CN116102574A - 4-nitrophthaloyl nitrogen oxygen heterocyclic compound, preparation method and application thereof - Google Patents
4-nitrophthaloyl nitrogen oxygen heterocyclic compound, preparation method and application thereof Download PDFInfo
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- -1 4-nitrophthaloyl nitrogen oxygen heterocyclic compound Chemical class 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 239000007822 coupling agent Substances 0.000 claims abstract description 7
- 229940125904 compound 1 Drugs 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 230000035484 reaction time Effects 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-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 5
- 230000008569 process Effects 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229940078552 o-xylene Drugs 0.000 claims description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims 6
- 239000007787 solid Substances 0.000 description 54
- 239000000243 solution Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 18
- 238000002425 crystallisation Methods 0.000 description 16
- 230000008025 crystallization Effects 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 15
- 238000004321 preservation Methods 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 12
- 150000003983 crown ethers Chemical class 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- SLBQXWXKPNIVSQ-UHFFFAOYSA-N 4-nitrophthalic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1C(O)=O SLBQXWXKPNIVSQ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- GNJQAVDGUWVKEE-UHFFFAOYSA-N 4-nitrobenzene-1,2-dicarbonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C(C(Cl)=O)=C1 GNJQAVDGUWVKEE-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical compound C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- PWSKHLMYTZNYKO-UHFFFAOYSA-N heptane-1,7-diamine Chemical compound NCCCCCCCN PWSKHLMYTZNYKO-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000005372 isotope separation Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/08—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and more than one oxygen atom
Abstract
The invention discloses a 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound and a preparation method thereof, and a method for preparing aza crown ether by adopting the compound, wherein the preparation method comprises the steps of (a) adding a compound 6 into a first reaction solvent under the condition of isolating air, wherein the reaction temperature is 0-100 ℃ and the reaction time is 2-48 hours under the condition of a condensation reagent, and the mass ratio of the compound 1 to the compound 6 is 1:1-1.5; (b) Adding triphenylphosphine and a coupling agent into a second reaction solvent, wherein the reaction temperature is-20-100 ℃, the reaction time is 2-24 hours, and the mass ratio of the compound of the formula 2 to the compound of the formula 3 is 1:1-1.5. The invention has low cost, high yield and high purity of the synthesized aza crown ether, and is more suitable for the requirement of industrialized mass production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound and a preparation method thereof, and a method for preparing aza crown ether by adopting the compound.
Background
Crown ethers, also known as "macrocyclic ethers", are macrocyclic compounds containing multiple oxygen atoms. The technology has been developed for the first time from the paper in which petersen reported crown ethers in 1967, until the time of Pedersen, lehn and Cram three who obtained nobel's chemical prize, and crown ether chemistry has been the subject of a popular study of modern chemistry in the last decades. Crown ether chemistry and application research is currently penetrating into many branch disciplines, such as fields of organic synthesis, coordination chemistry, analytical chemistry, extraction chemistry, metal and isotope separations, biochemistry, and the like. Different metal ions can be selected for crown ether rings with different sizes, and the crown ether rings have important supermolecule recognition function.
The aza crown ether is obtained when the oxygen atom on the crown ether ring is replaced by the nitrogen atom, and the synthesis and application of the crown ether are valued by people because the crown ether has stronger complexing ability to transition metal and heavy metal ions. Because the hydrogen on the nitrogen atom of the aza-crown ether is relatively active and is a growth point of other substituents, a side chain is introduced to generate the nitrogen-branch-crown ether, which is also called arm-type crown ether. Such functional side arms typically contain electron donating atoms that can coordinate to atoms of the side arms while the metal ion is bound to a ring atom. The arm crown ether has certain flexibility, can regulate the induced three-dimensional space in the coordination process, enhances the coordination capability and improves the selectivity to metal ions, and is a good ligand for the hardness and softness.
Regarding the synthesis of aza crown ethers, chaves and Silvia et al reported a synthesis in Polyhedron (17 (1), 93-104, 1998), specifically as follows:
however, the method has the series of problems of long steps, low yield of the ring closing step, harsh reaction conditions during removal of the Ts protecting group, high corrosion to equipment, low yield, need of acid-base neutralization, large wastewater amount and the like, so the development of an industrial production method of the nitrogen-oxygen heterocyclic compound with green synthesis, low cost and high yield has urgent requirements.
