CN112010853A - Synthetic method of heterocyclic amine risk substance norrharman and analogues in food - Google Patents
Synthetic method of heterocyclic amine risk substance norrharman and analogues in food Download PDFInfo
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- -1 heterocyclic amine Chemical class 0.000 title claims abstract description 36
- 239000000126 substance Substances 0.000 title claims abstract description 20
- 235000013305 food Nutrition 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000001308 synthesis method Methods 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 239000012074 organic phase Substances 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 238000007865 diluting Methods 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000003760 magnetic stirring Methods 0.000 claims abstract description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 230000005526 G1 to G0 transition Effects 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 229910001386 lithium phosphate Inorganic materials 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- CPWJKGIJFGMVPL-UHFFFAOYSA-K tricesium;phosphate Chemical compound [Cs+].[Cs+].[Cs+].[O-]P([O-])([O-])=O CPWJKGIJFGMVPL-UHFFFAOYSA-K 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 239000012530 fluid Substances 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a synthesis method of heterocyclic amine risk substances norrharman and analogues in food, which comprises the following steps: (1) with a compound<Ⅱ>Adding alkali into the raw materials under magnetic stirring, then adding a solvent into the mixture under the nitrogen atmosphere, and heating the mixture to 100-200 ℃ under a closed condition to react for 1-24 hours; (2) after the reaction is completed, cooling the reaction system to room temperature, diluting with water, extracting for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating with a chromatographic column to obtain a crystalline solid, namely the heterocyclic amine risk substance norrharman. The synthesis method provided by the invention has the advantages of simple and efficient synthesis of C-N bonds, no heavy metal introduced in the reaction, simple operation, and the yield of the obtained heterocyclic amine is more than 60%, and can well meet the production requirements of scientific research on the heterocyclic amine compounds. The structural formula of the heterocyclic amine risk substance norrharman is shown as the formula<Ⅰ>：
Said compounds<Ⅱ>Has the structural formula<Ⅱ>：
Description
Technical Field
The invention belongs to the technical field of synthesis of heterocyclic amine, and particularly relates to a synthesis method of a heterocyclic amine risk substance norrharman and analogues in food.
Background
The risk substance heterocyclic amine compounds are commonly present in daily life of people, and a series of heterocyclic amine compounds are generated in food processing, particularly in heating and processing food materials rich in protein such as meat. Such compounds enter the human body and may be carcinogenic/mutagenic or cause a range of physiological disorders. Therefore, it is important to investigate the formation of the risk substance heterocyclic amines and their effect on physiology.
About 20 of these heterocyclic amine compounds have been discovered, and how to better study their formation and physiological effects, it is first necessary to obtain a sample of these compounds for convenient detection, comparison and subsequent testing. Access to such heterocyclic amines is currently available primarily through two routes, the separation of off-the-shelf compounds in the processing system and the synthesis. Because the content of the compounds is very low, the target compounds cannot be obtained in large quantity at one time by a method for separating and purifying the existing compounds in a processing system, so that the requirements of the current research cannot be well met, and therefore, the method for obtaining the compounds by an organic synthesis method is very important.
With the rapid development of organic synthesis methodology in recent years, a good foundation is provided for synthesizing a risk substance heterocyclic amine compound. For example, in recent years, CN coupling realized by a chemical method can construct a series of C-N bonds, so that various heterocyclic amine compounds containing C-N bonds can be conveniently synthesized. For example, the existing literature reports that such compounds are prepared by Pd/C dehydrogenation, the method has the advantages of simple operation, but palladium (Pd) metal is used in the reaction, the reaction steps are complex, and the reaction usually takes tens of hours, so that the preparation cannot be rapidly realized, and heavy metals are often introduced in the reaction, which brings certain inconvenience to subsequent research and development. In addition, the prior literature reports that the transition metal-catalyzed CN coupling method requires relatively short time, but the transition metal, even the ligand, is used, so that heavy metal is also introduced, and since the synthesis of the compound is mostly required by food researchers, the operation requirements of the transition metal are generally high, and the food researchers cannot effectively operate the transition metal to prepare the heterocyclic amine compound.
