CN108218803A - A kind of method of hexa-atomic imines cycle compound and the hexa-atomic imines cycle compound of one pot process - Google Patents
A kind of method of hexa-atomic imines cycle compound and the hexa-atomic imines cycle compound of one pot process Download PDFInfo
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- 238000005580 one pot reaction Methods 0.000 title claims abstract description 16
- 150000002466 imines Chemical class 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 title claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 14
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 14
- 150000004988 m-phenylenediamines Chemical class 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000004440 column chromatography Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims 2
- 150000007942 carboxylates Chemical class 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 2
- 239000010452 phosphate Substances 0.000 claims 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 31
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 16
- 150000002500 ions Chemical class 0.000 abstract description 4
- 239000012217 radiopharmaceutical Substances 0.000 abstract description 4
- 229940121896 radiopharmaceutical Drugs 0.000 abstract description 4
- 230000002799 radiopharmaceutical effect Effects 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000002738 chelating agent Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 102000004310 Ion Channels Human genes 0.000 abstract 1
- 125000005462 imide group Chemical group 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- -1 imine ring compound Chemical class 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 229940047889 isobutyramide Drugs 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 239000011734 sodium Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- IZALUMVGBVKPJD-UHFFFAOYSA-N benzene-1,3-dicarbaldehyde Chemical class O=CC1=CC=CC(C=O)=C1 IZALUMVGBVKPJD-UHFFFAOYSA-N 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 125000003172 aldehyde group Chemical group 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 description 4
- JNBXUZUEBXPEMC-UHFFFAOYSA-N methyl 3,5-diformyl-4-hydroxybenzoate Chemical compound COC(=O)C1=CC(C=O)=C(O)C(C=O)=C1 JNBXUZUEBXPEMC-UHFFFAOYSA-N 0.000 description 4
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- WZCQRUWWHSTZEM-UHFFFAOYSA-N 1,3-phenylenediamine Chemical compound NC1=CC=CC(N)=C1 WZCQRUWWHSTZEM-UHFFFAOYSA-N 0.000 description 3
- BNZPJAAPYDPZFM-UHFFFAOYSA-N 2-[2-(2-methoxyethoxy)ethoxy]ethyl 4-hydroxybenzoate Chemical compound COCCOCCOCCOC(=O)C1=CC=C(O)C=C1 BNZPJAAPYDPZFM-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940018564 m-phenylenediamine Drugs 0.000 description 3
- 150000002678 macrocyclic compounds Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- DZMDWVBSFUHHTH-UHFFFAOYSA-N 3,5-diamino-4-fluorobenzoic acid Chemical compound NC1=CC(C(O)=O)=CC(N)=C1F DZMDWVBSFUHHTH-UHFFFAOYSA-N 0.000 description 2
- NNOHXABAQAGKRZ-UHFFFAOYSA-N 3,5-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=CC([N+]([O-])=O)=C1 NNOHXABAQAGKRZ-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 2
- 0 CC[C@](C=C(C(C)C(CCN)CC1)O)*=C=C1C(OC)=O Chemical compound CC[C@](C=C(C(C)C(CCN)CC1)O)*=C=C1C(OC)=O 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DQCNIBCDZAAPPQ-UHFFFAOYSA-N 4-fluoro-3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(F)C([N+]([O-])=O)=C1 DQCNIBCDZAAPPQ-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- GZIAPVRPEHCKSB-UHFFFAOYSA-N C(=O)Cl.[N+](=O)([O-])C=1C=CC=C(C1)[N+](=O)[O-] Chemical compound C(=O)Cl.[N+](=O)([O-])C=1C=CC=C(C1)[N+](=O)[O-] GZIAPVRPEHCKSB-UHFFFAOYSA-N 0.000 description 1
- FQQLZWLHRQJNEI-QMMMGPOBSA-N CCCCOC([C@H](C)NC(c(cc1N)cc(N)c1F)=O)=O Chemical compound CCCCOC([C@H](C)NC(c(cc1N)cc(N)c1F)=O)=O FQQLZWLHRQJNEI-QMMMGPOBSA-N 0.000 description 1
- OFTONHLYYXABDW-UHFFFAOYSA-N COCCOCCOCCOC(c(cc1C=O)cc(C=O)c1O)=O Chemical compound COCCOCCOCCOC(c(cc1C=O)cc(C=O)c1O)=O OFTONHLYYXABDW-UHFFFAOYSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- WIQIWPPQGWGVHD-JEDNCBNOSA-N [(2s)-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]azanium;chloride Chemical compound Cl.C[C@H](N)C(=O)OC(C)(C)C WIQIWPPQGWGVHD-JEDNCBNOSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- RJJXSCQQRYCPLW-LURJTMIESA-N butyl (2s)-2-aminopropanoate Chemical compound CCCCOC(=O)[C@H](C)N RJJXSCQQRYCPLW-LURJTMIESA-N 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002555 ionophore Substances 0.000 description 1
- 230000000236 ionophoric effect Effects 0.000 description 1
- YTJXGDYAEOTOCG-UHFFFAOYSA-N lithium;di(propan-2-yl)azanide;oxolane Chemical compound [Li+].C1CCOC1.CC(C)[N-]C(C)C YTJXGDYAEOTOCG-UHFFFAOYSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- VHNQIURBCCNWDN-UHFFFAOYSA-N pyridine-2,6-diamine Chemical compound NC1=CC=CC(N)=N1 VHNQIURBCCNWDN-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域technical field
本发明属于化学合成领域，具体涉及一种六元亚胺环化合物，此外，本发明还提出了一锅法合成六元亚胺环化合物的方法。The invention belongs to the field of chemical synthesis, and specifically relates to a six-membered imine ring compound. In addition, the invention also proposes a one-pot method for synthesizing the six-membered imine ring compound.
背景技术Background technique
双功能团或者多功能团大环因其可以选择性的络合不同放射性金属离子，可以诊断或治疗不同的肿瘤，且影响药物在体内的稳定性和药代动力学等性质，因此，设计不同的类型的功能性大环是放药领域研究的热点之一。同时，大环因具有独特的物理性质、特定的结构特征和化学行为而区别与线性分子，具有不同结构和几何形状的这类分子在分子识别、分子组装、离子载体、药物分子传输、纳米成像、化学反应催化剂、人工模拟酶等领域有着广阔的应用。Bifunctional or multifunctional macrocycles can selectively complex different radioactive metal ions, can diagnose or treat different tumors, and affect the stability and pharmacokinetics of drugs in vivo. Therefore, different designs The types of functional macrocycles are one of the hotspots in the field of radiopharmaceutical research. At the same time, macrocycles are distinguished from linear molecules due to their unique physical properties, specific structural features, and chemical behaviors. Such molecules with different structures and geometries are useful in molecular recognition, molecular assembly, ionophores, drug molecule transport, and nanoimaging. , chemical reaction catalysts, artificial enzymes and other fields have a wide range of applications.
发明内容Contents of the invention
有鉴于此，本发明的第一个目的在于提供一种六元亚胺环化合物，其孔径大小可调，侧链可以修饰，可用于放射性药物的多功能团的螯合剂，纳米成像，离子识别，自组装，药物传输等领域，具有很高的应用价值。In view of this, the first object of the present invention is to provide a six-membered imine ring compound with adjustable pore size and side chain modification, which can be used as a chelating agent for multifunctional groups in radiopharmaceuticals, nanoimaging, and ion recognition. , self-assembly, drug delivery and other fields, has high application value.
本发明的第二个目的在于提出一锅法合成六元亚胺环化合物的方法。The second object of the present invention is to propose a one-pot method for synthesizing a six-membered imine ring compound.
为解决上述技术问题，本发明的第一个目的采用以下技术方案予以实现：In order to solve the problems of the technologies described above, the first purpose of the present invention is achieved by adopting the following technical solutions:
一种六元亚胺环化合物，其化学结构式如下：A six-membered imine ring compound, its chemical structural formula is as follows:
其中R1，R2，R3，R4，R5，R6为除端基为氨基、醛基以外的任何基团，如：氢原子、烷基、卤素原子、羟基、羧酸酯的衍生物、磷酸酯衍生物和酰胺衍生物等，R1，R2，R3，R4，R5，R6可以相同也可以不同，R7，R8为C或N原子。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are any groups other than amino groups and aldehyde groups, such as hydrogen atoms, alkyl groups, halogen atoms, hydroxyl groups, and carboxylic acid esters. derivatives, phosphate derivatives and amide derivatives, etc., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 can be the same or different, and R 7 , R 8 are C or N atoms.