Disclosure of Invention
In view of the problems in the prior art, the invention develops the 4-nitrophthaloyl azacrown ether compound, the preparation method thereof and the application of the compound in the preparation of the azacrown ether compound, and has the advantages of low cost, high yield and high purity.
One of the technical problems to be solved by the invention is to disclose a 4-nitrophthaloyl nitrogen oxygen heterocyclic compound, the chemical structure of which is shown as 4,
wherein n is greater than 0 and less than or equal to 10; m is greater than 0 and less than or equal to 20.
The second technical problem to be solved by the invention is to disclose a preparation method of a 4-nitrophthaloyl nitrogen heterocyclic compound, which comprises the following steps of;
(a) Under the condition of isolating air, adding a compound 6 into a first reaction solvent under the condition of a condensation reagent, wherein the reaction temperature is 0-100 ℃ and the reaction time is 2-48 hours, the mass ratio of the compound 1 to the compound 6 is 1:1-1.5, and the first reaction solvent is one or more of 1, 2-dichloroethane, dichloromethane, chlorobenzene, nitrobenzene and o-dichlorobenzene;
(b) Adding triphenylphosphine and a coupling agent into a second reaction solvent of the compound of the formula 2 and the compound of the formula 3, wherein the reaction temperature is-20-100 ℃, the reaction time is 2-24 hours, the mass ratio of the compound of the formula 2 to the compound of the formula 3 is 1:1-1.5, and the second reaction solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, acetonitrile, p-xylene, o-xylene, benzene and toluene.
In a preferred embodiment of the present invention, in the step (a), the condensing agent is one of N ' N-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N ' -tetramethylurea hexafluorophosphate.
In a preferred embodiment of the present invention, in the step (a), when the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the step (a), triethylamine is further added.
In a preferred embodiment of the present invention, in step (a), the amount of condensing agent is 2-6 times the amount of compound 1.
In a preferred embodiment of the present invention, in the step (b), the coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate.
In a preferred embodiment of the present invention, in the step (b), the amount of the substance of the coupling agent is 2 to 4 times the amount of the substance of the compound 2.
In a preferred embodiment of the present invention, in the step (b), the amount of the triphenylphosphine substance is 2 to 6 times the amount of the compound 2 substance.
The invention further discloses an application of the preparation method of the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound in the preparation of aza crown ethers, and the preparation method further comprises the following steps of (c) stirring the compound 4 in a third reaction solvent under the condition of isolating air, adding a third alkaline reagent, heating and refluxing for 4-10 hours to obtain a compound 5，Wherein the third reaction solvent is one or more of ethanol, methanol, isopropanol, n-butanol and nitrobenzene,
n is greater than 0 and less than or equal to 10, m is greater than 0 and less than or equal to 20.
In a preferred embodiment of the present invention, in the step (c), the third alkaline reagent is one or more of potassium hydroxide, sodium hydroxide and lithium hydroxide.
Advantageous effects
The invention adopts glycol to directly carry out one-step cyclization reaction, and the reaction is simple; in addition, in the protection process, proton alkali such as potassium hydroxide is adopted, and the removed protecting group can be directly used as a raw material for recycling. The whole reaction process has low cost, high yield and high purity of the synthesized aza crown ether, and is more suitable for the requirement of industrialized mass production.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1:
step (a): preparation of 9-nitro-3, 4,5, 6-tetrahydro-1H-benzo [ g ] [1,5] diazepine-1, 7 (2H) -dione as Compound of formula 2-1
To a 5L reaction flask, 750. 750 ml methylene chloride and 211.13. 211.13 g (1.0 mol) 4-nitrophthalic acid as a compound of formula 1 were added in sequence while maintaining a slight positive pressure of nitrogen, and stirred. The reaction mixture was cooled to 0℃and to this was added 383.40 g (2.0 mol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, followed by stirring, and 202.38 g (2.0 mol) of triethylamine was then added dropwise thereto, followed by stirring. The reaction mixture was allowed to react at 0℃for 1 hour, and 74.12 g (1.0 mol) of 1, 3-propanediamine, a compound of formula 6-1, was added thereto and stirred uniformly. The reaction solution was naturally warmed to room temperature, and stirred at room temperature for 24 hours to complete the reaction.
