 一种帕博西尼中间体的制备方法 | |
CN111018782A (zh) | 9-氨基吖啶及其衍生物的制备方法 | |
NO147838B (no) | Mellomprodukt til bruk ved fremstilling av det hypotensive middel 2-(4-(2-furoyl)piperazin-1-yl)-4-amino-6,7-dimetoksykinazolin | |
CZ294957B6 (cs) | Způsob přípravy substituované imidazopyridinové sloučeniny | |
JP2003518016A (ja) | 6−メチル−2−(4−メチル−フェニル)−イミダゾ[1,2−a]ピリジン−3−(N,N−ジメチル−アセトアミド)の製法及び中間体 | |
CN105001200A (zh) | 一种抗血管新生化合物及其中间体的制备方法 | |
CN114181145B (zh) | 一种依匹哌唑中间体的制备方法 | |
CN102391170A (zh) | 一种n,n-二烯丙基-5-甲氧基色胺盐酸盐的制备方法 | |
JPH07121931B2 (ja) | ベンゾ〔b〕フラン誘導体 |
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 |