CN117164602A - Synthesis method of rhodamine substance - Google Patents
Synthesis method of rhodamine substance Download PDFInfo
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- CN117164602A CN117164602A CN202311130406.7A CN202311130406A CN117164602A CN 117164602 A CN117164602 A CN 117164602A CN 202311130406 A CN202311130406 A CN 202311130406A CN 117164602 A CN117164602 A CN 117164602A
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- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 239000000126 substance Substances 0.000 title claims abstract description 8
- 238000001308 synthesis method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- 239000012445 acidic reagent Substances 0.000 claims abstract description 9
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 8
- 238000006277 sulfonation reaction Methods 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 229940126214 compound 3 Drugs 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 229960000583 acetic acid Drugs 0.000 claims description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 5
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 3
- 239000013067 intermediate product Substances 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007850 fluorescent dye Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- NCYNKWQXFADUOZ-UHFFFAOYSA-N 1,1-dioxo-2,1$l^{6}-benzoxathiol-3-one Chemical compound C1=CC=C2C(=O)OS(=O)(=O)C2=C1 NCYNKWQXFADUOZ-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- ZMPRRFPMMJQXPP-UHFFFAOYSA-N 2-sulfobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1S(O)(=O)=O ZMPRRFPMMJQXPP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- VYXSBFYARXAAKO-WTKGSRSZSA-N chembl402140 Chemical compound Cl.C1=2C=C(C)C(NCC)=CC=2OC2=C\C(=N/CC)C(C)=CC2=C1C1=CC=CC=C1C(=O)OCC VYXSBFYARXAAKO-WTKGSRSZSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- GMXFZBZOVZOYNQ-UHFFFAOYSA-N hydron;(3-methoxyphenyl)hydrazine;chloride Chemical compound Cl.COC1=CC=CC(NN)=C1 GMXFZBZOVZOYNQ-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000000990 laser dye Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- MYIOYATURDILJN-UHFFFAOYSA-N rhodamine 110 Chemical compound [Cl-].C=12C=CC(N)=CC2=[O+]C2=CC(N)=CC=C2C=1C1=CC=CC=C1C(O)=O MYIOYATURDILJN-UHFFFAOYSA-N 0.000 description 1
- TUFFYSFVSYUHPA-UHFFFAOYSA-M rhodamine 123 Chemical compound [Cl-].COC(=O)C1=CC=CC=C1C1=C(C=CC(N)=C2)C2=[O+]C2=C1C=CC(N)=C2 TUFFYSFVSYUHPA-UHFFFAOYSA-M 0.000 description 1
- 239000001022 rhodamine dye Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000004557 single molecule detection 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
- 238000003756 stirring Methods 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 150000003732 xanthenes Chemical class 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing rhodamine substances, which relates to the field of rhodamine substance preparation and aims to solve the problems of more byproducts, low yield and complex post-treatment in the prior art. By introducing an acidic reagent to perform reaction, then sequentially performing demethylation reaction, reduction reaction, heating reaction and sulfonation reaction, and finally purifying, the indole rhodamine with high yield and high purity can be efficiently and quickly obtained, and a novel efficient and universal method is established for the chemical synthesis of rhodamine.
Description
Technical Field
The invention relates to the field of rhodamine material preparation, in particular to a method for synthesizing rhodamine materials.
Background
Rhodamine compounds are dyes taking xanthenes as a matrix, and because of a special structure and corresponding fluorescence characteristics, rhodamine fluorescent dyes become a relatively wide subject for research in the chemical and biological analysis fields. There are many reports on the synthesis, ionization, structure, optical properties, analysis and the like of Guan Luodan fluorescent dyes. Compared with other commonly used fluorescent dyes, rhodamine fluorescent dyes have the advantages of good light stability, insensitivity to pH, wider wavelength range, higher fluorescence quantum yield and the like, so that the rhodamine fluorescent dyes are widely applied to the aspects of pharmacology, physiology, molecular biology, cell biology, molecular genetics, environmental chemistry, single molecule detection, information science, fluorescent labeling, laser dyes and the like, the biological fluorescent probes prepared from the rhodamine fluorescent dyes can be used for measuring the performances of ions, charges, metabolism and the like in biological cells, such as rhodamine 123 and rhodamine 6G can be used for labeling mitochondria of living cells, and rhodamine 110 can be used for preparing protease diagnostic reagents. Rhodamine dyes are the most commonly used fluorescent dyes in biotechnology fields such as analytical chemistry and biomedical science.