The reaction solution was washed with 2L of water 2 times, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying is distilled under normal pressure to recover the solvent. Recrystallization of the residue from xylene-ethyl acetate gave 218.33 g (0.876 mol) as a yellow solid product.
Yield 87.60% HPLC purity 98.54%. 1 H NMR (400MHz，DMSO-d6)：δ11.15(br s，2H)，8.73(s，1H)，8.63(d，1H)，8.22(d，1H)，3.19(t，4H) ，1.83-1.88(m，2H)。
Step (b): preparation of 11-nitro-3, 4,6, 7-tetrahydro-2, 8-propylbenzo [ f ] [1] oxo [4,9] diazepane-1, 9-dione as compound of formula 4-1
2130 ml tetrahydrofuran, 218.33 g (0.876 mol) of the compound of formula 2-1, 92.96g (0.876 mol) of diethylene glycol of the compound of formula 3-1, 505.49g (1.927 mol) of triphenylphosphine were added in this order to a 5L reaction flask, and stirred uniformly. The reaction solution was cooled to 0-5℃and then 354.27 g (1.752 mol) diisopropyl azodicarboxylate was added dropwise thereto, followed by stirring after completion of the dropwise addition within 30 minutes. After the addition, the reaction is carried out for 2 hours by heat preservation and stirring, then the temperature is raised to reflux reaction, the reflux reaction is carried out for 20 hours by heat preservation, and the reaction is finished.
The reaction solution was naturally cooled to room temperature, 1000 mL petroleum ether was added thereto, and then cooled to 0℃to effect crystallization. The temperature is kept for crystallization overnight, and a large amount of yellow solid is precipitated. The filter cake was collected, washed with 200. 200 mL cold petroleum ether and drained to give 250.35 g (0.784 mol) as a yellow solid.
The yield was 89.5%, the HPLC purity was 99.12%, 1 H NMR (400MHz，DMSO-d6)：δ8.75(s，1H)，8.64(d，1H)，8.22(d，1H)，3.67(t，4H) ，3.39(t，4H) ，3.21(t，4H) ，1.83-1.88 (m，2H)。
step (c): preparation of the Compound 1,4, 8-oxadiazole Cyclodecane of formula 5-1
A reaction flask of 5L was charged with 2750 mL anhydrous methanol, 250.35 g (0.784 mol) of the compound of formula 4-1, and stirred uniformly while maintaining a slight positive pressure of nitrogen. 146.64g (2.352 mol) of potassium hydroxide was added thereto in portions and stirred. After the addition, the temperature was raised to reflux. And (3) carrying out heat preservation and reflux reaction for 4 hours, and finishing the reaction.
The reaction solution is cooled to room temperature, a large amount of dark yellow solid is precipitated, filtered, and a filter cake is collected to obtain solid insoluble matter 1.
About two thirds of the solvent was recovered by rotary evaporation of the filtrate, and 500 mL tetrahydrofuran was added to the residue to obtain a pale yellow solution. The pale yellow solution was cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight to precipitate a small amount of yellow solid. Filtering and collecting filter cake to obtain solid insoluble 2.
200 mL petroleum ether is added into the filtrate, and the filtrate is cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight, and precipitating a large amount of white solid. The filtrate was filtered and the cake was collected to give 101.99g (0.707 mol) of a pure white solid.
The yield is 90.2%, and the total yield of the four-step reaction is 70.7%.
Purity of product: 98.25% (HPLC); nuclear magnetic data: 1H NMR (400 MHz, CDCl 3): delta 3.54 (t, 4H), 3.03 (t, 4H), 2.87 (t, 4H), 1.70-1.74 (m, 2H), 1.68 (br s, 2H).
