CN113773299B - Acridine salt derivative and synthesis method and application thereof - Google Patents
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Abstract
The general formula of the acridine salt derivative disclosed by the invention is shown as a formula I or a formula II, wherein R1 is selected from O, N, S, and R2 is selected from C, O and N; the preferred acridine salt derivative of the present invention is 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate, and the acridine salt derivative is 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate having the structural formula III and IV, respectively; methods of synthesizing the compounds of formulas III and IV, respectively, are disclosed. The acridine salt derivative can be used for chemiluminescence and immunoassay detection research, and has low cost of synthetic raw materials and high purity of the prepared product.
Description
Technical Field
The invention relates to an acridine salt derivative, in particular to a chemiluminescent acridine salt derivative, and a synthesis method and application thereof.
Background
Chemiluminescent immunoassay is a novel labeled immunoassay technology combining a chemiluminescent or bioluminescent system with an immune reaction for detecting trace amounts of antigen or antibody. The detection immune reaction principle is the same as that of radioimmunoassay and enzyme immunity, except that luminescent substances are used to replace chromogenic substances, and the content of the to-be-detected substance is quantitatively or qualitatively deduced by detecting the relative luminous intensity of a sample. The analytical method has the advantages of simple operation, high sensitivity, rapidness and easy standardized operation, does not use harmful reagents in the test, has long reagent retention period, and is widely applied to the fields of biology, medical research, clinical experiment diagnosis and the like.
Through the rapid development of CLIA over the last decade, various types of chemiluminescent substrates have been developed, with the common types being mainly acridines, luminols and their derivatives, peroxyoxalates, adamantanes, and the like. Among them, acridinium esters and acridinium amide acridine derivatives have many advantages as immunoassay tracers: no catalyst, high specificity, high luminous quantum yield, good stability and the like, thereby being widely applied.
At present, a chemiluminescent immunoassay tracer which has high sensitivity, strong stability, simple operation and rapidness is not available in the process of taking acridine salt as a chemiluminescent marker.
Disclosure of Invention
Aiming at the problems, the invention provides a novel chemiluminescent acridinium salt derivative which can be used for chemiluminescent and immunoassay detection research, and has the advantages of low cost of synthetic raw materials and high purity of prepared products, and the technical scheme is as follows.
An acridine salt derivative has the structural formula shown in formula I or formula II, wherein
R1 is selected from one of O, N and S, and R2 is selected from one of C, O and N;
further, one of the above-mentioned acridine salt derivatives is 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate; the structural formula is shown as the following formula III:
further, the invention provides a synthetic method for synthesizing the chemiluminescent substance 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo-butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate shown in the formula III, wherein the synthetic route is as follows:
the method comprises the following steps:
1) Acid chloride reaction: and dissolving the dibenzoacridine methylacetic acid in thionyl chloride for reflux reaction, and evaporating the solvent after the reaction is finished to obtain the dibenzoacridine formyl chloride.
2) Amide reaction: dissolving methyl p-toluenesulfonyl aminobutyrate in tetrahydrofuran, adding sodium hydrogen at 0 ℃ for reaction, adding tetrahydrofuran solution of dibenzoacridine formyl chloride, stirring for reaction at normal temperature, quenching with water, extracting with ethyl acetate, and concentrating to obtain methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate.
3) Propanesulfonic acid salt reaction: methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate, 1, 3-propane sultone is added, the mixture is reacted for 5 hours at 90 ℃, cooled and the mixture is put into a column by methylene dichloride: methanol=20: the 3- (13- ((4-methoxy (4-oxo-butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate is obtained by column separation.
4) Hydrolysis reaction: 3- (13- ((4-methoxy (4-oxo butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate) is added into tetrahydrofuran and 1mol/L sulfuric acid aqueous solution, reflux reaction is carried out for 4 hours, and the 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate is obtained by rotary evaporation and suction filtration.
5) Condensation reaction: adding 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate, adding N-hydroxysuccinimide, diisopropylcarbodiimide (DIC), stirring at normal temperature for reaction, rotary steaming, extracting with dichloromethane, concentrating and separating by a column to obtain 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate.
Wherein, step 2) the amide reaction, sodium hydrogen: methyl p-toluenesulfonylamino butyrate: dibenzoacridine formyl chloride molar ratio = 1.05:1.05:1.
wherein, step 3) the propanesulfonate salt reacts with methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate: mass ratio of 1, 3-propane sultone=1: 1.5 to 8. The reaction temperature is 80-130 ℃.
Wherein, the condensation reaction in the step 5) is carried out, and the mole ratio of 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate, N-hydroxysuccinimide and Diisopropylcarbodiimide (DIC) and DMAP is=1:1.5:1.5:0.2 percent.