The rhodamine fluorescent dye is typically prepared by reacting aminophenol with various benzoic acid, phthalic anhydride, sulfobenzoic acid and anhydride thereof, and condensing with concentrated sulfuric acid or Lewis acid as a catalyst.
Disclosure of Invention
In view of the problems of more byproducts, low yield and difficult post-treatment in the prior art, the invention discloses a method for synthesizing rhodamine substances.
The technical scheme adopted is that the method comprises the following steps:
step 1, adding a compound 1 and an acidic reagent into ethanol for reaction to obtain a compound 2;
step 2, carrying out a demethylation reaction on the compound 2 obtained in the step 1 to obtain a compound 3;
step 3, adding a reducing substance into the solution of the compound 3 obtained in the step 2 under a first solvent and an inert atmosphere to react to obtain an intermediate product, and pulping to obtain a compound 4;
step 4, sequentially adding the compound 4, the 1,2, 4-trimellitic anhydride and the zinc chloride obtained in the step 3 into a reaction system to carry out heating reaction under inert atmosphere, pulping, and recrystallizing to obtain a compound 5;
step 5, dissolving the compound 5 obtained in the step 4 in a sulfonating reagent for reaction to obtain a medium crude product, and purifying to obtain a compound 6, namely a product;
the reaction formula of the method is shown as follows:
in a preferred embodiment of the present invention, in the step 1, the reaction is performed under an inert gas atmosphere, and the inert gas may be argon.
As a preferred technical scheme of the invention, in the step 1, the ethanol is absolute ethanol, the acidic reagent is one or more of hydrochloric acid, sulfuric acid and glacial acetic acid, and glacial acetic acid is preferred.
The ratio of the amounts of acidic reagent and ethanol species was 1:0.01: 20-30 parts; preferably 1:0.01:25.
the reaction conditions are reflux reaction for 3-6 hours, preferably 4 hours
In a preferred embodiment of the present invention, in the step 2, the compound 2 is subjected to a demethylation reaction in a solvent under the condition of boron tribromide, wherein the solvent is one of dichloromethane, N-dimethylformamide, methanol and ethanol.
The solvent is preferably methylene dichloride, and the molar ratio of the compound 2 to the boron tribromide is 1:1 to 10; preferably 1:1.5.
the condition of the demethylation reaction is room temperature reaction, and the reaction time is 2 hours.
In a preferred embodiment of the present invention, in the step 3, the first solvent is one or more of glacial acetic acid, N-dimethylformamide, tetrahydrofuran, ethanol, and methanol.
In a preferred embodiment of the present invention, in the step 3, the reducing substance is one or more of sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, stannous chloride, and sodium iodide.
The reducing substance is preferably sodium cyanoborohydride, and the sodium cyanoborohydride has the advantages of less reaction byproducts, high yield, simple post-treatment, green reagent and environmental friendliness.
The ratio of the amounts of compound 3 and sodium cyanoborohydride species is 1:2 to 8; preferably 1:3.
the reaction condition is room temperature reaction, and the reaction time is 2 hours.
In the preferred embodiment of the present invention, in the step 4, the molar ratio of the compound 4, the 1,2, 4-trimellitic anhydride, and the zinc chloride is (1 to 5): 1: (0.02-0.5), preferably 2:1:0.1.
The reaction temperature was 180℃and the reaction time was 18 hours.
In the step 5, the sulfonation reagent is one or more of fuming sulfuric acid, sulfuric acid and chlorosulfuric acid. Preferably oleum, the advantage of using oleum is that the reaction by-products are few and the post-treatment is simple.
As a preferable technical scheme of the invention, the mass fraction of the fuming sulfuric acid is 60%.
As a preferred embodiment of the present invention, in the step 5, the purification is performed using a chromatographic column.
The reaction time was 3 hours.
The invention has the beneficial effects that: according to the invention, an acidic reagent is introduced for reaction, and then the demethylation reaction, the reduction reaction, the heating reaction and the sulfonation reaction are sequentially carried out, so that the method is finally purified, the indole rhodamine with high yield and high purity can be efficiently and rapidly obtained, and a novel efficient and universal method is established for the chemical synthesis of rhodamine. In particular, the acid reagent adopts glacial acetic acid to prepare intermediate products, so that the reaction byproducts are few, the yield is high, the acid reagent is easy to obtain, and the post-treatment is simple. The reduction reaction uses sodium cyanoborohydride as a reducing agent, and has the advantages of few reaction byproducts, high yield, simple post-treatment, green reagent and environmental friendliness. 60% fuming sulfuric acid is used as a sulfonating reagent in the sulfonation reaction, so that the reaction byproducts are few, and the post-treatment is simple.