Mixing solid insoluble substance 1 and solid insoluble substance 2, adding into 2L pure water, stirring, adding hydrochloric acid to adjust pH to 2, filtering, collecting filter cake to obtain pale yellow solid, and vacuum drying the pale yellow solid to obtain 162.99g (0.772 mol) pale yellow solid powder. The pale yellow solid powder is identified as 4-nitrophthalic acid, the recovery rate of the protecting group raw material is 77.2 percent, the HPLC purity is 98.51 percent, 1 H NMR (400MHz，DMSO-d6)：δ8.47(s，1H)，8.43(d，1H)，7.91(d，1H)。
example 2:
step (a): preparation of the Compound 10-nitro-2, 3,4,5,6, 7-hexahydrobenzo [ c ] [1,6] diazepine-1, 8-dione of formula 2-2
600 ml chlorobenzene, 211.13 g (1.0 mol) 4-nitrophthalic acid of formula 1 are added into a 5L reaction flask in sequence, and stirred uniformly, while keeping a slight positive pressure of nitrogen. The reaction mixture was cooled to 0℃and 618.99 g (3.0 mol) of N' -N-dicyclohexylcarbodiimide was added thereto, followed by stirring. The reaction mixture was allowed to react at 0℃for 1 hour, and 88.15. 88.15 g (1.1 mol) of 1, 4-butanediamine was added thereto and stirred uniformly. The reaction liquid naturally rises to 100 ℃, and the reaction is carried out for 2 hours under the condition of heat preservation and stirring, thus completing the reaction.
The reaction solution was washed with 2L of water 2 times, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying is distilled under normal pressure to recover the solvent. Recrystallization of the residue from xylene-ethyl acetate gave 231.66 g (0.88 mol) as a yellow solid product.
Yield 88.0% and HPLC purity 98.91%. 1 H NMR (400MHz，DMSO-d6)：δ11.21(br s，2H)，8.73(s，1H)，8.64 (d，1H)，8.22(d，1H)，3.19(t，4H) ，1.54-1.58(m，4H)。
Step (b): preparation of 11-nitro-3, 4,6, 7-tetrahydro-2, 8-butylbenzo [ f ] [1] oxo [4,9] diazepane-1, 9-dione as compound of formula 4-2
2140. 2140 ml acetonitrile, 231.66 g (0.88 mol) of the compound of formula 2-1, 93.39g (0.88 mol) of the compound of formula 3-2, diethylene glycol, 507.79g (1.936 mol) of triphenylphosphine were added in this order to a 5L reaction flask, and stirred uniformly. The reaction solution was cooled to 0-5℃and then 355.89 g (1.76 mol) diisopropyl azodicarboxylate was added dropwise thereto, followed by stirring after completion of the dropwise addition within 30 minutes. After the addition, the reaction is carried out for 2 hours with heat preservation and stirring, then the temperature is raised to reflux reaction, the reflux reaction is carried out for 16 hours with heat preservation, and the reaction is finished.
The reaction solution was naturally cooled to room temperature, 1000 ml petroleum ether was added thereto, and then cooled to 0℃to effect crystallization. The temperature is kept for crystallization overnight, and a large amount of yellow solid is precipitated. The filter cake was collected, washed with 200. 200 ml cold petroleum ether and drained to give 266.06 g (0.798 mol) as a yellow solid.
The yield is 90.7%, the HPLC purity is 99.25%, 1 H NMR (400MHz，DMSO-d6)：δ8.74(s，1H)，8.64(d，1H)，8.22(d，1H)，3.67(t，4H) ，3.39(t，4H) ，3.19(t，4H) ，1.54-1.58(m，4H)。
step (c): preparation of 1-oxo-4, 9-diazacycloundecane as a compound of formula 5-2
A reaction flask of 5L was charged with 2800ml of n-butanol and 266.06 g (0.798 mol) of the compound of formula 4-2, with a slight positive pressure of nitrogen, and stirred. Further, 149.28 g (2.394 mol) potassium hydroxide was added thereto in portions and stirred. After the addition, the temperature was raised to reflux. And (3) carrying out heat preservation and reflux reaction for 6 hours, and finishing the reaction.
The reaction solution is cooled to room temperature, a large amount of dark yellow solid is precipitated, filtered, and a filter cake is collected to obtain solid insoluble matter 1.
About two thirds of the solvent was recovered by rotary evaporation of the filtrate, and 500 mL tetrahydrofuran was added to the residue to obtain a pale yellow solution. The pale yellow solution was cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight to precipitate a small amount of yellow solid. Filtering and collecting filter cake to obtain solid insoluble 2.
1000 mL petroleum ether is added into the filtrate, and the filtrate is cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight, and precipitating a large amount of white solid. The filter cake was collected by filtration to give 114,44g (0.723 mol) of a pure white solid.
The yield is 90.6%, and the total yield of the four-step reaction is 72.3%.