一种一锅法合成六元亚胺环化合物的方法，其是以间苯二胺衍生物和间苯二甲醛衍生物为原料，以硼氢化钠为还原剂，一锅法合成六元亚胺环衍生物，其反应式如下：A method for synthesizing a six-membered imine ring compound by a one-pot method, which uses m-phenylenediamine derivatives and m-phthalaldehyde derivatives as raw materials, and uses sodium borohydride as a reducing agent to synthesize six-membered imines by one-pot method Ring derivatives, whose reaction formula is as follows:
其中R1，R2，R3，R4，R5，R6为除端基为氨基、醛基以外的任何基团，如：氢原子、烷基、卤素原子、羟基、羧酸酯的衍生物、磷酸酯衍生物和酰胺衍生物等，R1，R2，R3，R4，R5，R6可以相同也可以不同，R7，R8为C或N原子。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are any groups other than amino groups and aldehyde groups, such as hydrogen atoms, alkyl groups, halogen atoms, hydroxyl groups, and carboxylic acid esters. derivatives, phosphate derivatives and amide derivatives, etc., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 can be the same or different, and R 7 , R 8 are C or N atoms.
本发明中间苯二胺衍生物包括间苯二胺，由于只要氨基处于间位，所有的化合物都叫间苯二胺衍生物，同样的，间苯二甲醛衍生物包括间苯二甲醛，由于只要醛基处于间位，所有的化合物都叫间苯二甲醛衍生物。The m-phenylenediamine derivatives of the present invention include m-phenylenediamine, because as long as the amino group is in the meta-position, all compounds are called m-phenylenediamine derivatives. The aldehyde group is in the meta position, and all compounds are called isophthalaldehyde derivatives.
上述的一锅法合成六元亚胺环化合物的合成方法，包括如下步骤：The synthetic method of above-mentioned one-pot synthetic six-membered imine ring compound, comprises the steps:
1)无水的条件下，将间苯二胺或其衍生物和间苯二甲醛或其衍生物按摩尔比为1:1注射到的两口瓶中，加入溶剂二氯甲烷或者三氯甲烷后，在0-80℃的条件下反应2-7天；1) Under anhydrous conditions, m-phenylenediamine or its derivatives and m-phthalaldehyde or its derivatives are injected into a two-necked bottle with a molar ratio of 1:1, and after adding the solvent dichloromethane or chloroform , reacting at 0-80°C for 2-7 days;
2)将步骤1)中的溶剂除去，加入溶剂乙醇或者甲醇或者四氢呋喃，后加入10倍初始原料量的还原剂，反应10分钟；2) Remove the solvent in step 1), add the solvent ethanol or methanol or tetrahydrofuran, and then add a reducing agent 10 times the amount of the initial raw material, and react for 10 minutes;
3)除去步骤2)产物中的溶剂，用浓度为1-3mol/L的稀盐酸作为中和剂进行中和，后加入乙酸乙酯萃取，无水硫酸钠干燥，后柱层析，得产品。3) Remove the solvent in the product of step 2), neutralize with dilute hydrochloric acid with a concentration of 1-3mol/L as a neutralizing agent, then add ethyl acetate for extraction, dry over anhydrous sodium sulfate, and perform column chromatography to obtain the product .
作为优选地，所述步骤2)中，还原剂为硼氢化钠。As preferably, in the step 2), the reducing agent is sodium borohydride.
本发明首次设计并合成了六元亚胺环，其孔径大小可调，侧链可以修饰，可用于放射性药物的多功能团的螯合剂，纳米成像，离子识别，自组装，药物传输等领域，具有很高的应用价值。The present invention designs and synthesizes a six-membered imine ring for the first time. Its pore size can be adjusted and its side chain can be modified. It can be used as a chelating agent for multifunctional groups of radiopharmaceuticals, nanoimaging, ion recognition, self-assembly, drug delivery and other fields. It has high application value.
本发明的特点在于：1)合成条件简单，采用一锅法；2)反应条件温和；3)反应操作简单，易操作；3)产物孔径可控，适合不同离子的络合；4)反应条件应用范围广，适用与不同类型底物的合成。The present invention is characterized in that: 1) the synthesis condition is simple, using a one-pot method; 2) the reaction condition is mild; 3) the reaction operation is simple and easy to operate; 3) the pore size of the product is controllable, suitable for the complexation of different ions; 4) the reaction condition It has a wide range of applications and is suitable for the synthesis of different types of substrates.
具体实施方式Detailed ways
为使本发明要解决的技术问题、技术方案和优点更加清楚，下面将通过具体实施例进行详细描述。In order to make the technical problems, technical solutions and advantages to be solved by the present invention clearer, specific embodiments will be described in detail below.
一种六元亚胺环化合物，其化学结构式如下：A six-membered imine ring compound, its chemical structural formula is as follows:
其中R1，R2，R3，R4，R5，R6为除端基为氨基、醛基以外的任何基团，如：氢原子、烷基、卤素原子、羟基、羧酸酯的衍生物、磷酸酯衍生物和酰胺衍生物等，R1，R2，R3，R4，R5，R6可以相同也可以不同，R7，R8为C或N原子。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are any groups other than amino groups and aldehyde groups, such as hydrogen atoms, alkyl groups, halogen atoms, hydroxyl groups, and carboxylic acid esters. derivatives, phosphate derivatives and amide derivatives, etc., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 can be the same or different, and R 7 , R 8 are C or N atoms.
六元亚胺环化合物采用一锅法合成，以间苯二胺衍生物和间苯二甲醛衍生物为原料，以硼氢化钠为还原剂，一锅法合成六元亚胺环衍生物，其反应式如下：The six-membered imine ring compound is synthesized by a one-pot method, using m-phenylenediamine derivatives and m-phthalaldehyde derivatives as raw materials, using sodium borohydride as a reducing agent, and synthesizing six-membered imine ring derivatives in one pot. The reaction formula is as follows:
其中R1，R2，R3，R4，R5，R6为除端基为氨基、醛基以外的任何基团，如：氢原子、烷基、卤素原子、羟基、羧酸酯的衍生物、磷酸酯衍生物和酰胺衍生物等，R1，R2，R3，R4，R5，R6可以相同也可以不同，R7，R8为C或N原子具体包括如下步骤：Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are any groups other than amino groups and aldehyde groups, such as hydrogen atoms, alkyl groups, halogen atoms, hydroxyl groups, and carboxylic acid esters. Derivatives, phosphate derivatives and amide derivatives, etc., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 can be the same or different, and R 7 and R 8 are C or N atoms, specifically including the following steps :
1)无水的条件下，将间苯二胺或其衍生物和间苯二甲醛或其衍生物按摩尔比为1:1注射到的两口瓶中，加入溶剂二氯甲烷或者三氯甲烷后，在0-80℃的条件下反应2-7天；1) Under anhydrous conditions, m-phenylenediamine or its derivatives and m-phthalaldehyde or its derivatives are injected into a two-necked bottle with a molar ratio of 1:1, and after adding the solvent dichloromethane or chloroform , reacting at 0-80°C for 2-7 days;
2)将步骤1)中的溶剂除去，加入溶剂乙醇或者甲醇或者四氢呋喃，后加入10倍初始原料量的硼氢化钠，反应10分钟；2) Remove the solvent in step 1), add solvent ethanol or methanol or tetrahydrofuran, and then add sodium borohydride 10 times the amount of the initial raw material, and react for 10 minutes;
3)除去步骤2)产物中的溶剂，用浓度为1-3mol/L的稀盐酸作为中和剂进行中和，后加入乙酸乙酯萃取，无水硫酸钠干燥，后柱层析，得产品。3) Remove the solvent in the product of step 2), neutralize with dilute hydrochloric acid with a concentration of 1-3mol/L as a neutralizing agent, then add ethyl acetate for extraction, dry over anhydrous sodium sulfate, and perform column chromatography to obtain the product .