Detailed Description
Example 1
The invention discloses a method for synthesizing rhodamine substances, which adopts the technical scheme that the method comprises the following steps:
step 1 3-methoxy phenylhydrazine hydrochloride (compound 1, 17.5g,0.1 mol) was dissolved in 150mL of absolute ethanol, compound 1 having the formula:
1mL glacial acetic acid was added, the temperature was raised to reflux under argon, the reaction continued for 4h, and TLC monitored until the starting material disappeared. After the reaction, the temperature is reduced to room temperature, most of the solvent is removed by reduced pressure rotary evaporation, ethyl acetate is added into the crude reaction solution to dissolve, water is added into the crude reaction solution to extract, saturated saline water is used for washing the organic phase, and anhydrous sodium sulfate is dried and then spin-dried. Purification of the crude product by chromatography (PE/ea=4/1) finally gives compound 2 (4.5 g, yield 24%) as a brown liquid, compound 2 having the structure:
the nuclear magnetic data of compound 2 are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.28(d,J＝8.1Hz,1H),7.01(d,J＝2.3Hz,1H),6.73(dd,J＝8.1,2.4Hz,1H),3.76(s,3H),2.19(s,3H),1.21(s,6H)。
step 2, compound 2 (1.89 g,10 mmol) was dissolved in 20mL of dichloromethane, and boron tribromide (15 mL,1M. In DCM) was slowly added dropwise under ice-bath to effect a demethylation reaction, and after 2h the starting material disappeared. Water quenching, DCM extraction after pH adjustment to neutral with saturated sodium bicarbonate solution, combined organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, spin-drying the solvent, purification of the crude product by column chromatography (DCM/meoh=10/1) afforded compound 3 (1.24 g, 70% yield) as a pale yellow solid, compound 3 having the structure:
the nuclear magnetic data of compound 3 are as follows:
1 H NMR(500MHz,DMSO-d6)δ9.27(s,1H),7.14(d,J＝7.9Hz,1H),6.81(d,J＝2.2Hz,1H),6.56(dd,J＝8.0,2.2Hz,1H),2.17(s,3H),1.19(s,6H)。
step 3, compound 3 (1.77 g,10mmol, the portion of Compound 3 used in an amount larger than that obtained in step 2 was obtained by the secondary preparation) was dissolved in 10mL of glacial acetic acid, and sodium cyanoborohydride (about 0.5g each time, 1.86g,30mmol in total) was added in portions at room temperature, and the solution became viscous during the reaction, and was stirred for 2 hours at a stirring speed of 500rpm. TLC monitoring the reaction process until the raw materials are completely reacted, adding water to quench the reaction after finishing, adjusting the pH to be neutral by using 2M sodium hydroxide solution, extracting by Ethyl Acetate (EA) for three times, combining organic phases, washing by saturated saline water, drying by anhydrous sodium sulfate, and spin-drying the solvent. The crude product was purified by column chromatography (PE/ea=10/1) to finally give compound 4 (1.56 g, yield 82%) as a pale yellow liquid, the structure of compound 4 being as follows:
the nuclear magnetic data of compound 4 are as follows:
1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),6.69(d,J＝7.8Hz,1H),5.94(dd,J＝7.8,2.2Hz,1H),5.92(d,J＝2.1Hz,1H),5.40(d,J＝2.6Hz,1H),1.14(s,3H),1.04(d,J＝6.5Hz,3H),0.88(s,3H)。
step 4, compound 4 (354 mg,2 mmol) and 1,2, 4-trimellitic anhydride (192 mg,1 mmol) were added to a reactor, a catalytic amount (13.6 mg) of zinc chloride was added, and the temperature was raised to 180℃under argon atmosphere to melt the raw materials. After 18h reaction, cooled to room temperature, dissolved in methanol, and the crude product was purified by column chromatography (DCM/meoh=5/1) after spin-drying to give product 5 (102 mg, yield 20%), compound 5 had the following structure:
the nuclear magnetic data of compound 5 are as follows:
1 H NMR(500MHz,DMSO-d6)：δ8.37(d,J＝1.4Hz,1H),7.96(dd,J＝7.5,1.5Hz,1H),7.52(d,J＝7.4Hz,1H),7.18(s,2H),6.08(s,2H),5.56(d,J＝9.2Hz,2H),4.28–4.18(m,2H),1.35(d,J＝1.6Hz,6H),1.30(d,J＝1.4Hz,6H),0.94(d,J＝6.8Hz,6H)。