Purity of product: 98.55% (HPLC); nuclear magnetic data: 1H NMR (400 MHz, CDCl 3): delta 3.55 (t, 4H), 3.01 (t, 4H), 2.85 (t, 4H), 1.37-1.42 (m, 4H), 1.56 (br s, 2H).
Mixing solid insoluble substance 1 and solid insoluble substance 2, adding into 2L pure water, stirring, adding hydrochloric acid to adjust pH to 2, filtering, collecting filter cake to obtain pale yellow solid, and vacuum drying to obtain 161.35g (0.764 mol) pale yellow solid powder. The pale yellow solid powder was identified as 4-nitrophthalic acid, the recovery of the protecting group starting material was 76.4%, the HPLC purity was 98.81%, and the nuclear magnetic data were consistent with example 1.
Example 3:
step (a): preparation of 11-nitro-3, 4,5,6,7, 8-hexahydro-1H-benzo [ c ] [1,6] diazepane-1, 9 (2H) -dione as Compound of formula 2-3
600 ml nitrobenzene, 211.13 g (1.0 mol) 4-nitrophthalic acid compound of formula 1 are added sequentially into a 5L reaction flask with nitrogen slight positive pressure maintained, and stirred. The reaction mixture was cooled to 0℃and 1520.92 g (4.0 mol) of 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate was added thereto, followed by stirring. The reaction mixture was allowed to react at 0℃for 1 hour, and 132.83g (1, 3 mol) of 1, 5-pentanediamine was added thereto and stirred uniformly. The reaction liquid naturally rises to 80 ℃, and the reaction is carried out for 10 hours under the condition of heat preservation and stirring, thus completing the reaction.
The reaction solution was washed with 2L of water 2 times, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying is distilled under normal pressure to recover the solvent. Recrystallization of the residue from xylene-ethyl acetate gave 238.46 (0.86 mol) as a yellow solid product.
Yield 86%, HPLC purity 98.91%. 1 H NMR (400MHz，DMSO-d6)：δ11.18(br s，2H), 8.74(s，1H), 8.64(d，1H), 8.22(d，1H), 3.19(t，4H), 1.54-1.58(m，4H), 1.23-1.26(m，2H)。
Step (b): preparation of 11-nitro-3, 4,6, 7-tetrahydro-2, 8-propylbenzo [ f ] [1] oxo [4,9] diazepane-1, 9-dione as compound of formula 4-3
2100ml of t-butyl methyl ether, 238.46 (0.86 mol) of the compound of formula 2-1, 129.15g (0.86 mol) of triethylene glycol of formula, 496.25g (1.892 mol) of triphenylphosphine were successively added to a 5L reaction flask, and stirred uniformly. The reaction solution was cooled to 0-5℃and then 449.31 g (2.58 mol) diethyl azodicarboxylate was added dropwise thereto, followed by stirring after completion of the dropwise addition within 30 minutes. After the addition, the reaction is carried out for 2 hours by heat preservation and stirring, then the temperature is raised to reflux reaction, the reflux reaction is carried out for 20 hours by heat preservation, and the reaction is finished.
The reaction solution was naturally cooled to room temperature, 1000 mL petroleum ether was added thereto, and then cooled to 0℃to effect crystallization. The temperature is kept for crystallization overnight, and a large amount of yellow solid is precipitated. The filter cake was collected, washed with 300. 300 mL cold petroleum ether and drained to give 306.33g (0.783 mol) of a yellow solid product.
Yield 91.0%, HPLC purity 99.23%, 1 H NMR (400MHz，DMSO-d6)：δ8.74(s，1H), 8.64(d，1H), 8.22(d，1H), 3.71(br s，4H),3.67(t，4H), 3.39(t，4H), 3.19(t，4H), 1.54-1.58(m，4H), 1.23-1.26(m，2H)。
step (c): preparation of the Compound 1, 4-Dioxa-7, 13-diazacyclopentane of formula 5-3
A reaction flask of 5L was charged with 2750 ml isopropyl alcohol, 306.33g (0.783 mol) of the compound of formula 4-3, and stirred while maintaining a slight positive pressure of nitrogen. Then, 104.35 g (2.348 mol) sodium hydroxide was added thereto in portions and stirred. After the addition, the temperature was raised to reflux. And (3) carrying out heat preservation and reflux reaction for 8 hours, and finishing the reaction.