实施例1：甲基3-(((3-氨基-5-(((S)-1-(叔丁氧基)-1-氧丙烷-2-基)氨基甲酰)苯基)氨基)甲基)-5-(((3-((3-(((3-((3-(甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)-5-(((S)-1-(叔丁氧基)-1-氧丙烷-2-基)氨基甲酰)苯基)氨基)甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)甲基)-5-(((S)-1-(叔丁氧基)-1-氧丙烷-2-yl)氨基甲酰)苯基)氨基)甲基)-4-羟基苯甲酸甲酯Example 1: Methyl 3-(((3-amino-5-(((S)-1-(tert-butoxy)-1-oxypropan-2-yl)carbamoyl)phenyl)amino) Methyl)-5-(((3-((3-(((3-((3-(methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)-5-(( (S)-1-(tert-butoxy)-1-oxypropan-2-yl)carbamoyl)phenyl)amino)methyl)-2-hydroxyl-5-(methoxycarbonyl)benzyl)amino )methyl)-5-(((S)-1-(tert-butoxy)-1-oxypropane-2-yl)carbamoyl)phenyl)amino)methyl)-4-hydroxybenzoic acid ester
结构式1：Structural formula 1:
反应式1Reaction 1
原料的合成：Synthesis of raw materials:
(S)-叔丁基2-(3,5-二氨基苯甲酰)丙甲酸甲酯的合成Synthesis of (S)-tert-butyl methyl 2-(3,5-diaminobenzoyl)propionate
反应式如下：The reaction formula is as follows:
在0℃下，将L-丙氨酸叔丁酯盐酸盐(1g,5.5mmol)和Et3N(2mL,22mmol)溶于20mL二氯甲烷中,后将3,5-二硝基苯甲酰氯(1.27g,5.5mmol)5ml溶液缓慢滴加到上述溶液中,后再室温条件下，反应1小时，将反应液用H2O水洗，Na2SO4干燥，柱层析得到(S)-叔丁基2-(3,5-二硝基苯甲酰)丙甲酸甲酯(1.74g,93.2％).1H NMR(400MHz,CDCl3)δ:9.18(d,J＝2.2Hz,2H),8.98(d,J＝2.2Hz,2H),7.14(s,1H),4.71-4.69(m,1H),1.57(d,J＝7.1Hz,3H),1.54(s,9H).13C NMR(100MHz,CDCl3)δ:171.95,161.91,148.69,137.59,127.17,121.19,83.16,49.64,27.97,18.55.HRMS calcd for C14H17N3O7 339.1066,found:701.2056[2M+Na]+。At 0°C, L-alanine tert-butyl ester hydrochloride (1g, 5.5mmol) and Et 3 N (2mL, 22mmol) were dissolved in 20mL of dichloromethane, and then 3,5-dinitrobenzene Formyl chloride (1.27g, 5.5mmol) 5ml solution was slowly added dropwise to the above solution, and then reacted at room temperature for 1 hour, the reaction solution was washed with H 2 O, dried with Na 2 SO 4 , and obtained by column chromatography (S )-tert-butyl methyl 2-(3,5-dinitrobenzoyl)propionate (1.74g, 93.2%). 1 H NMR (400MHz, CDCl3) δ: 9.18 (d, J=2.2Hz, 2H), 8.98(d, J=2.2Hz, 2H), 7.14(s, 1H), 4.71-4.69(m, 1H), 1.57(d, J=7.1Hz, 3H), 1.54(s, 9H). 13C NMR (100MHz, CDCl3) δ: 171.95, 161.91, 148.69, 137.59, 127.17, 121.19, 83.16, 49.64, 27.97, 18.55.HRMS calcd for C14H17N3O7 339.1066, found: 701.2056[2M+Na .
将(S)-叔丁基2-(3,5-二硝基苯甲酰)丙甲酸甲酯(1g,2.94mmol)溶于20mL的乙醇中,后将Pd/C(100mg)加入,在氢气条件下，室温条件下反应4小时。后将反应液过滤，浓缩，纯化得到(S)-叔丁基2-(3,5-二氨基苯甲酰)丙甲酸甲酯(0.76g,92.6％)。1H NMR(400MHz,CDCl3)δ:6.65(s,1H),6.52(d,J＝2.0Hz,2H),6.13(t,J＝2.0Hz,1H),4.65-4.62(m,1H),3.68(s,4H),1.59(s,9H),1.46(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ:172.62,167.07,147.75,136.62,104.42,104.21,48.92,28.00,18.88HRMS calcd for C14H21N3O3279.1583,found:280.1657[M+H]+。(S)-Methyl tert-butyl 2-(3,5-dinitrobenzoyl)propanoate (1 g, 2.94 mmol) was dissolved in 20 mL of ethanol, and then Pd/C (100 mg) was added, in Under hydrogen condition, react at room temperature for 4 hours. Afterwards, the reaction solution was filtered, concentrated, and purified to obtain (S)-tert-butyl methyl 2-(3,5-diaminobenzoyl)propionate (0.76 g, 92.6%). 1 H NMR (400MHz, CDCl 3 ) δ: 6.65(s, 1H), 6.52(d, J=2.0Hz, 2H), 6.13(t, J=2.0Hz, 1H), 4.65-4.62(m, 1H) ,3.68(s,4H),1.59(s,9H),1.46(d,J=6.8Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ:172.62,167.07,147.75,136.62,104.42,104.21, 48.92, 28.00, 18.88 HRMS calcd for C14H21N3O3 279.1583, found: 280.1657 [M+H]+.
实验步骤：Experimental steps:
将(S)-叔丁基2-(3,5-二氨基苯甲酰)丙甲酸甲酯与3,5-二甲酰基-4-羟基-苯甲酸甲酯(1：1，mol/mol)的条件下，加入到50mL的氯仿中，在50度的条件下，反应三天，后除去三氯甲烷溶液。Mix (S)-tert-butyl 2-(3,5-diaminobenzoyl)propanoic acid methyl ester with 3,5-diformyl-4-hydroxy-benzoic acid methyl ester (1:1, mol/mol ), added to 50 mL of chloroform, reacted for three days at 50 degrees, and then removed the chloroform solution.
后加入20mL的乙醇，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，石油醚乙酸乙酯柱层析，得产品。产率为65％，1H NMR(400MHz,CD3Cl)δ:9.28(s,2H),7.61(s,4H),7.36(s,2H),6.88-6.80(m,6H),4.94-4.87(m,5H),4.76-4.71(m,3H),4.47-4.39(m,6H),4.23-4.12(s,6H),3.86(s,9H)1.74-1.61(m,10H),1.47-1.39(m,11H),0.95(t,J＝7.6Hz,3H).HRMS calcd forC72H84F3N9O181419.5886,found:1420.5918[M+H]+。Then add 20mL of ethanol, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, petroleum ether ethyl acetate Ester column chromatography to obtain the product. The yield is 65%, 1 H NMR (400MHz, CD 3 Cl) δ: 9.28(s, 2H), 7.61(s, 4H), 7.36(s, 2H), 6.88-6.80(m, 6H), 4.94- 4.87(m,5H),4.76-4.71(m,3H),4.47-4.39(m,6H),4.23-4.12(s,6H),3.86(s,9H)1.74-1.61(m,10H),1.47 -1.39 (m, 11H), 0.95 (t, J=7.6Hz, 3H). HRMS calcd for C72H84F3N9O181419.5886, found: 1420.5918[M+H] + .
实施例2：甲基3-(((3-氨基-5-(异丁酰胺)苯基)氨基)甲基)-5-(((3-((3-(((3-((3-(甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)-5-(异丁酰胺)苯基)氨基)甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)甲基)-5-(异丁酰胺)苯基)氨基)甲基)-4-羟基苯甲酸甲酯Embodiment 2: Methyl 3-(((3-amino-5-(isobutyramide) phenyl) amino) methyl)-5-(((3-((3-(((3-((3 -(Methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)-5-(isobutyramide)phenyl)amino)methyl)-2-hydroxy-5-(methoxycarbonyl) Benzyl)amino)methyl)-5-(isobutyramide)phenyl)amino)methyl)-4-hydroxybenzoic acid methyl ester
结构式2：Structural formula 2:
反应式2Reaction 2
原料的合成：Synthesis of raw materials:
3,5-二氨基苯甲异丁酰胺的合成Synthesis of 3,5-Diaminobenzylisobutyramide
反应式如下：The reaction formula is as follows:
在0℃下，将异丁胺(0.4g,5.5mmol)和Et3N(2mL,22mmol)溶于20mL二氯甲烷中,后将3,5-二硝基苯甲酰氯(1.34g,5.5mmol)5ml溶液缓慢滴加到上述溶液中,后再室温条件下，反应1小时，将反应液用H2O水洗，Na2SO4干燥，柱层析得到3,5-二硝基苯甲异丁酰胺(1.74g,91.3％).1H NMR(400MHz,CDCl3)δ:9.19(d,J＝2.2Hz,2H),8.95(d,J＝2.2Hz,2H),6.34(s,1H),3.41-3.38(m,2H),2.00-1.95(m,1H),1.55(s,6H).13C NMR(100MHz,CDCl3)δ:162.93,148.67,138.26,127.01,120.99,48.00,28.56,20.16.HRMS calcd for,C11H13N3O5 267.0855found:535.1810[2M+H]+。At 0°C, isobutylamine (0.4g, 5.5mmol) and Et 3 N (2mL, 22mmol) were dissolved in 20mL of dichloromethane, and then 3,5-dinitrobenzoyl chloride (1.34g, 5.5 mmol) 5ml solution was slowly added dropwise to the above solution, and then reacted at room temperature for 1 hour, the reaction solution was washed with H 2 O, dried with Na 2 SO 4 , and 3,5-dinitrobenzyl was obtained by column chromatography Isobutyramide (1.74g, 91.3%).1H NMR (400MHz, CDCl3) δ: 9.19(d, J=2.2Hz, 2H), 8.95(d, J=2.2Hz, 2H), 6.34(s, 1H) ,3.41-3.38(m,2H),2.00-1.95(m,1H),1.55(s,6H). 13 C NMR(100MHz,CDCl3)δ:162.93,148.67,138.26,127.01,120.99,48.00,28.56, 20.16. HRMS calcd for, C11H13N3O5 267.0855 found: 535.1810 [2M+H]+.