step 5, compound 5 (52 mg,0.1 mmol) was dissolved in 0.1mL oleum with an ice bath at 60% mass fraction, and the ice bath stirred until the starting materials were completely reacted at 500rpm. To the reaction solution was added 20mL of methyl tert-butyl ether, and after precipitation, the precipitate was filtered, and the precipitate was separated by reverse-phase chromatography (eluent: water/acetonitrile) to give compound 6 (14 mg, yield 22%) as a product. The structure of compound 6 is shown in the following formula:
the nuclear magnetic data of compound 6 are as follows:
1 H NMR(500MHz,DMSO-d6)：δ9.86(s,2H),8.36(d,J＝1.5Hz,1H),7.97(dd,J＝7.5,1.6Hz,1H),7.48(d,J＝7.5Hz,1H),7.33(s,2H),7.27(d,J＝9.0Hz,2H),4.21–4.11(m,2H),1.37(d,J＝1.6Hz,6H),1.32(d,J＝1.4Hz,6H),0.99(d,J＝6.8Hz,6H)。
although the specific embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes and modifications without inventive labor may be made within the scope of the present invention without departing from the spirit of the present invention, which is within the scope of the present invention.
Claims (10)
1. The method for synthesizing the rhodamine substance is characterized by comprising the following steps of:
step 1, adding a compound 1 and an acidic reagent into ethanol for reaction to obtain a compound 2;
step 2, carrying out a demethylation reaction on the compound 2 obtained in the step 1 to obtain a compound 3;
step 3, adding a reducing substance into the solution of the compound 3 obtained in the step 2 under a first solvent and an inert atmosphere to react to obtain an intermediate product, and pulping to obtain a compound 4;
step 4, sequentially adding the compound 4, the 1,2, 4-trimellitic anhydride and the zinc chloride obtained in the step 3 into a reaction system to carry out heating reaction under inert atmosphere, pulping, and recrystallizing to obtain a compound 5;
step 5, dissolving the compound 5 obtained in the step 4 in a sulfonating reagent for reaction to obtain a medium crude product, and purifying to obtain a compound 6, namely a product;
the reaction formula of the method is shown as follows:
2. the method for synthesizing rhodamine materials according to claim 1, characterized in that: in the step 1, the reaction is carried out under the protection of inert gas.
3. A method for synthesizing rhodamine materials according to claim 1 or 2, characterized in that: in the step 1, the ethanol is absolute ethanol, and the acidic reagent is one or more of hydrochloric acid, sulfuric acid and glacial acetic acid.
4. The method for synthesizing rhodamine materials according to claim 1, characterized in that: in the step 2, the compound 2 is subjected to a demethylation reaction in a solvent under the condition of boron tribromide, wherein the solvent is one of dichloromethane, N-dimethylformamide, methanol and ethanol.
5. The method for synthesizing rhodamine materials according to claim 1, characterized in that: in the step 3, the first solvent is one or more of glacial acetic acid, N, N-dimethylformamide, tetrahydrofuran, ethanol and methanol.
6. The method for synthesizing rhodamine materials according to claim 1 or 5, characterized in that: in the step 3, the reducing substance is one or more of sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, stannous chloride and sodium iodide.
7. The method for synthesizing rhodamine materials according to claim 1, characterized in that: in the step 4, the molar ratio of the compound 4, the 1,2, 4-trimellitic anhydride and the zinc chloride is (1-5): 1: (0.02-0.5).
8. The method for synthesizing rhodamine materials according to claim 1, characterized in that: in the step 5, the sulfonation reagent is one or more of fuming sulfuric acid, sulfuric acid and chlorosulfuric acid.
9. The method for synthesizing rhodamine materials according to claim 8, characterized in that: the mass fraction of fuming sulfuric acid is 60%.
10. The method for synthesizing rhodamine materials according to claim 1, characterized in that: in the step 5, the purification is performed using a chromatographic column.
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