The reaction solution is cooled to room temperature, a large amount of dark yellow solid is precipitated, filtered, and a filter cake is collected to obtain solid insoluble matter 1.
About two thirds of the solvent was recovered by rotary evaporation of the filtrate, and 500 ml tetrahydrofuran was added to the residue to obtain a pale yellow solution. The pale yellow solution was cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight to precipitate a small amount of yellow solid. Filtering and collecting filter cake to obtain solid insoluble 2.
1000 mL petroleum ether is added into the filtrate, and the filtrate is cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight, and precipitating a large amount of white solid. The filter cake was collected by filtration to give 148.98g (0.689 mol) of a pure white solid.
The yield is 88.0%, and the total yield of the four-step reaction is 68,9%.
Purity of product: 98.63% (HPLC); nuclear magnetic data: 1H NMR (400 MHz, CDCl 3): delta 3.67 (br s, 4H), 3.54 (t, 4H), 3.01 (t, 4H), 2.85 (t, 4H), 1.62 (br s, 2H), 1.35-1.40 (m, 4H), 1.23-1.26 (m, 2H).
Mixing solid insoluble substance 1 and solid insoluble substance 2, adding into 2L pure water, stirring, adding hydrochloric acid to adjust pH to 2, filtering, collecting filter cake to obtain pale yellow solid, and vacuum drying to obtain 164.21g (0.777 mol) pale yellow solid powder. The pale yellow solid powder was identified as 4-nitrophthalic acid, the recovery of the protecting group starting material was 77.7%, the HPLC purity was 99.12%, and the nuclear magnetic data were consistent with example 1.
Example 4:
step (a): preparation of the Compound 13-nitro-3, 4,5,6,7,8,9, 10-octahydro-1H-benzo [ c ] [1,6] diazo Cyclotridecyl-1, 11 (2H) -dione of formula 2-4
The nitrogen slight positive pressure is kept, 600 ml o-dichlorobenzene, 211.13 g (1.0 mol) of 4-nitrophthalic acid as a compound of formula 1 are sequentially added into a 5L reaction bottle, and the mixture is stirred uniformly. The reaction mixture was cooled to 0℃and 2275.44g (6.0 mol) of benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate was added thereto, followed by stirring. The reaction mixture was allowed to react at 0℃for 1 hour, and 195.36 g (' 1.5 mol) 1, 7-heptanediamine was added thereto and stirred uniformly. The reaction liquid is naturally heated to 60 ℃, stirred and reacted for 12 hours under heat preservation, and the reaction is completed.
The reaction solution was washed with 2L of water 2 times, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase obtained after drying is distilled under normal pressure to recover the solvent. Recrystallization of the residue from xylene-ethyl acetate gave 266.55g (0.873 mol) of a yellow solid product.
Yield 87.3% HPLC purity 98.71%. 1 H NMR (400MHz，DMSO-d6)：δ11.12(br s，2H), 8.73(s，1H), 8.62(d，1H), 8.21(d，1H), 3.19(t，4H), 1.53-1.57(m，4H), 1.22-1.27(m，6H)。
Step (b): preparation of Compounds of formulas 4-4
Into a 5L reaction flask were successively charged 2150 ml paraxylene, 266.55g (0.873 mol) of a compound of formula 2-4, 246.47g (0.873 mol) of hexaglycol of formula, 503.75g (1.927 mol) of triphenylphosphine, and stirred uniformly. The reaction solution was cooled to 0-5℃and then 419.56g (3.492 mol) of dimethyl azodicarboxylate was added dropwise thereto, followed by stirring after completion of the dropwise addition within 30 minutes. After the addition, the reaction is carried out for 2 hours with heat preservation and stirring, then the temperature is raised to reflux reaction, the reflux reaction is carried out for 2 hours with heat preservation, and the reaction is finished.
The reaction solution was naturally cooled to room temperature, 2000 mL petroleum ether was added thereto, and then cooled to 0℃to effect crystallization. The temperature is kept for crystallization overnight, and a large amount of yellow solid is precipitated. The filter cake was collected, washed with 400 g mL cold petroleum ether and drained to give 426.2g (0.773 mol) of a yellow solid product.
