CN118638433A - Preparation method of xylene blue FF compounds - Google Patents
Preparation method of xylene blue FF compounds Download PDFInfo
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- CN118638433A CN118638433A CN202410625997.3A CN202410625997A CN118638433A CN 118638433 A CN118638433 A CN 118638433A CN 202410625997 A CN202410625997 A CN 202410625997A CN 118638433 A CN118638433 A CN 118638433A
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- acid
- xylene blue
- ethylamino
- methylphenyl
- bis
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- IKHKJYWPWWBSFZ-UHFFFAOYSA-N 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]benzene-1,3-disulfonate;hydron Chemical compound C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=CC=1)S([O-])(=O)=O)S(O)(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 IKHKJYWPWWBSFZ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 150000001875 compounds Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 31
- -1 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol Chemical compound 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 13
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- MWOUGPLLVVEUMM-UHFFFAOYSA-N n-ethyl-2-methylaniline Chemical compound CCNC1=CC=CC=C1C MWOUGPLLVVEUMM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- YADSGOSSYOOKMP-UHFFFAOYSA-N dioxolead Chemical compound O=[Pb]=O YADSGOSSYOOKMP-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 4
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 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
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- MLIWQXBKMZNZNF-KUHOPJCQSA-N (2e)-2,6-bis[(4-azidophenyl)methylidene]-4-methylcyclohexan-1-one Chemical compound O=C1\C(=C\C=2C=CC(=CC=2)N=[N+]=[N-])CC(C)CC1=CC1=CC=C(N=[N+]=[N-])C=C1 MLIWQXBKMZNZNF-KUHOPJCQSA-N 0.000 description 1
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a xylene blue FF intermediate compound, which comprises the following steps: (1) Adding 3-hydroxybenzaldehyde, N-ethyl-o-methylaniline and a first reaction solvent thereof into a reaction bottle, and carrying out heating reflux reaction under the catalysis of acid to obtain 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol; (2) Sulfonating the compound prepared in the step (1) by sulfuric acid at the reaction temperature of 60-120 ℃ for a reaction time to obtain 4- (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid, wherein the sulfuric acid is sulfuric acid solution with the concentration of more than or equal to 90%; (3) The method for preparing the target product xylene blue FF compounds by oxidizing the compound prepared in the step (2) in the second solvent has the advantages of simple operation, convenient raw material source, higher purity of the prepared compound, environmental friendliness and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of dyes and indicators, in particular to a preparation method of a xylene blue FF compound.
Background
Xylene blue FF, molecular formula C 25H27N2NaO7S2, is used for agarose nucleic acid electrophoresis or polyacrylamide gel electrophoresis, is a kind of excellent dye, and is easy to dissolve in water and alcohol. In agarose gel electrophoresis, a loading buffer solution can be prepared with bromophenol blue according to a certain proportion.
Xylene blue FF can be used for histochemical staining of hemoglobin peroxidase or as a tracking dye for DNA sequencing in electrophoresis. With the addition of the dual oxidants hydrogen peroxide and potassium periodate, iron and aluminum will catalyze the accelerated oxidation of xylene-cyanohydrin FF. Thus, xylene-cyanohydrin FF is capable of spectrophotometrically measuring Fe and Al in a solution to be measured. Meanwhile, xylene blue FF is also an oxidation-reduction indicator, and is widely studied and applied in the field of chemical analysis.
Although the application of the xylene blue FF is very wide, the preparation of the compound is difficult, and the related literature report is lacking, so that the development of a preparation method of the xylene blue FF compound is necessary.
Disclosure of Invention
In view of the problems in the prior art, the invention develops a preparation method of the xylene blue FF compounds, which has the advantages of simple operation, few steps, easily obtained raw materials, mild reaction conditions and contribution to industrial production.
One of the technical problems to be solved by the invention is to provide a preparation method of a xylene blue FF intermediate compound, which comprises the following steps:
(1) Adding 3-hydroxybenzaldehyde, N-ethyl-o-methylaniline and a first reaction solvent thereof into a reaction bottle, and carrying out heating reflux reaction under the catalysis of acid to obtain 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol, wherein the first solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, benzene, toluene and dioxane, and the acid is one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, aluminum chloride and zinc chloride;
(2) Sulfonating the 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol prepared in the step (1) by sulfuric acid, wherein the reaction temperature is 60-120 ℃, the reaction time is kept for 2-4 hours, and then stirring at room temperature for 16-24 hours to obtain 4- (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid, wherein the sulfuric acid is sulfuric acid solution with the concentration of more than or equal to 90%;
(3) Preparing a target product of xylene blue FF compounds from (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid prepared in the step (2) by oxidation in a second solvent, wherein the second solvent is hydrochloric acid, dilute sulfuric acid, glacial acetic acid and the like or one or more of ethyl acetate, dichloromethane, methanol, ethanol and tetrahydrofuran, and the oxidant is one or more of lead dioxide, potassium permanganate, sodium periodate, ferric trichloride, benzoquinone, tetrachlorobenzoquinone and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone;
The synthetic route is as follows:
。
In a preferred embodiment of the present invention, in the step (1), the mass ratio of the 3-hydroxybenzaldehyde N-ethyl-o-methylaniline is 1:2-2.5.