Further, one of the above-mentioned acridine salt derivatives is 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate; the structural formula is shown as the following formula IV:
furthermore, the invention also provides a synthetic method for synthesizing the chemiluminescent substance 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo-butyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate shown in the formula IV, wherein the synthetic route is as follows:
the method comprises the following steps:
1) Acid chloride reaction: and dissolving the difuran acridine carboxylic acid in thionyl chloride for reflux reaction, and evaporating the solvent after the reaction is finished to obtain the difuran acridine formyl chloride.
2) Amide reaction: dissolving methyl p-toluenesulfonyl aminobutyrate in tetrahydrofuran, adding sodium hydrogen at 0 ℃ for reaction, adding tetrahydrofuran solution of difuran acridine formyl chloride, stirring for reaction at normal temperature, quenching with water, extracting with ethyl acetate, and concentrating to obtain methyl 4- (N-p-toluenesulfonyl difuran acridine-5-carboxamide) butyrate.
3) Propanesulfonic acid salt reaction: methyl 4- (N-p-toluenesulfonyldifuran acridine-5-formamide) butyrate, 1, 3-propane sultone is added, reaction is carried out for 5 hours at 90 ℃, cooling is carried out, and dichloromethane is adopted as an upper column: methanol=25: the 3- (5- ((4-methoxy (4-oxo-butyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate is obtained by column separation.
4) Hydrolysis reaction: 3- (5- ((4-methoxy (4-oxo butyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate) is added into tetrahydrofuran and 1mol/L sulfuric acid water solution, reflux reaction is carried out for 4 hours, and rotary evaporation and suction filtration are carried out to obtain the 3- (5- ((3-carboxypropyl (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate.
5) Condensation reaction: adding 3- (5- ((3-carboxypropyl (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate, adding N-hydroxysuccinimide, diisopropylcarbodiimide (DIC), stirring at normal temperature for reaction, rotary steaming, extracting with dichloromethane, concentrating, and separating by column to obtain 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo butyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate.
Wherein, step 2) the amide reaction, sodium hydrogen: methyl p-toluenesulfonylamino butyrate: difurano acridine formyl chloride molar ratio = 1.05:1.05:1.
wherein, step 3) the propanesulfonate salt reacts with methyl 4- (N-p-toluenesulfonyl difuran acridine-5-carboxamide) butyrate: mass ratio of 1, 3-propane sultone=1: 1.5 to 8. The reaction temperature is 80-130 ℃.
Wherein, the condensation reaction in the step 5) is carried out, 3- (5- ((3-carboxypropyl (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate, N-hydroxysuccinimide, diisopropylcarbodiimide (DIC) and DMAP molar ratio=1:1.5:1.5:0.2%.
The invention has the following beneficial effects:
due to the application of the technical scheme, the acridine salt derivative can be used for chemiluminescence and immunoassay detection research, and has low cost of synthetic raw materials and high purity of the prepared product. The application verification of chemiluminescent immunity shows that the fluorescent dye has good use effect. The light-emitting device has the advantages of high sensitivity, long light-emitting duration, simple use and the like.
Drawings
FIG. 1 is a synthetic reaction scheme for a chemiluminescent acridinium salt derivative 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate disclosed herein;
FIG. 2 is a nuclear magnetic resonance spectrum of a chemiluminescent acridinium salt derivative 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate salt disclosed herein;
FIG. 3 shows a comparison of the luminescence spectra of a chemiluminescent acridinium salt derivative 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate and acridinium ester NSP-SA-NHS disclosed herein;
FIG. 4 is a synthetic reaction scheme for a chemiluminescent acridinium salt derivative 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate disclosed herein.
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
A method for synthesizing a chemiluminescent substance 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate, as shown in figure 1, comprising the following steps:
1) Acid chloride reaction: 52.5g of dibenzo acridine formic acid and 500ml of thionyl chloride are put into a 1L single-neck flask for reflux reaction for 8 hours, and after the reaction is finished, 50g of dibenzo acridine formyl chloride is obtained by concentration, and the molar yield is 90%.
2) Amide reaction: a1000 ml three-necked flask was charged with 42g of methyl sulfonylaminobutyrate, 200ml of tetrahydrofuran, cooled to 0℃and then 6.17g of sodium hydrogen was added thereto in portions to stir the reaction. 50g of dibenzoacridine formyl chloride is dissolved in 150ml of tetrahydrofuran and added into the solution dropwise, the reaction is stirred at normal temperature, the reaction is complete, the quenching is carried out, the ethyl acetate extraction and concentration are carried out, 70g of methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate is obtained, and the molar yield is 85%.