Yield 88.5%, HPLC purity 99.27%, 1 H NMR (400MHz，DMSO-d6)：δ8.73(s，1H), 8.62(d，1H), 8.21(d，1H), 3.71(br s，16H), 3.67(t，4H), 3.39(t，4H), 3.19(t，4H),1.53-1.57(m，4H), 1.22-1.27(m，6H)。
step (c): preparation of Compounds of formulas 5-4
While maintaining a slight positive pressure of nitrogen, 2700 ml absolute ethanol, 426.2g (0.773 mol) of the compound of formula 4-4 were added to a 5L reaction flask, and stirred uniformly. Then, 61.81 g (2.318 mol) lithium hydroxide was added thereto in portions and stirred. After the addition, the temperature was raised to reflux. And (5) carrying out heat preservation and reflux reaction for 10 hours, and finishing the reaction.
The reaction solution is cooled to room temperature, a large amount of dark yellow solid is precipitated, filtered, and a filter cake is collected to obtain solid insoluble matter 1.
About two thirds of the solvent was recovered by rotary evaporation of the filtrate, and 500 mL tetrahydrofuran was added to the residue to obtain a pale yellow solution. The pale yellow solution was cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight to precipitate a small amount of yellow solid. Filtering and collecting filter cake to obtain solid insoluble 2.
200 mL petroleum ether is added into the filtrate, and the filtrate is cooled to-20 ℃ for crystallization. Preserving heat and crystallizing overnight, and precipitating a large amount of white solid. The filtrate was filtered and the cake was collected to give 265.61g (0.705 mol) of a pure white solid.
The yield is 91.3 percent, and the total yield of the four-step reaction is 70.5 percent.
Purity of product: 98.63% (HPLC); nuclear magnetic data: 1H NMR (400 MHz, CDCl 3): delta 3.67 (br s, 16H), 3.54 (t, 4H), 3.01 (t, 4H), 2.83 (t, 4H), 1.64 (br s, 2H), 1.34-1.38 (m, 4H), 1.23-1.26 (m, 6H).
Mixing solid insoluble substance 1 and solid insoluble substance 2, adding into 2L pure water, stirring, adding hydrochloric acid to adjust pH to 2, filtering, collecting filter cake to obtain pale yellow solid, and vacuum drying to obtain 162.35g (0.769 mol) pale yellow solid powder. The pale yellow solid powder is identified as 4-nitrophthalic acid, the recovery rate of the protecting group raw material is 76.9%, and the HPLC purity is 98.51%. The nuclear magnetic data are consistent with example 1.
Comparative example 1:
referring to the same procedure as in steps (a) and (b) of example 1, the starting compound 1 was replaced with an equivalent amount of phthalic acid. During the experiment, it was found that the product obtained when compound 8 was converted to compound 9 was very heterogeneous and failed to isolate the pure product of compound 9.
It follows that the 4-nitrophthalic acid of the invention is a very good reactive group here, which makes possible a subsequent ring closure step.
Comparative example 2:
2000 mL acetonitrile, 228.93g (0.923 mol) of 4-nitrophthaloyl chloride, which is a compound of formula 10, and 255.14 g (1.85 mol) of potassium carbonate were sequentially added to a 5L reaction flask, and stirred uniformly. Then 68.42 g (0.923 mol) of 1, 3-propylene diamine is added dropwise, and after the addition is finished, the mixture is stirred uniformly; the reaction solution is heated to 50 ℃ for reaction, the reaction is kept for 8 hours, a large amount of yellow solid is generated in the reaction solution, and the spot plate confirms that all the reactions of 4-nitrophthaloyl chloride and 1, 3-propanediamine are completed.
The reaction solution was filtered while it was still hot, and the filtrate was collected and dried by spin-drying, without any product found. The cake was poured into 2L of pure water, 10% sulfuric acid was added dropwise thereto, and the pH of the aqueous solution was adjusted to 6 with a large amount of bubbles being formed therebetween. The resulting solution was filtered under reduced pressure to give 225g of a yellow solid. The yellow solid was extremely poor in solubility, and even in DMF and DMSO, it was often presumed from the solubility properties that the following structural polymer was likely formed.
At the same time, we have also tested the substitution of equivalent amounts of 1, 4-butanediamine and 1, 5-pentanediamine for 1, 3-propanediamine, which likewise does not give the desired ring-closure product, but gives polymers of very poor solubility.
It follows that the process for preparing the heterocyclic compounds by direct reaction of 4-nitrophthaloyl chloride with diamine compounds is not suitable for use with 1, 3-propanediamine and diamine compounds having longer alkane chain lengths.