将3,5-二硝基苯甲异丁酰胺(1g,3.74mmol)溶于20mL的乙醇中,后将Pd/C(100mg)加入,在氢气条件下，室温条件下反应4小时。后将反应液过滤，浓缩，纯化得到3,5-二氨基苯甲异丁酰胺(0.76g,92.6％)。1H NMR(400MHz,CDCl3)δ:6.44(d,J＝2.0Hz,2H),6.26(s,1H),6.09(t,J＝2.0Hz,1H),3.22-3.19(m,2H),1.90-1.80(m,1H),0.95(s,6H).13C NMR(100MHz,CDCl3)δ:168.41,147.82,137.29,104.29,104.13,50.62,47.25,28.57,20.13.HRMS calcd for,C11H17N3O207.1372found:208.1497[M+H]+。3,5-Dinitrobenzylisobutyramide (1g, 3.74mmol) was dissolved in 20mL of ethanol, then Pd/C (100mg) was added, and reacted under hydrogen at room temperature for 4 hours. Afterwards, the reaction solution was filtered, concentrated, and purified to obtain 3,5-diaminobenzylisobutyramide (0.76 g, 92.6%). 1 H NMR (400MHz, CDCl 3 )δ: 6.44(d, J=2.0Hz, 2H), 6.26(s, 1H), 6.09(t, J=2.0Hz, 1H), 3.22-3.19(m, 2H) ,1.90-1.80(m,1H),0.95(s,6H).13C NMR(100MHz,CDCl3)δ:168.41,147.82,137.29,104.29,104.13,50.62,47.25,28.57,20.13.HRMS calcd for,C11H17N3O207. 1372found: 208.1497[M+H]+.
实验步骤：Experimental steps:
将3,5-二氨基苯甲异丁酰胺与3,5-二甲酰基-4-羟基-苯甲酸甲酯(1：1，mol/mol)的条件下,加入到50mL的氯仿中，在常温条件下，反应五天，后除去三氯甲烷溶液。后加入20mL的乙醇，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，石油醚乙酸乙酯柱层析，得产品。产率为31％，1H NMR(400MHz,CDCl3)δ:7.77(s,6H),6.58(s,6H),6.13-9.09(m,6H),4.32(s,12H),3.85(s,9H),3.24-3.19(m,6H),1.87-1.79(m,3H),0.94(s,18H).13C NMR(100MHz,CDCl3)δ:HRMS calcd for C63H75N9O12 1149.5535,found:1150.5462[M+H]+。Add 3,5-diaminobenzylisobutyramide and 3,5-diformyl-4-hydroxyl-benzoic acid methyl ester (1:1, mol/mol) into 50 mL of chloroform, Under normal temperature conditions, react for five days, and finally remove the chloroform solution. Then add 20mL of ethanol, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, petroleum ether ethyl acetate Ester column chromatography to obtain the product. The yield is 31%, 1 H NMR (400MHz, CDCl 3 ) δ: 7.77(s,6H),6.58(s,6H),6.13-9.09(m,6H),4.32(s,12H),3.85(s ,9H),3.24-3.19(m,6H),1.87-1.79(m,3H),0.94(s,18H). 13 C NMR(100MHz,CDCl 3 )δ:HRMS calcd for C 63 H 75 N 9 O 12 1149.5535,found:1150.5462[M+H] + .
实施例3：甲基3-(((3-氨基-5-(2,5,8,11-四甘醇醇酯-1-氧基)苯基)氨基)甲基)-5-(((3-((3-(((3-((3-(甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)-5-(2,5,8,11-四甘醇醇酯-1-氧基)苯基)氨基)甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)甲基)-5-(2,5,8,11-四甘醇醇酯-1-氧基)苯基)氨基)甲基)-4-羟基苯甲酸甲酯Example 3: Methyl 3-(((3-amino-5-(2,5,8,11-tetraethylene glycol ester-1-oxyl)phenyl)amino)methyl)-5-(( (3-((3-(((3-((3-(methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)-5-(2,5,8,11-tetra Glycol ester-1-oxyl)phenyl)amino)methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)methyl)-5-(2,5,8,11- Tetraethylene glycol ester-1-oxyl)phenyl)amino)methyl)-4-hydroxybenzoic acid methyl ester
结构式3：Structural formula 3:
反应式3Reaction 3
原料的合成：Synthesis of raw materials:
2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二氨基苯甲酸甲酯的合成Synthesis of methyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl 3,5-diaminobenzoate
反应式如下：The reaction formula is as follows:
在0℃下，将三甘醇单甲醚(0.9g,5.5mmol)和Et3N(2mL,22mmol)溶于20mL二氯甲烷中,后将3,5-二硝基苯甲酰氯(1.27g,5.5mmol)5ml溶液缓慢滴加到上述溶液中,后再室温条件下，反应1小时，将反应液用H2O水洗，Na2SO4干燥，柱层析得到2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二硝基苯甲酸甲酯(1.75g,89.3％).1H NMR(400MHz,CDCl3)δ:9.24(d,J＝2.2Hz,2H),9.19(d,J＝2.2Hz,2H),4.63-4.61(m,2H),3.91-3.89(m,2H),3.74-3.65(m,6H),3.56-3.54(m,2H),3.37(s,3H).13C NMR(100MHz,CDCl3)δ:162.53,148.67,133.85,129.54,122.39,71.92,70.69,70.66,70.61,68.76,65.79,59.00.HRMS calcd forC14H18N2O9358.1012,found:359.1051[M+H]+。At 0°C, triethylene glycol monomethyl ether (0.9g, 5.5mmol) and Et 3 N (2mL, 22mmol) were dissolved in 20mL of dichloromethane, and then 3,5-dinitrobenzoyl chloride (1.27 g, 5.5mmol) 5ml solution was slowly added dropwise to the above solution, then reacted for 1 hour at room temperature, washed the reaction solution with H 2 O, dried with Na 2 SO 4 , and obtained 2-(2-( 2-Methoxyethoxy)ethoxy)ethyl 3,5-dinitrobenzoic acid methyl ester (1.75g, 89.3%). 1 H NMR (400MHz, CDCl 3 )δ:9.24(d,J =2.2Hz, 2H), 9.19(d, J=2.2Hz, 2H), 4.63-4.61(m, 2H), 3.91-3.89(m, 2H), 3.74-3.65(m, 6H), 3.56-3.54( m,2H),3.37(s,3H).13C NMR(100MHz,CDCl3)δ:162.53,148.67,133.85,129.54,122.39,71.92,70.69,70.66,70.61,68.76,65.79,59.00. ,found: 359.1051[M+H]+.
将2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二硝基苯甲酸甲酯(1g,2.79mmol)溶于20mL的乙醇中,后将Pd/C(100mg)加入,在氢气条件下，室温条件下反应4小时。后将反应液过滤，浓缩，纯化得到2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二氨基苯甲酸甲酯(0.73g,88.3％)。1H NMR(400MHz,CDCl3)δ:6.83(d,J＝1.7Hz,2H),6.29(s,1H),4.41(t,J＝4.4Hz,2H),4.14(s,4H),3.80(t,J＝4.8Hz,2H),3.71-3.64(m,6H),3.66-3.53(m,2H),3.37(s,3H).13C NMR(100MHz,CDCl3)δ:166.71,146.69,131.90,107.79,106.59,71.90,70.69,70.58,70.53,69.25,63.99,58.97.HRMS calcd for C14H22N2O5 298.1529,found:299.1627[M+H]+。Dissolve 2-(2-(2-methoxyethoxy)ethoxy)ethyl 3,5-dinitrobenzoic acid methyl ester (1 g, 2.79 mmol) in 20 mL of ethanol, and then add Pd/ C (100 mg) was added, and reacted at room temperature for 4 hours under hydrogen atmosphere. Afterwards, the reaction solution was filtered, concentrated, and purified to obtain methyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl 3,5-diaminobenzoate (0.73 g, 88.3%). 1H NMR (400MHz, CDCl 3 ) δ: 6.83(d, J=1.7Hz, 2H), 6.29(s, 1H), 4.41(t, J=4.4Hz, 2H), 4.14(s, 4H), 3.80( t,J=4.8Hz,2H),3.71-3.64(m,6H),3.66-3.53(m,2H),3.37(s,3H).13C NMR(100MHz,CDCl3)δ:166.71,146.69,131.90, 107.79, 106.59, 71.90, 70.69, 70.58, 70.53, 69.25, 63.99, 58.97. HRMS calcd for C14H22N2O5 298.1529, found: 299.1627[M+H] + .