In a preferred embodiment of the present invention, in the step (2), the concentration of the sulfuric acid is preferably greater than or equal to 95%.
In a preferred embodiment of the present invention, in the step (2), the reaction temperature is preferably 80 to 100 ℃.
In a preferred embodiment of the present invention, in the step (3), the oxidizing agent is preferably one or more of lead dioxide, potassium permanganate and benzoquinone.
In a preferred embodiment of the present invention, in the step (3), the mass ratio of the bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid and the oxidizing agent is 1:1.1-10.
In a preferred embodiment of the present invention, in the step (3), the mass ratio of the bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid and the oxidizing agent is preferably 1:1.5.
The second technical problem to be solved by the invention is to provide a preparation method of the xylene blue FF salt compound, which comprises the preparation method of the xylene blue FF intermediate compound, and further comprises the step of reacting the xylene blue FF intermediate compound with an alkaline solution to obtain the xylene blue FF salt compound, wherein the alkaline solution is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate solution.
In a preferred embodiment of the present invention, the xylene blue FF salt compound is a xylene blue FF potassium salt or a xylene blue FF sodium salt.
Advantageous effects
The method has reasonable design, simple operation, suitability for industrial mass production, convenient raw material source, higher purity of the prepared compound, environmental friendliness and popularization and application.
Drawings
FIG. 1 is a nuclear magnetic pattern of 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol obtained in example 1;
FIG. 2 is a nuclear magnetic pattern of 4- (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid prepared in example 3;
FIG. 3 is a nuclear magnetic resonance chart of xylene blue FF produced in example 4.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent 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: preparation of 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol
3-Hydroxybenzaldehyde (10 g,81.9mmol,1 eq), urea (2.45 g,40.9mmol,0.5 eq), N-ethyl-o-methylaniline (22.15 g,163.8mmol,2 eq), 10ml ethanol were added in one portion to a 100ml three-necked flask, the mixture was stirred and cooled to 0 ℃, 37% aqueous HCl (13.65 ml,163.8mmol,2 eq) was added dropwise to the flask, after this, the flask was transferred to an oil bath, the temperature was slowly raised to 100℃and the reaction system was refluxed for 20h, and TLC monitored whether the reaction was complete. The reaction solution was then concentrated, extracted 5 times with ethyl acetate, the ethyl acetate phases were combined and concentrated to give about 19g of crude product, which was purified by column chromatography to give 9.76g of product .1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 6.5 Hz, 4H), 6.56–6.45 (m, 3H), 6.42 (d, J = 8.7 Hz, 2H), 5.08 (s, 1H), 4.54 (t, J = 5.5 Hz, 2H), 3.11–2.99 (m, 4H), 2.00 (s, 6H), 1.17 (t, J = 7.1 Hz, 6H).
Example 2: preparation of 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol
To a 250mL three-necked flask, 3-hydroxybenzaldehyde (10 g,81.9mmol,1 eq), N-ethyl-o-methylaniline (22.15 g,163.8mmol,2 eq), p-toluenesulfonic acid (1.72 g,10mmol,1 eq) and toluene (30 mL) were sequentially added, a water knockout vessel was connected, heated and refluxed for 8 hours, cooled to room temperature, toluene (40 mL) was added to dilute the reaction mixture, and the mixture was washed twice with 100mL of 10% sodium hydrogencarbonate solution and 100mL of saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to silica gel column chromatography to purify to obtain 2.85 product.
Example 3: preparation of 4- (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid
3- (Bis (4- (ethylamino) -3-methylphenyl) methyl) phenol (5 g,13.4mmol,1 eq) was added to 25ml concentrated sulfuric acid and reacted at 90℃for 3h, then cooled to room temperature, stirred overnight at room temperature, then ethanol was added dropwise: isopropyl ether=1:1 (100 ml), diluted reaction solution, stirred, ice-bath, solid precipitated, filtered, cake washed with a small amount of isopropyl ether, product dried in vacuo to constant weight, 3.18g product, and the next reaction was carried out without purification .1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 2.0 Hz, 2H), 7.08 (dd, J = 8.3, 2.1 Hz, 2H), 6.86 (s, 1H), 6.43 (s, 1H), 3.30 (q, J = 7.2 Hz, 4H), 2.32 (s, 7H), 1.24 (t, J = 7.2 Hz, 7H).