Therefore, how to provide a simple and convenient C-N bond synthesis method to rapidly synthesize the risk substance heterocyclic amine compound generated in food processing is beneficial to subsequent research and becomes a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to solve the technical problems and provide a method for synthesizing a risk substance heterocyclic amine norrharman and analogues in food. The synthesis method provided by the invention has the advantages of simple and efficient synthesis of C-N bonds, no heavy metal introduced in the reaction, simple operation, and the yield of the obtained risk substance heterocyclic amine norrharman of more than 60 percent, and can well meet the production requirements of scientific research on the heterocyclic amine compounds.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for synthesizing risk substance heterocyclic amine norrharman and analogues in food, wherein the structural formula of the heterocyclic amine norrharman is as shown in formula < I >:
the synthesis method comprises the following steps:
(1) with a compound
Adding alkali into the raw materials under magnetic stirring, adding a solvent into the mixture under the nitrogen atmosphere, and heating the mixture to 100-2 ℃ under a closed conditionReacting for 1-24h at 00 ℃; wherein the compound<Ⅱ>Wherein R1 and R2 are both selected from: h, Me, Et, propyl, isopropyl, butyl, sec-butyl, tert-butyl, phenyl, heterocyclyl, alkoxy, ester, trifluoromethyl, nitrile, mono-or di-substituted nitrogen-containing group, amide group, carbonyl-containing compound, phosphine-containing group or sulfur-containing group; the X is selected from F, Cl, Br, I, OMs, OTs, ester group, sulfur-containing group or nitrogen-containing group;
(2) after the reaction is completed, cooling the reaction system to room temperature, diluting with water, extracting for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating with a chromatographic column to obtain a crystalline solid, namely the risk substance heterocyclic amine norrharman.
Further, the molar ratio of the compound < II > to the base is 1: 3.
Further, the base in the step (1) includes any one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate salt, potassium carbonate, sodium carbonate, lithium carbonate, cesium phosphate, potassium phosphate, sodium phosphate, and lithium phosphate.
Further, the solvent in the step (1) includes any one of DMF, DMAc, NMP, DMSO, tetrahydrofuran, 1, 4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, tert-butyl methyl ether, tert-butyl ether, n-butyl ether, isopropyl ether.
Further, the reaction temperature in the step (1) is 140 ℃.
Further, the reaction time in step (1) was 15 hours.
Further, the solvent is added in the step (1) in an amount of 1mmol in terms of the molar volume ratio of the compound < II >: 10 ml.
Further, the volume of water added upon dilution with water in the step (2) is 4 times the volume of the solvent.
Further, the extracting agent adopted in the extraction in the step (2) is ethyl acetate, and the volume ratio of the dosage of the extracting agent added each time to the water is 3: 4.
Further, the liquid phase adopted by the chromatographic column in the step (2) is a mixed liquid of petroleum ether and ethyl acetate, and the stationary phase is 200-mesh and 300-mesh silica gel.
Compared with the prior art, the invention has the following beneficial effects:
(1) the synthesis method provided by the invention has the characteristics of simplicity and high efficiency, the synthesis steps are simple, no heavy metal is introduced in the synthesis process, no special operation of transition metal is involved, and the like, and the synthesis operation is simple;
(2) the synthesis method provided by the invention has short synthesis time, and can prepare the required risk substance heterocyclic amine only by 1-24 h;
(3) the yield of the risk substance heterocyclic amine obtained by the synthesis method is more than 60 percent, and the production requirement of scientific research on the heterocyclic amine compound can be well met.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail below with reference to the following embodiments, and it should be noted that the following embodiments are only for explaining and illustrating the present invention and are not intended to limit the present invention. The invention is not limited to the embodiments described above, but rather, may be modified within the scope of the invention.
Example 1
A method for synthesizing a risk substance heterocyclic amine norrharman in food is carried out according to the following reaction formula:
the specific synthesis steps are as follows: in a glove box, a 25mL Schlenk flask was charged with a magnetic stirrer, 0.5mmol of Compound 1 and 1.5mmol of potassium tert-butoxide were added, the flask was closed and taken out of the glove box, the flask was purged with nitrogen three times in a double-vented tube, 5mL of dry DMSO was added under nitrogen, and the flask was sealed and heated at 140 ℃ for 15 hours. After the reaction was complete, the reaction was cooled to room temperature and diluted with 20mL of water and extracted three times with ethyl acetate (15 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried and separated by column chromatography (the liquid phase used was a mixture of petroleum ether and ethyl acetate, the stationary phase used was 200-mesh and 300-mesh silica gel) to give 51mg of a crystalline solid, i.e., the heterocyclic amine norrharman, with a yield of 61%.