实验步骤：Experimental steps:
将2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二氨基苯甲酸甲酯与3,5-二甲酰基-4-羟基-苯甲酸甲酯(1：1，mol/mol)的条件下,加入到50mL的氯仿中，常温下，反应三天，后除去三氯甲烷溶液。后加入20mL的乙醇，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，二氯甲烷和甲醇柱层析，得产品。产率为60％，1H NMR(400MHz,CDCl3)δ:7.75(s,6H),6.95(d,J＝0.8Hz,6H),6.19(s,3H),4.39(t,J＝4.8Hz,6H),4.30(s,12H),3.80-3.77(m,15H),3.70-3.62(m,18H),3.52(dd,J＝3.6Hz,6H),3.34(s,9H).HRMS calcd for C72H90N6O24 1422.6006,found:1423.6714[M+H]+。2-(2-(2-Methoxyethoxy)ethoxy)ethyl 3,5-diaminobenzoic acid methyl ester and 3,5-diformyl-4-hydroxy-benzoic acid methyl ester ( 1:1, mol/mol), added to 50mL of chloroform, reacted for three days at room temperature, and finally removed the chloroform solution. Then add 20mL of ethanol, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, dichloromethane and The product was obtained by methanol column chromatography. The yield is 60%, 1 H NMR (400MHz, CDCl 3 ) δ: 7.75(s, 6H), 6.95(d, J=0.8Hz, 6H), 6.19(s, 3H), 4.39(t, J=4.8 Hz,6H),4.30(s,12H),3.80-3.77(m,15H),3.70-3.62(m,18H),3.52(dd,J＝3.6Hz,6H),3.34(s,9H).HRMS calcd for C 72 H 90 N 6 O 24 1422.6006, found: 1423.6714[M+H] + .
实施例4：2-(2-(2-甲氧乙氧基)乙氧基)乙基3-氨基-5-((3-(((3-((3-(((3-((3-(甲基)-5-(异丁酰胺)苄基)氨基)-5-(2,5,8,11-四甘醇酯-1-氧基)苯基)氨基)甲基)-5-(异丁酰胺)苄基)氨基)甲基)-5-(2,5,8,11-四甘醇酯-1-氧基)苯基)氨基)甲基)-5-(异丁酰胺)苄基)氨基)苯甲酸甲酯Example 4: 2-(2-(2-methoxyethoxy) ethoxy) ethyl 3-amino-5-((3-(((3-((3-(((3-(( 3-(methyl)-5-(isobutyramide)benzyl)amino)-5-(2,5,8,11-tetraethylene glycol ester-1-oxyl)phenyl)amino)methyl)- 5-(isobutyramide)benzyl)amino)methyl)-5-(2,5,8,11-tetraethylene glycol ester-1-oxyl)phenyl)amino)methyl)-5-(iso Butyramide) benzyl) amino) methyl benzoate
结构式4Formula 4
反应式4Reaction 4
原料的合成：Synthesis of raw materials:
N-(3,5-二甲酰基-苯基)-异丁酰胺的合成Synthesis of N-(3,5-diformyl-phenyl)-isobutyramide
反应式如下：The reaction formula is as follows:
将5-硝基苯-1,3-间苯二甲醛(2g,11.2mmol),乙二醇(1.38g,22.3mmol)和对甲苯磺酸(0.12g,1.1mmol)加入50mL的甲苯中,在分水装置的条件下，回流过夜，后除去溶剂，柱层析得到白色固体2,2'-(5-硝基-1,3-苯烯)双(1,3-二氧戊环)(2.6g,87.4％).1H NMR(400MHz,CD3Cl)δ:8.27(d,J＝2.0Hz,2H),7.86(s,1H),5.83(s,2H),4.26-3.94(m,8H).13CNMR(100MHz,CD3Cl)δ:189.51,148.28,140.73,130.66,121.98,101.99,65.43,60.27,20.90,14.12.HRMS calcd for C12H13NO6267.0743,found:268.0906[M+H]+。Add 5-nitrobenzene-1,3-isophthalaldehyde (2g, 11.2mmol), ethylene glycol (1.38g, 22.3mmol) and p-toluenesulfonic acid (0.12g, 1.1mmol) into 50mL of toluene, Under the conditions of the water separation device, reflux overnight, and then remove the solvent, column chromatography to obtain a white solid 2,2'-(5-nitro-1,3-phenylene)bis(1,3-dioxolane) (2.6g, 87.4%). 1 H NMR (400MHz, CD 3 Cl) δ: 8.27(d, J=2.0Hz, 2H), 7.86(s, 1H), 5.83(s, 2H), 4.26-3.94( m,8H) .13 CNMR(100MHz,CD 3 Cl)δ:189.51,148.28,140.73,130.66,121.98,101.99,65.43,60.27,20.90,14.12.HRMS calcd for C12H13NO6267.0743,found:268.0H906 ] + .
将2,2'-(5-硝基-1,3-苯烯)双(1,3-二氧戊环)(1.5g,5.6mmol)溶于EtOH(20mL)中，后加入10％Pd/C(0.2g)，氢气条件下反应3h。后将反应液过滤，浓缩，得黄色固体3,5-二(1,3-二氧戊环-2)苯胺(1.33g,100％).1H NMR(400MHz,CD3OD)δ:6.91(s,1H),6.84(d,J＝2.0Hz,2H),5.66(s,2H),4.08-3.98(m,8H).13C NMR(100MHz,CD3OD)δ:147.31,139.10,113.95,103.52,64.82,62.93.HRMS calcd for C12H15NO4 237.1001,found:238.1206[M+H]+。2,2'-(5-nitro-1,3-phenylene)bis(1,3-dioxolane) (1.5 g, 5.6 mmol) was dissolved in EtOH (20 mL), followed by the addition of 10% Pd /C (0.2g), reacted under hydrogen for 3h. Afterwards, the reaction solution was filtered and concentrated to obtain 3,5-bis(1,3-dioxolane-2)aniline (1.33g, 100%) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ: 6.91(s ,1H),6.84(d,J=2.0Hz,2H),5.66(s,2H),4.08-3.98(m,8H). 13 C NMR(100MHz,CD 3 OD)δ:147.31,139.10,113.95, 103.52, 64.82, 62.93. HRMS calcd for C12H15NO4 237.1001, found: 238.1206[M+H] + .
将3,5-二(1,3-二氧戊环-2)苯胺(0.5g,2.1mmol)，异丁酸(0.18g,2.1mmol)溶于25mL DCM中,后加入Et3N(1mL),HOBt(10mg)和EDCI(0.8g,4.2mmol)，得白色固体N-(3,5-二(1,3-二氧戊环-2)苯基)异丁酰胺(0.39g,61.1％).1H NMR(400MHz,CD3COCD3)δ:7.83(s,2H),7.27(s,1H),6.78(d,J＝2.0Hz,2H),4.07-3.98(m,8H),1.98(s,1H),1.18(d,J＝7.2Hz,6H).HRMS calcd for C16H21NO5307.142,found:308.1467[M+H]+。3,5-bis(1,3-dioxolane-2)aniline (0.5g, 2.1mmol), isobutyric acid (0.18g, 2.1mmol) were dissolved in 25mL DCM, and Et 3 N (1mL ), HOBt (10mg) and EDCI (0.8g, 4.2mmol) to give white solid N-(3,5-bis(1,3-dioxolane-2)phenyl)isobutyramide (0.39g, 61.1 %). 1 H NMR (400MHz, CD 3 COCD 3 )δ: 7.83(s, 2H), 7.27(s, 1H), 6.78(d, J=2.0Hz, 2H), 4.07-3.98(m, 8H) , 1.98(s, 1H), 1.18(d, J=7.2Hz, 6H). HRMS calcd for C16H21NO5307.142, found: 308.1467[M+H] + .