3) Propanesulfonic acid salt reaction: a500 ml three-necked flask was charged with 70g of methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate, 150g of 1, 3-propane sultone, reacted at 90℃for 5 hours, cooled and put on a column using methylene chloride: methanol=20: 1 column separation gave 59.36g of 3- (13- ((4-methoxy (4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate in 70% molar yield.
4) Hydrolysis reaction: a3000 ml single-neck flask was charged with 59g of 3- (13- ((4-methoxy (4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate, 885ml of tetrahydrofuran and 885ml of 1mol/L sulfuric acid aqueous solution were added, and the reaction was carried out under reflux for 4 hours, to obtain 49.1g of 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate by rotary evaporation and suction filtration, and the molar yield was 85%.
5) Condensation reaction: 49g of 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate) was added to 250ml of acetonitrile, 12.3. 12.3g N-hydroxysuccinimide, 13.5g of Diisopropylcarbodiimide (DIC), 0.1g of DMAP, stirred at room temperature, reacted completely, distilled by spin, extracted with methylene chloride, washed with water, dried and concentrated and separated by column to give 44.76g of 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate in a molar yield of 80% HNMR (500 MHz, CDCl 3. Delta.: 8.88 (m, 4H), 8.37 (m, 2H), 8.30 (m, 2H), 8.26 (m, 2H), 7.91 (m, 2H), 7.77 (m, 2H), 7.23 (m, 2H), 5.63 (m, 2H), 5.95 (m, 2H), and a magnetic spectrum of 3.60 (m, 2H), as shown in FIG. 3.5.6.88 (m, 4H).
The luminescent performance of the synthesized chemiluminescent substance 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate is detected, and the specific operation steps are as follows;
the multifunctional enzyme label instrument is matched with an automatic sampler (BioTek) to detect luminescence, and a signal receiving filter 460 (+ -40) nm is set. After 2.5mg/ml of a DMSO solution of 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyloxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate was diluted 500-fold with DMSO (signal intensity, instrument burn out prevention) to a final concentration of 5. Mu.g/ml, 20. Mu.l was added to a black 96-well plate and 3 complex wells were set, and an autosampler was sequentially fed with 100. Mu.l of luminescence (luminescence preparation: 0.01M NaOH+0.05% hydrogen peroxide), sample feeding rate 300. Mu.l/s, gain 135, and signal values were recorded. The graph shows the comparison of the luminous patterns of the chemiluminescent substance 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate (dibenzoacridine salt) and acridinium ester NSP-SA-NHS, and the result is shown in the graph in figure 3.
Experiments prove that the 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo-butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate (dibenzoacridine salt) has the advantages of long luminous intensity, long duration, high sensitivity, good stability, simple use and the like.
Example 2
A method for synthesizing a chemiluminescent substance 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate, as shown in fig. 4, comprising the following steps:
1) Acid chloride reaction: into a 1L single-neck flask, 40g of difuran acridine formic acid and 400ml of thionyl chloride are put for reflux reaction for 8 hours, and after the reaction is finished, 37.3g of difuran acridine formyl chloride is obtained by concentration, and the molar yield is 88%.
2) Amide reaction: a1000 ml three-necked flask was charged with 33.3g of methyl sulfonylaminobutyrate and 180ml of tetrahydrofuran, and 4.89g of sodium hydrogen was added thereto in portions and stirred for reaction after cooling to 0 ℃.37.3g of difuran acridine formyl chloride is dissolved in 150ml of tetrahydrofuran and added into the solution dropwise, the reaction is stirred at normal temperature, the reaction is complete, the quenching is carried out, and 55g of 4- (N-p-toluenesulfonyl difuran acridine-5-formamide) methyl butyrate is obtained by extraction and concentration of ethyl acetate, and the molar yield is 86%.
3) Propanesulfonic acid salt reaction: a500 ml three-necked flask was charged with 55g of methyl 4- (N-p-toluenesulfonyldifuran acridine-5-carboxamide) butyrate, 140g of 1, 3-propane sultone, reacted at 90℃for 5 hours, cooled and taken up in methylene chloride: methanol=25: 1 column separation gave 45.6g of 3- (5- ((4-methoxy (4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate, molar yield 68%.
4) Hydrolysis reaction: a3000 ml single-neck flask was charged with 45.6g of 3- (5- ((4-methoxy (4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate, 684ml of tetrahydrofuran and 684ml of 1mol/L sulfuric acid aqueous solution were added, and the mixture was refluxed for 4 hours, and the mixture was filtered by suction with rotary evaporation to obtain 36.6g of 3- (5- ((3-carboxypropyl (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate in a molar yield of 82%.