Example 2
According to the synthetic procedure of example 1, the base was replaced with sodium tert-butoxide and the solvent was replaced with tetrahydrofuran, the reaction temperature was 170 ℃ and the heating time was 12 hours, and the final yield of the heterocyclic amine norrharman was 65%.
Example 3
The procedure of example 1 was followed, wherein the base was replaced with sodium hydroxide and the solvent was replaced with DMF, the reaction temperature was 120 ℃ and the heating time was 10 hours, and the final yield of the heterocyclic amine norrharman was 67%.
Claims (10)
1. A method for synthesizing heterocyclic amine risk substances norrharman and analogues in food is characterized in that the structural formula of the heterocyclic amine norrharman is as shown in formula < I >:
the synthesis method comprises the following steps:
(1) with a compound
Adding alkali into the raw materials under magnetic stirring, then adding a solvent into the mixture under the nitrogen atmosphere, and heating the mixture to 100-200 ℃ under a closed condition to react for 1-24 hours; wherein the compound<Ⅱ>Wherein R1 and R2 are both selected from: h, Me, Et, propyl, isopropyl, butyl, sec-butyl, tert-butyl, phenyl, heterocyclyl, alkoxy, ester, trifluoromethyl, nitrile, mono-or di-substituted nitrogen-containing group, amide group, carbonyl-containing compound, phosphine-containing group or sulfur-containing group; the X is selected from F, Cl, Br, I, OMs, OTs, ester group, sulfur-containing group or nitrogen-containing group;
(2) after the reaction is completed, cooling the reaction system to room temperature, diluting with water, extracting for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating with a chromatographic column to obtain a crystalline solid, namely the heterocyclic amine risk substance norrharman.
2. The method of claim 1, wherein the molar ratio of compound < II > to base is 1: 3.
3. The synthesis method according to claim 1 or 2, wherein the base in step (1) comprises any one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, cesium phosphate, potassium phosphate, sodium phosphate, and lithium phosphate.
4. The method of claim 1, wherein the solvent in step (1) comprises any one of DMF, DMAc, NMP, DMSO, tetrahydrofuran, 1, 4-dioxane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, tert-butyl methyl ether, tert-butyl ether, n-butyl ether, and isopropyl ether.
5. The synthesis method according to claim 1, wherein the reaction temperature in step (1) is 140 ℃.
6. The synthesis method according to claim 5, wherein the reaction time in step (1) is 15 h.
7. The synthesis method according to claim 1, wherein the solvent is added in the step (1) in an amount of 1 mmol: 10 ml.
8. The method of claim 1, wherein the water is diluted in step (2) and added in a volume of 4 times the volume of the solvent.
9. The synthesis method of claim 1, wherein the extraction agent used in the step (2) is ethyl acetate, and the volume ratio of the amount of the extraction agent added in each time to the water is 3: 4.
10. The method as claimed in claim 1, wherein the chromatographic column in step (2) is prepared from a mixture of petroleum ether and ethyl acetate as a fluid phase, and 200-mesh 300-mesh silica gel as a stationary phase.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105492444A (en) * | 2013-07-02 | 2016-04-13 | 百时美施贵宝公司 | Tricyclic pyri do-carboxam i d e derivatives as ROCK inhibitors |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105492444A (en) * | 2013-07-02 | 2016-04-13 | 百时美施贵宝公司 | Tricyclic pyri do-carboxam i d e derivatives as ROCK inhibitors |
Non-Patent Citations (2)
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| PATRICK ROCCA ET AL: "Carbolines. Part VIII. An original synthesis of the antibiotic Eudistomin T.", 《SYNTHETIC COMMUNICATIONS》 * |
| XIAOXIA ZHANG ET AL: "Synthesis of substituted quinolines by the electrophilic cyclization of n-(2-alkynyl)anilines", 《ORGANIC LETTERS》 * |
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