将N-(3,5-二(1,3-二氧戊环-2)苯基)异丁酰胺(0.5g,1.6mmol)溶于10mL的甲醇中,1N HCl 10Ml加入,室温搅拌2小时，后用1N NaOH将反应液调至pH＝7,后乙酸乙酯萃取，无水硫酸钠干燥，浓缩，柱层析得白色固体N-(3,5-二甲酰基-苯基)-异丁酰胺(0.33g,94.1％).1H NMR(400MHz,CD3COCD3)δ:10.08(s,2H),9.61(s,1H),8.47(s,2H),8.09(s,1H),2.75-2.69(m,1H),1.21(d,J＝7.2Hz,6H).13C NMR(100MHz,CD3COCD3)δ:191.31,175.97,141.26,137.88,125.01,124.26,124.16,35.84,29.40,29.21,29.02,28.83,28.63,18.88.HRMS calcd for C12H13NO3 219.0895,found:220.0923[M+H]+。Dissolve N-(3,5-bis(1,3-dioxolane-2)phenyl)isobutyramide (0.5g, 1.6mmol) in 10mL of methanol, add 1N HCl 10Ml, stir at room temperature for 2 hours , then adjusted the reaction solution to pH = 7 with 1N NaOH, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and column chromatography gave white solid N-(3,5-diformyl-phenyl)-iso Butanamide (0.33g, 94.1%). 1 H NMR (400MHz, CD 3 COCD 3 )δ:10.08(s,2H),9.61(s,1H),8.47(s,2H),8.09(s,1H) ,2.75-2.69(m,1H),1.21(d,J=7.2Hz,6H).13C NMR(100MHz,CD3COCD3)δ:191.31,175.97,141.26,137.88,125.01,124.26,124.16,35.84,29.40,29.21 , 29.02, 28.83, 28.63, 18.88. HRMS calcd for C12H13NO3 219.0895, found: 220.0923 [M+H]+.
实验步骤：Experimental steps:
将2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二氨基苯甲酸甲酯与N-(3,5-二甲酰基-苯基)-异丁酰胺(1：1，mol/mol)的条件下,加入到50mL的氯仿中，常温下，反应三天，后除去三氯甲烷溶液。后加入20mL的乙醇，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，二氯甲烷和甲醇柱层析，得产品。产率为12％，HRMS calcd for C78H105N9O18 1455.7578,found:1456.7653[M+H]+。Methyl 2-(2-(2-methoxyethoxy)ethoxy)ethyl 3,5-diaminobenzoate and N-(3,5-diformyl-phenyl)-isobutyl Under the condition of amide (1:1, mol/mol), it was added into 50mL of chloroform, and reacted for three days at room temperature, and then the chloroform solution was removed. Then add 20mL of ethanol, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, dichloromethane and The product was obtained by methanol column chromatography. Yield 12%, HRMS calcd for C78H105N9O18 1455.7578, found: 1456.7653 [M+H] + .
实施例5：甲基3-(((3-氨基-5-(((S)-1-丁氧基-1-氧丙烷-2-基)氨基甲酰)-2-氟苯基)氨基)甲基)-5-(((5-(((S)-1-丁氧基-1-氧丙烷-2-基)氨基甲酰)-3-((3-(((5-(((S)-1-丁氧基-1-氧丙烷-2-基)氨基甲酰)-2-氟-3-((3-(甲基)-2-羟基5-(甲氧羰基)苄基)氨基)苯基)氨基)甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)甲基)-2-氟苯基)氨基)甲基)-4-羟基苯甲酸甲酯Example 5: Methyl 3-(((3-amino-5-(((S)-1-butoxy-1-oxypropan-2-yl)carbamoyl)-2-fluorophenyl)amino )methyl)-5-(((5-(((S)-1-butoxy-1-oxypropan-2-yl)carbamoyl)-3-((3-(((5-( ((S)-1-butoxy-1-oxypropan-2-yl)carbamoyl)-2-fluoro-3-((3-(methyl)-2-hydroxyl 5-(methoxycarbonyl) Benzyl)amino)phenyl)amino)methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)methyl)-2-fluorophenyl)amino)methyl)-4-hydroxybenzene Methyl formate
结构式5Structural formula 5
反应式5Reaction 5
原料的合成：Synthesis of raw materials:
(S)-叔丁基2-(3,5-二氨基-4-氟苯甲酰)丙酸酯的合成反应式如下：The synthetic reaction formula of (S)-tert-butyl 2-(3,5-diamino-4-fluorobenzoyl) propionate is as follows:
将4-氟-3,5-二硝基苯甲酸(1g,4.39mmol)溶于30mL的甲醇中,将10％Pd/C(100mg)加入上述溶液，在氢气条件下，50℃下反应过夜。滤掉Pd/C,浓缩得产品3,5-二氨基-4-氟苯甲酸。1H NMR(400MHz,DMSO-d6)δ:6.64(d,J＝7.6Hz,2H),5.02(s,4H).13C NMR(100MHz,DMSO-d6)δ:168.12,143.86,141.51,136.58,136.46,126.73,126.69,106.18,106.14.HRMS calcd for C7H7FN2O2170.0492,found:171.0478[M+H]+。Dissolve 4-fluoro-3,5-dinitrobenzoic acid (1g, 4.39mmol) in 30mL of methanol, add 10% Pd/C (100mg) to the above solution, and react overnight at 50°C under hydrogen . Pd/C was filtered off and concentrated to obtain the product 3,5-diamino-4-fluorobenzoic acid. 1 H NMR (400MHz, DMSO-d 6 ) δ: 6.64 (d, J = 7.6 Hz, 2H), 5.02 (s, 4H). 13 C NMR (100 MHz, DMSO-d 6 ) δ: 168.12, 143.86, 141.51, 136.58, 136.46, 126.73, 126.69, 106.18, 106.14. HRMS calcd for C7H7FN2O2 170.0492, found: 171.0478[M+H]+.
将3,5-二氨基-4-氟苯甲酸(0.5g,2.94mmol)和(S)-丁基2-氨基丙酸酯(0.53g,2.94mmol)溶于25mL二氯甲烷中,后加入Et3N(3mL),HOBt(10mg),EDCI(1.12g,5.88mmol)，反应过夜。后将反应液经过水洗，Na2SO4干燥，柱层析，得(S)-叔丁基2-(3,5-二氨基-4-氟苯甲酰)丙酸酯(0.4g,46.3％)。1H NMR(400MHz,CD3Cl)δ:6.76(s,1H),6.61(d,J＝7.6Hz,2H),4.71-4.67(m,1H),4.17-4.13(m,2H),3.82(s,4H),1.64-1.61(m,2H),1.46(d,J＝7.2Hz,3H),1.38-1.22(m,2H),0.94(t,J＝1.2Hz,3H).13C NMR(100MHz,CD3Cl)δ:173.44,166.77,162.53,143.88,141.53,134.99,134.78,130.32,105.62,105.59,105.07,65.37,56.90,48.51,45.48,44.83,36.45,31.39,30.52,29.33,19.01,18.52,13.64.HRMS calcdfor C14H20FN3O3 297.1489,found:298.1513[M+H]+。Dissolve 3,5-diamino-4-fluorobenzoic acid (0.5 g, 2.94 mmol) and (S)-butyl 2-aminopropionate (0.53 g, 2.94 mmol) in 25 mL of dichloromethane, and then add Et 3 N (3 mL), HOBt (10 mg), EDCI (1.12 g, 5.88 mmol), react overnight. Afterwards, the reaction solution was washed with water, dried over Na 2 SO 4 , and subjected to column chromatography to obtain (S)-tert-butyl 2-(3,5-diamino-4-fluorobenzoyl)propionate (0.4g, 46.3 %). 1 H NMR (400MHz, CD3Cl) δ: 6.76(s, 1H), 6.61(d, J=7.6Hz, 2H), 4.71-4.67(m, 1H), 4.17-4.13(m, 2H), 3.82(s ,4H),1.64-1.61(m,2H),1.46(d,J=7.2Hz,3H),1.38-1.22(m,2H),0.94(t,J=1.2Hz,3H).13C NMR(100MHz ,CD3Cl)δ:173.44,166.77,162.53,143.88,141.53,134.99,134.78,130.32,105.62,105.59,105.07,65.37,56.90,48.51,45.48,44.83,36.45,31.39,30.52,29.33,19.01,18.52,13.64 .HRMS calcd for C14H20FN3O3 297.1489, found: 298.1513[M+H] + .