The above examples are provided for illustrating the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the contents of the present invention and implement the same, and are not intended to limit the scope of the present invention; all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (10)
1. A4-nitrophthaloyl nitrogen oxygen heterocyclic compound is characterized in that the chemical structure is shown as 4,
wherein n is greater than 0 and less than or equal to 10; m is greater than 0 and less than or equal to 20.
2. A preparation method of a 4-nitrophthaloyl nitrogen heterocyclic compound is characterized by comprising the following steps:
(a) Under the condition of isolating air, adding a compound 6 into a first reaction solvent under the condition of a condensation reagent, wherein the reaction temperature is 0-100 ℃ and the reaction time is 2-48 hours, the mass ratio of the compound 1 to the compound 6 is 1:1-1.5, and the first reaction solvent is one or more of 1, 2-dichloroethane, dichloromethane, chlorobenzene, nitrobenzene and o-dichlorobenzene;
(b) Adding triphenylphosphine and a coupling agent into a second reaction solvent of the compound of the formula 2 and the compound of the formula 3, wherein the reaction temperature is-20-100 ℃, the reaction time is 2-24 hours, the mass ratio of the compound of the formula 2 to the compound of the formula 3 is 1:1-1.5, and the second reaction solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, acetonitrile, p-xylene, o-xylene, benzene and toluene.
3. The method for producing 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 2, wherein in the step (a), the condensing agent is one of N ' N-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2- (7-azobenzotriazole) -N, N ' -tetramethylurea hexafluorophosphate, benzotriazol-N, N ' -tetramethylurea hexafluorophosphate.
4. The process for producing 4-nitrophthaloyl nitrogen oxide heterocyclic compound according to claim 3, wherein in the step (a), when the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, triethylamine is further added.
5. A process for the preparation of 4-nitrophthaloyl nitrogen oxide heterocycle compounds according to claim 3, wherein in step (a) the amount of the condensing agent is 2-6 times the amount of the compound 1 substance.
6. The method for preparing 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound according to claim 2, wherein in the step (b), the coupling agent is one or more of diisopropyl azodicarboxylate, diethyl azodicarboxylate or dimethyl azodicarboxylate.
7. The method for producing 4-nitrophthaloyl nitrogen oxygen heterocyclic compound according to claim 2, wherein in step (b), the amount of the substance of the coupling agent is 2-4 times the amount of the substance of the compound 2.
8. The method for producing 4-nitrophthaloyl nitrogen oxygen heterocyclic compound according to claim 2, wherein in step (b), the amount of the triphenylphosphine substance is 2-6 times the amount of the compound 2 substance.
9. The application of the preparation method of the 4-nitrophthaloyl nitrogen-oxygen heterocyclic compound in the preparation of aza crown ethers is characterized by further comprising the step (c) of stirring the compound 4 in a third reaction solvent under the condition of isolating air, adding a third alkaline reagent, heating and refluxing for 4-10 hours to obtain a compound 5, wherein the third reaction solvent is one or more of ethanol, methanol, isopropanol, n-butanol and nitrobenzene,
n is greater than 0 and less than or equal to 10, m is greater than 0 and less than or equal to 20.
10. The use of the process for the preparation of 4-nitrophthaloyl nitrogen oxide heterocycle compounds according to claim 9 for the preparation of aza crown ethers, wherein in step (c) the third alkaline reagent is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide.
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| A. I. INGHAM: "Synthesis of the macrotricyclic ligands 8, 18 dioxa-1, 5, 11, 15-tetraaza-[13.5.2.2]-eicosane (L1) and 7, 16 dioxa-1, 4, 10, 13-tetraaza-[11.5.3.3]-octadecane (L2). Crystal structures of the copper(II) complexes, [Cu(L1)](ClO4)2 and [Cu(L2)](ClO4)2.CH3NO2", 《J INCL PHENOM MACROCYCL CHEM》, vol. 71, 31 December 2011 (2011-12-31), pages 445 - 453, XP019976437, DOI: 10.1007/s10847-011-9997-3 * |
| 罗新湘: "几个新型含氟化合物的合成", 《有 机 化 学》, vol. 26, no. 6, 31 December 2006 (2006-12-31), pages 874 - 877 * |
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