5) Condensation reaction: 36.6g of 3- (5- ((3-carboxypropyl (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate was added to 250ml of acetonitrile, 9.47. 9.47g N-hydroxysuccinimide, 10.4g of Diisopropylcarbodiimide (DIC), 0.077g of DMAP, stirred at room temperature, reacted completely, distilled off by a rotary machine, extracted with dichloromethane, washed with water, dried and concentrated and separated by a column to obtain 34.4g of 3- (5- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) difuranacridine-11-propyl-1-sulfonate in 82% molar yield.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, i.e. the present invention is not limited to the above embodiments, but is capable of being modified and varied in all ways according to the following claims and the detailed description.
Claims (7)
1. An acridinium salt derivative which is 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxobutyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate; the structural formula is as follows:
2. a process for the synthesis of the acridine salt derivative according to claim 1, which comprises the steps of:
1) Acid chloride reaction: dissolving dibenzoacridine methylacetic acid in thionyl chloride for reflux reaction, and evaporating the solvent after the reaction is finished to obtain dibenzoacridine formyl chloride;
2) Amide reaction: dissolving methyl p-toluenesulfonyl aminobutyrate in tetrahydrofuran, adding sodium hydrogen at 0 ℃ for reaction, adding tetrahydrofuran solution of dibenzoacridine formyl chloride, stirring at normal temperature for reaction, quenching with water, extracting with ethyl acetate, and concentrating to obtain methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate;
3) Propanesulfonic acid salt reaction: methyl 4- (N-p-toluenesulfonyl dibenzoacridine-13-carboxamide) butyrate, 1, 3-propane sultone is added, the mixture is reacted for 5 hours at 90 ℃, cooled and the mixture is put into a column by methylene dichloride: methanol=20: separating 1 by column to obtain 3- (13- ((4-methoxy (4-oxo butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate;
4) Hydrolysis reaction: 3- (13- ((4-methoxy (4-oxo butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate) is added into tetrahydrofuran and 1mol/L sulfuric acid water solution to carry out reflux reaction for 4 hours, and the 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate is obtained by rotary evaporation and suction filtration;
5) Condensation reaction: 3- (13- ((3-carboxypropyl (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate, adding acetonitrile, adding N-hydroxysuccinimide, diisopropylcarbodiimide (DIC), stirring at normal temperature for reaction, rotary evaporation, dichloromethane extraction, concentration and column separation to obtain 3- (13- (4- ((2, 5-dioxo-1-pyrrolidinyl) oxy) 4-oxo butyl) (tosyl) carbamoyl) dibenzoacridine-6-propyl-1-sulfonate.
3. The process of claim 2, wherein step 2) the amide reaction, sodium hydrogen: methyl p-toluenesulfonylamino butyrate: molar ratio of acid chloride = 1.05:1.05:1.
4. the process according to claim 2, wherein step 3) the propanesulfonate reaction, methyl 4- (N-p-toluenesulfonyldibenzoacridine-13-carboxamide) butyrate: mass ratio of 1, 3-propane sultone=1: 1.5 to 8; the reaction temperature is 80-130 ℃.
5. The method according to claim 2, wherein the condensation reaction of step 5) is carried out by: n-hydroxysuccinimide: diisopropylcarbodiimide (DIC): DMAP molar ratio = 1:1.5:1.5:0.2%.
6. The use of an acridinium salt derivative according to claim 1 for the preparation of chemiluminescent and immunoassay detection reagents.
7. Use of the acridine salt derivative according to claim 1 as a tracer for the preparation of chemiluminescent immunoassay.
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| EP1403254A1 (en) * | 2002-09-27 | 2004-03-31 | Bayer Healthcare, LLC | Novel applications of acridinium compounds and derivatives in homogeneous assays |
| CN103288802A (en) * | 2013-06-21 | 2013-09-11 | 深圳市美凯特科技有限公司 | Preparation method for a series of acridine chemiluminescence agents |
| CN111170994A (en) * | 2020-03-05 | 2020-05-19 | 合肥华纳生物医药科技有限公司 | Preparation method of acridine inner salt |
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| EP1403254A1 (en) * | 2002-09-27 | 2004-03-31 | Bayer Healthcare, LLC | Novel applications of acridinium compounds and derivatives in homogeneous assays |
| CN103288802A (en) * | 2013-06-21 | 2013-09-11 | 深圳市美凯特科技有限公司 | Preparation method for a series of acridine chemiluminescence agents |
| CN111170994A (en) * | 2020-03-05 | 2020-05-19 | 合肥华纳生物医药科技有限公司 | Preparation method of acridine inner salt |
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