实验步骤：Experimental steps:
将(S)-叔丁基2-(3,5-二氨基-4-氟苯甲酰)丙酸酯与3,5-二甲酰基-4-羟基-苯甲酸甲酯(1：1，mol/mol)的条件下,加入到50mL的氯仿中，常温下，反应三天，后除去三氯甲烷溶液。后加入20mL的乙醇，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，二氯甲烷和甲醇柱层析，得产品。产率为40％，1H NMR(400MHz,CD3Cl)δ:9.28(s,2H),7.61(s,4H),7.36(s,2H),6.88-6.80(m,6H),4.94-4.87(m,5H),4.76-4.71(m,3H),4.47-4.39(m,6H),4.23-4.12(s,6H),3.86(s,9H)1.74-1.61(m,10H),1.47-1.39(m,11H),0.95(t,J＝7.6Hz,3H).HRMS calcd forC72H84F3N9O18 1419.5886,found:1420.5918[M+H]+。Mix (S)-tert-butyl 2-(3,5-diamino-4-fluorobenzoyl)propionate with 3,5-diformyl-4-hydroxy-benzoic acid methyl ester (1:1, mol/mol), added to 50mL of chloroform, reacted for three days at room temperature, and finally removed the chloroform solution. Then add 20mL of ethanol, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, dichloromethane and The product was obtained by methanol column chromatography. The yield was 40%, 1 H NMR (400MHz, CD 3 Cl) δ: 9.28(s, 2H), 7.61(s, 4H), 7.36(s, 2H), 6.88-6.80(m, 6H), 4.94- 4.87(m,5H),4.76-4.71(m,3H),4.47-4.39(m,6H),4.23-4.12(s,6H),3.86(s,9H)1.74-1.61(m,10H),1.47 -1.39 (m, 11H), 0.95 (t, J=7.6Hz, 3H). HRMS calcd for C72H84F3N9O18 1419.5886, found: 1420.5918 [M+H] + .
实施例6：(S)-叔丁基2-(3-((5-(((3-((5-(((3-((2,4-双(2-(2-(2-甲氧乙氧基)乙氧基)乙氧基)-5-甲基苄基)氨基)甲基)-5-(((S)-1-叔丁氧基-1-氧乙烷-2-yl)氨基甲酰)苯基)氨基)甲基)-2,4-双(2-(2-(2-甲氧乙氧基)乙氧基)乙氧基)苄基)氨基)甲基)-5-(((S)-1-(叔丁基)-1-氧丙烷2-基)氨基甲酰)苯基)氨基)甲基)-2,4-双(2-(2-(2-甲氧乙氧基)乙氧基)乙氧基)苄基)氨基)苯甲酰丙酯Example 6: (S)-tert-butyl 2-(3-((5-(((3-((5-(((3-((2,4-bis(2-(2-(2- Methoxyethoxy)ethoxy)ethoxy)-5-methylbenzyl)amino)methyl)-5-(((S)-1-tert-butoxy-1-oxoethane-2 -yl)carbamoyl)phenyl)amino)methyl)-2,4-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzyl)amino)methyl Base)-5-(((S)-1-(tert-butyl)-1-oxypropan2-yl)carbamoyl)phenyl)amino)methyl)-2,4-bis(2-(2 -(2-Methoxyethoxy)ethoxy)ethoxy)benzyl)amino)benzoylpropyl ester
结构式6Formula 6
反应式6Reaction 6
原料(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)间苯二醛的合成：Synthesis of starting material (2-(2-(2-methoxyethoxy)ethoxy)ethoxy)mphthalaldehyde:
反应式如下：The reaction formula is as follows:
无水无氧的条件下，-78度下，将1mmol的1,5-二溴-2,4-双(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)苯溶于20mL THF中，后缓慢加入3mmol的LDA THF溶液，后反应在该温度下，反应2小时，后加入1mL DMF，继续反应4小时，后用20mL饱和氯化铵溶液,除去大部分THF溶液，乙酸乙酯萃取，无水硫酸钠干燥，柱层析，得无色油状化合物，产率为62％。1H NMR(400MHz,CD3COCD3)δ:10.35(s,2H),8.21(s,1H),7.03(s,1H),4.50-4.47(m,4H),3.96(t,J＝4.4Hz,4H),3.96(t,J＝2.4Hz,4H),3.69-3.58(m,8H),3.48-3.45(m,4H),3.28(s,6H).13CNMR(100MHz,CD3COCD3)δ:186.89,167.13,128.61,118.85,97.91,71.76,70.64,70.39,70.18,69.22,69.05,57.87.HRMS calcd for C22H34O10 458.2152found459.2271[M+H]+。Under anhydrous and oxygen-free conditions, at -78 degrees, 1 mmol of 1,5-dibromo-2,4-bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy Base) benzene was dissolved in 20mL THF, then slowly added 3mmol of LDA THF solution, reacted at this temperature, reacted for 2 hours, then added 1mL DMF, continued to react for 4 hours, and then used 20mL saturated ammonium chloride solution to remove large Part of the THF solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain a colorless oily compound with a yield of 62%. 1 H NMR (400MHz, CD 3 COCD 3 ) δ: 10.35(s, 2H), 8.21(s, 1H), 7.03(s, 1H), 4.50-4.47(m, 4H), 3.96(t, J=4.4 Hz,4H),3.96(t,J＝2.4Hz,4H),3.69-3.58(m,8H),3.48-3.45(m,4H),3.28(s,6H). 13 CNMR(100MHz,CD 3 COCD 3 ) δ:186.89,167.13,128.61,118.85,97.91,71.76,70.64,70.39,70.18,69.22,69.05,57.87. HRMS calcd for C22H34O10 458.2152found459.2271[M+H] + .
实验步骤：Experimental steps:
将(S)-叔丁基2-(3,5-二氨基苯甲酰)丙甲酸甲酯与(2-(2-(2-甲氧基乙氧基)乙氧基)乙氧基)间苯二醛(1：1，mol/mol)的条件下,加入到50mL的氯仿中，常温下，反应五天，后除去三氯甲烷溶液。后加入20mL的乙醇，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，二氯甲烷和甲醇柱层析，得产品。产率为30％，1H NMR(400MHz,CDCl3)δ:7.18(s,3H),6.82(d,J＝6.8Hz,3H),6.49-6.46(m,2H),6.41-6.35(m,2H),6.08(t,J＝2.0Hz,3H),4.64-4.54(m,3H),4.23-4.21(m,12H),4.48-4.11(m,12H),3.86-3.82(m,12H),3.73-3.71(m,12H),3.66-3.60(m,24H),3.54-3.50(m,24H),3.38-3.31(m,18H),1.49-1.46(m,36H).HRMS calcd forC72H90N6O24C108H165N9O33 2116.151,found:1059.5761[M/2+H]+。Mix (S)-tert-butyl 2-(3,5-diaminobenzoyl)propanoic acid methyl ester with (2-(2-(2-methoxyethoxy)ethoxy)ethoxy) Under the condition of isophthalaldehyde (1:1, mol/mol), it was added into 50mL of chloroform, and reacted for five days at room temperature, and then the chloroform solution was removed. Then add 20mL of ethanol, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, dichloromethane and The product was obtained by methanol column chromatography. The yield is 30%, 1 H NMR (400MHz, CDCl 3 )δ: 7.18(s, 3H), 6.82(d, J=6.8Hz, 3H), 6.49-6.46(m, 2H), 6.41-6.35(m ,2H),6.08(t,J=2.0Hz,3H),4.64-4.54(m,3H),4.23-4.21(m,12H),4.48-4.11(m,12H),3.86-3.82(m,12H ),3.73-3.71(m,12H),3.66-3.60(m,24H),3.54-3.50(m,24H),3.38-3.31(m,18H),1.49-1.46(m,36H).HRMS calcd forC 72 H 90 N 6 O 24 C108H165N9O33 2116.151, found: 1059.5761[M/2+H] + .