Example 4: preparation of xylene blue FF (free acid)
4- (Bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid (2.1 g, 3.8mmol,1 eq) was added to 1M hydrochloric acid (25 ml), stirred, pbO2 (1.05 g,4.4mmol,1.15 eq) was added and stirred overnight at room temperature. After completion, methanol was added: dichloromethane = 1:5 (50 ml), filtered, separated and the aqueous phase was purified with methanol: dichloromethane = 1:5 (60 ml) repeatedly extracting until the water phase is free of product, drying with anhydrous sodium sulfate, concentrating to obtain the product 1.54g.1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.29 (dd, J = 9.1, 2.2 Hz, 2H), 7.15 (d, J = 2.2 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 3.50 (q, J = 7.2 Hz, 4H), 2.13 (s, 6H), 1.26 (t, J = 7.1 Hz, 6H).
And (3) reacting the product with sodium hydroxide solution or sodium carbonate solution, and adding methanol or isopropanol for crystallization to obtain the xylene blue FF monosodium salt.
Example 5: preparation of xylene blue FF free acid
4- (Bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid (0.27 g,0.5mmol,1 eq) was dissolved in 10ml of methanol/dichloromethane (1:2) mixture, and tetrachlorobenzoquinone (0.16 g, 0.65mmol,1.3 eq) was added and stirred at room temperature overnight. After completion of the reaction, the organic solvent was removed by concentration, and the residue was subjected to column chromatography to obtain 0.17g of a product.
Example 6: preparation of xylene blue FF (sodium salt)
Xylene blue FF (free acid) (1.2 g,2.13mmol,1 eq) was dissolved in 20ml methanol, 1.7ml of 5% aqueous sodium hydroxide solution was added, stirred at room temperature for 3 hours, after completion, the reaction mixture was concentrated, 15ml of isopropanol was added, stirred for 30 minutes, filtered, the filter cake was washed with 5ml of diethyl ether, and the product was dried under vacuum 1.06g.
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 present invention and to 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 (9)
1. A method for preparing a xylene blue FF intermediate compound, comprising the steps of:
(1) Adding 3-hydroxybenzaldehyde, N-ethyl-o-methylaniline and a first reaction solvent thereof into a reaction bottle, and carrying out heating reflux reaction under the catalysis of acid to obtain 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol, wherein the first solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, benzene, toluene and dioxane, and the acid is one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, aluminum chloride and zinc chloride;
(2) Sulfonating the 3- (bis (4- (ethylamino) -3-methylphenyl) methyl) phenol prepared in the step (1) by sulfuric acid, wherein the reaction temperature is 60-120 ℃, the reaction time is kept for 2-4 hours, and then stirring at room temperature for 16-24 hours to obtain 4- (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid, wherein the sulfuric acid is sulfuric acid solution with the concentration of more than or equal to 90%;
(3) Preparing a target product of xylene blue FF compounds from (bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid prepared in the step (2) through oxidation reaction in a second solvent, wherein the second solvent is hydrochloric acid, dilute sulfuric acid, glacial acetic acid and the like or one or more of ethyl acetate, dichloromethane, methanol, ethanol and tetrahydrofuran, and the oxidant is one or more of lead dioxide, potassium permanganate, sodium periodate, ferric trichloride, benzoquinone, tetrachlorobenzoquinone and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone;
The synthetic route is as follows:
。
2. The method for producing a xylene blue FF intermediate compound according to claim 1, characterized in that in the step (1), the mass ratio of the 3-hydroxybenzaldehyde and the N-ethyl-o-methylaniline is 1:2 to 2.5.
3. The process for the preparation of xylene blue FF intermediate compound according to claim 1, characterized in that in step (2) the sulfuric acid is preferably in a concentration of 95% or more.
4. The process for the preparation of xylene blue FF intermediate compounds according to claim 1, characterized in that in step (2) the reaction temperature is preferably 80-100 ℃.
5. The method for producing a xylene blue FF intermediate compound according to claim 1, characterized in that in step (3), the oxidizing agent is preferably one or more of lead dioxide, potassium permanganate and benzoquinone.
6. The method for producing a xylene blue FF intermediate compound according to claim 1, characterized in that in the step (3), the mass ratio of the bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid and the oxidizing agent is 1:1.1-10.
7. The method for producing a xylene blue FF intermediate compound according to claim 6, characterized in that in step (3), the mass ratio of the bis (4- (ethylamino) -3-methylphenyl) methyl) -6-hydroxy-1, 3-benzenesulfonic acid and the oxidizing agent is preferably 1:1.5.
8. The preparation method of the xylene blue FF salt compound is characterized by comprising the preparation method of the xylene blue FF intermediate compound according to any one of claims 1 to 7, and further comprising the step of reacting the xylene blue FF intermediate compound with an alkaline solution to obtain the xylene blue FF salt compound, wherein the alkaline solution is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate solution.
9. The method for preparing a xylene blue FF salt compound according to claim 8, wherein the xylene blue FF salt compound is a xylene blue FF potassium salt or a xylene blue FF sodium salt.
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