实施例7：2-(2-(2-甲氧乙氧基)乙氧基)乙基3-(((6-氨基吡啶-2-基)氨基)甲基)-5-(((6-((3-(((6-((3-(甲基)-5-(2,5,8,11-四甘醇酯-1-氧基)-2-羟基苄基)氨基)甲基)吡啶-2-基)氨基)甲基)-5-(2,5,8,11-四甘醇酯-1-氧基)-2-羟基苄基)氨基)吡啶-2-基)氨基)甲基)-4-羟基苯甲酯Embodiment 7: 2-(2-(2-Methoxyethoxy) ethoxy) ethyl 3-(((6-aminopyridin-2-yl) amino) methyl)-5-(((6 -((3-(((6-((3-(methyl)-5-(2,5,8,11-tetraethylene glycol ester-1-oxyl)-2-hydroxybenzyl)amino)methyl Base) pyridin-2-yl)amino)methyl)-5-(2,5,8,11-tetraethylene glycol ester-1-oxyl)-2-hydroxybenzyl)amino)pyridin-2-yl) Amino)methyl)-4-hydroxybenzyl ester
结构式7Formula 7
反应式7Reaction 7
原料的合成：Synthesis of raw materials:
4-羟基苯甲酸2-[2-(2-甲氧基-乙氧基)-乙氧基]-乙酯的合成Synthesis of 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl 4-hydroxybenzoate
反应式如下：The reaction formula is as follows:
将4-羟基苯甲酸2-[2-(2-甲氧基-乙氧基)-乙氧基]-乙酯(5g,17.6mmol)和乌洛托品(9.87g,70.4mmol)溶于TFA(50mL)中，回流24h，后将Water(400mL)加入到上述溶液中，加热至80度，后冷却，得黄色固体，后乙酸乙酯萃取，并溶解黄色固体，合并有机相，Na2SO4干燥，浓缩，柱层析得到产品(2g,34.1％).1H NMR(400MHz,CD3COCD3)δ:12.25(s,1H),10.37(s,2H),8.69(s,2H),4.51-4.49(m,2H),3.86(dd,J＝3.6,4.4Hz,2H),3.66(dd,J＝2.4,0.8Hz,2H),3.62-3.51(m,4H),3.47-3.44(m,2H),3.04(s,3H).13C NMR(100MHz,CD3COCD3)δ:192.31,172.74,162.81,138.20,123.12,100.10,71.75,70.40,70.35,70.21,68.70,64.52,57.85,HRMS calcd for C16H20O8 340.1158,found:363.1055[M+Na]+。2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl 4-hydroxybenzoate (5g, 17.6mmol) and urotropine (9.87g, 70.4mmol) were dissolved in In TFA (50mL), reflux for 24h, then add Water (400mL) to the above solution, heat to 80 degrees, and then cool to obtain a yellow solid, then extract with ethyl acetate, and dissolve the yellow solid, combine the organic phase, Na 2 SO 4 was dried, concentrated, and the product was obtained by column chromatography (2g, 34.1%). 1 H NMR (400MHz, CD 3 COCD 3 ) δ: 12.25(s, 1H), 10.37(s, 2H), 8.69(s, 2H ),4.51-4.49(m,2H),3.86(dd,J＝3.6,4.4Hz,2H),3.66(dd,J＝2.4,0.8Hz,2H),3.62-3.51(m,4H),3.47- 3.44(m,2H),3.04(s,3H). 13 C NMR(100MHz,CD 3 COCD 3 )δ:192.31,172.74,162.81,138.20,123.12,100.10,71.75,70.40,70.35,70.21,68.70,64.52 , 57.85, HRMS calcd for C16H20O8 340.1158, found: 363.1055[M+Na] + .
实验步骤：Experimental steps:
将2,6-二氨基吡啶与2-(2-(2-甲氧基乙氧基)乙氧基)乙基3,5-二甲酰基-4-羟基苯甲酸甲酯(1：1，mol/mol)的条件下,加入到50mL的氯仿中，常温下，反应五天，后除去三氯甲烷溶液。后加入10mL的乙醇和40mL四氢呋喃的混合溶剂，加入10倍初始原料摩尔比的硼氢化钠，反应10分钟，后用1M的稀盐酸中和，除去乙醇溶液，乙酸乙酯萃取，无水硫酸钠干燥，二氯甲烷和甲醇柱层析，得产品。产率为27％。HRMS calcd for C63H81N9O181252.3667,found:1253.3413[M+H]+。2,6-diaminopyridine and 2-(2-(2-methoxyethoxy)ethoxy)ethyl 3,5-diformyl-4-hydroxybenzoic acid methyl ester (1:1, mol/mol), added to 50mL of chloroform, reacted for five days at room temperature, and finally removed the chloroform solution. Then add 10mL of ethanol and 40mL of tetrahydrofuran as a mixed solvent, add 10 times the initial raw material molar ratio of sodium borohydride, react for 10 minutes, and then neutralize with 1M dilute hydrochloric acid, remove the ethanol solution, extract with ethyl acetate, anhydrous sodium sulfate After drying, dichloromethane and methanol column chromatography, the product was obtained. The yield was 27%. HRMS calcd for C63H81N9O181252.3667, found: 1253.3413[M+H] + .
实施例8：甲基3-(((3-氨基-5-(((S)-1-氧丙烷-2-基)氨基甲酰)苯基)氨基)甲基)-5-(((3-((3-(((3-((3-(甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)-5-(((S)-1-氧丙烷-2-yl)氨基甲酰)苯基)氨基)甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)甲基)-5-(((S)-氧丙烷-2-yl)氨基甲酰)苯基)氨基)甲基)-4-羟基苯甲酸Example 8: Methyl 3-(((3-amino-5-(((S)-1-oxypropan-2-yl)carbamoyl)phenyl)amino)methyl)-5-((( 3-((3-(((3-((3-(methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)-5-(((S)-1-oxypropane- 2-yl)carbamoyl)phenyl)amino)methyl)-2-hydroxy-5-(methoxycarbonyl)benzyl)amino)methyl)-5-(((S)-oxypropane-2- yl)carbamoyl)phenyl)amino)methyl)-4-hydroxybenzoic acid
结构式8Formula 8
反应式8Reaction 8
将化合物甲基3-(((3-氨基-5-(((S)-1-(叔丁氧基)-1-氧丙烷-2-基)氨基甲酰)苯基)氨基)甲基)-5-(((3-((3-(((3-((3-(甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)-5-(((S)-1-(叔丁氧基)-1-氧丙烷-2-yl)氨基甲酰)苯基)氨基)甲基)-2-羟基-5-(甲氧羰基)苄基)氨基)甲基)-5-(((S)-1-(叔丁氧基)-1-氧丙烷-2-yl)氨基甲酰)苯基)氨基)甲基)-4-羟基苯甲酸甲酯溶于3mL三氟甲酸中，室温条件下反应3小时，后除去三氟甲酸，加入乙醚，过滤得白色固体(100％)。1H NMR(400MHz,DMSO-d6)δ:8.37(d,J＝7.2Hz,6H),7.75(s,6H),5.91(s,3H),4.38(d,J＝7.2Hz,3H),4.24(s,12H),3.72(s,9H),1.37(s,9H).13C NMR(100MHz,DMSO-d6)δ:174.71,167.53,166.61,157.79,148.60,136.17,129.07,126.17,120.89,103.99,100.11,52.06,48.45,43.42,17.44.HRMS calcd for C60H63N9O181197.4291,found:1198.84[M+H]+。The compound methyl 3-(((3-amino-5-(((S)-1-(tert-butoxy)-1-oxypropan-2-yl)carbamoyl)phenyl)amino)methyl )-5-(((3-((3-(((3-((3-(methyl)-2-hydroxyl-5-(methoxycarbonyl)benzyl)amino)-5-(((S )-1-(tert-butoxy)-1-oxypropane-2-yl)carbamoyl)phenyl)amino)methyl)-2-hydroxyl-5-(methoxycarbonyl)benzyl)amino)methyl yl)-5-(((S)-1-(tert-butoxy)-1-oxypropane-2-yl)carbamoyl)phenyl)amino)methyl)-4-hydroxybenzoic acid methyl ester In 3 mL of trifluoroformic acid, react at room temperature for 3 hours, then remove the trifluoroformic acid, add diethyl ether, and filter to obtain a white solid (100%). 1 H NMR (400MHz, DMSO-d 6 )δ: 8.37(d, J=7.2Hz, 6H), 7.75(s, 6H), 5.91(s, 3H), 4.38(d, J=7.2Hz, 3H) ,4.24(s,12H),3.72(s,9H),1.37(s,9H). 13 C NMR(100MHz,DMSO-d 6 )δ:174.71,167.53,166.61,157.79,148.60,136.17,129.07,126.17 , 120.89, 103.99, 100.11, 52.06, 48.45, 43.42, 17.44. HRMS calcd for C60H63N9O181197.4291, found: 1198.84[M+H] + .
以上具体实例仅用于说明本发明的技术方案而非限制，尽管参照上述实施例详细描述了本发明，本领域的普通技术人员应当理解，对本发明的技术方案进行修改或等同替换，都不脱离本发明的技术方案的实质和保护范围，其均应涵盖在本发明的权利要求范围内。The above specific examples are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the above-mentioned embodiments, those of ordinary skill in the art should understand that modifications or equivalent replacements to the technical solutions of the present invention will not depart from The essence and protection scope of the technical solution of the present invention shall be covered by the claims of the present invention.
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