The invention relates to 4, 4apos; synthesis method of sodium-(1, 10-phenanthroline-4, 7-diyl) dibenzenesulfonate

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a synthesis method of 4, 4 '-(1, 10-phenanthroline-4, 7-diyl) sodium dibenzenesulfonate, which comprises the following steps: by taking p-bromobenzene sulfonyl chloride and o-phenylenediamine as raw materials, carrying out substitution and coupling on the p-bromobenzene sulfonyl chloride to obtain 4-pinacol ester benzenesulfonate neopentyl alcohol ester; the preparation method comprises the following steps: carrying out substitution, ring closure and bromination on o-phenylenediamine to obtain 4, 7-dibromo-1, 10-phenanthroline; according to the synthesis method, the two intermediates are subjected to eight steps of reactions including coupling, hydrolysis and salifying to obtain the target product 4, 4 '-(1, 10-phenanthroline-4, 7-diyl) sodium dibenzenesulfonate, each step of reaction operation is simple and safe, the yield is high, the repeatability is good, and the synthesis method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and specifically relates to a method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate. Background Art

[0002] Cisplatin is one of the most widely used anticancer drugs. Platinum complexes have received widespread attention as potential anticancer drugs. Among them, 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate and its analogs with platinum complexes have significant anticancer activity and are being widely studied by scientists.

[0003] The structural formula of the compound 4,4'-(1,10-phenanthroline-4,7-diyl) dibenzenesulfonate sodium is as follows:

[0004] There are few existing synthesis reports and corresponding patents. The synthesis method provided in patent CN110128481 is:

[0005] Although the method has a short number of steps, the product obtained is a mixture of multiple products, which is difficult to purify and is not suitable for process scale-up production. Therefore, it is urgent to provide a method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate, which has simple and safe reaction operations in each step, high yield, good repeatability, and is suitable for industrial scale-up production. Summary of the invention

[0006] The purpose of the present invention is to provide a method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate. The method has simple and safe operation in each step, high yield and good repeatability, and is suitable for industrialized scale-up production.

[0007] The objective of the present invention is achieved through the following technical solutions: The present invention provides a method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate, comprising the following steps: (1) Mix 4-bromobenzenesulfonyl chloride and a reaction solvent, add 2,2-dimethylpropanol and the reaction solvent at room temperature; after the addition, stir at room temperature overnight, then add a base, separate the liquids, wash the organic phase with hydrochloric acid 4 times, concentrate the organic phase to dryness, and crystallize it with acetonitrile and water to obtain IM1; (2) IM1 and the reaction solvent were mixed, and then a base and bipinacol diborane were added, and the atmosphere was replaced with nitrogen three times, and a catalyst was added. The temperature was raised to 60-65°C and the reaction was carried out overnight, and then the temperature was lowered to room temperature, and ethyl acetate and water were added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate; the organic phases were combined, washed with saturated brine, and dried and decolorized with anhydrous sodium sulfate and activated carbon. After filtering and concentration, the crude product was crystallized with acetonitrile and water, dried, and then slurried with petroleum ether, filtered and dried to obtain IM2; (3) Mix trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione, raise the temperature to 85-90°C, and stir for 2-3 hours; cool to 40-45°C, add o-phenylenediamine in batches, raise the temperature to 75-85°C, stir for 1-2 hours, then cool to room temperature, add methyl tert-butyl ether, stir for 1-2 hours, filter, and dry to obtain IM3.

[0008] (4) The reaction solvent was heated, IM3 was added in batches, and the reaction was continued for 10 minutes, and then the temperature was lowered to 60-65°C and filtered; the filtered solid was heated to reflux with methanol, slurried for 1-2 hours, cooled to room temperature, filtered and dried to obtain IM4; (5) Mix the reaction solvent and IM4, add phosphorus oxybromide, heat to reflux, react overnight, cool to room temperature, add methyl tert-butyl ether, stir for 1 hour, and filter; dissolve the solid in ammonia water in batches, add dichloromethane and methanol to filter and extract; filter the solid and then dissolve and filter with dichloromethane and methanol, and combine the organic phases; dry and decolorize the organic phase with activated carbon and anhydrous sodium sulfate; filter and concentrate, and beat with acetonitrile overnight, filter and dry the material to obtain IM5; (6) Mix the reaction solvent with water, add IM5 and IM2 and a base, replace the atmosphere with nitrogen three times, add a catalyst, heat to 85-90°C, react overnight, then cool to 40-50°C, concentrate, add dichloromethane and water to filter and extract, extract the aqueous phase with dichloromethane, combine the organic phases, wash once, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and pass the crude product through a column with dichloromethane and methanol. After concentration, dissolve the crude product in tetrahydrofuran and add activated carbon for decolorization. After filtering and concentration, slurry the crude product with methyl tert-butyl ether, filter and dry to obtain IM6. (7) Add the reaction solvent and IM6, raise the temperature to reflux and react overnight, then cool the reaction solution to room temperature, add isopropyl acetate dropwise, stir for 2-4 hours, and filter; beat the filter cake with isopropyl acetate, filter and dry to obtain the crude IM7, which is directly used in the next step; (8) Add the reaction solvent and IM7, cool to 10°C, add the base in batches, stir at room temperature overnight, filter, dissolve the filter cake with water, stir for 0.5-1 hour, add acetone dropwise, stir for 3-5 hours, filter, slurry the filter cake with acetone, filter and dry to obtain sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate; Furthermore, in step (1), the reaction solvent includes one of dichloromethane, toluene, tetrahydrofuran, and pyridine; The base includes one of pyridine, triethylamine, 4-dimethylaminopyridine and sodium bicarbonate; The weight ratio of the reaction solvent to the substrate is 5:1-15:1; The molar ratio of the base to the substrate is 1.1-3.5:1; The molar ratio of the 2,2-dimethylpropanol to the substrate is 2-4:1.

[0009] Furthermore, in step (2), the reaction solvent includes one of 1,4-dioxane, acetonitrile, toluene, and tetrahydrofuran; The base includes one of potassium acetate, potassium carbonate, sodium carbonate and cesium carbonate; The catalyst comprises one of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex, tetrakis(triphenylphosphine)palladium, and bis(triphenylphosphine)palladium dichloride; The weight ratio of the reaction solvent to the substrate is 5:1-25:1; The molar ratio of the base to the substrate is 1.5-5:1; The molar ratio of the bis-pinacol diborane to the substrate is 1-2:1; The weight ratio of the catalyst to the substrate is 2.5%-10%:1; The reaction temperature is 50-100°C.

[0010] Furthermore, in step (4), the reaction solvent includes one of diphenyl ether, N-methylpyrrolidone, xylene, and N,N-dimethylformamide; The weight ratio of the reaction solvent to the substrate is 5:1-25:1; The reaction temperature is 150-230°C.

[0011] Furthermore, in step (5), the reaction solvent includes one of acetonitrile, chloroform, toluene, and phosphorus oxybromide; The weight ratio of the reaction solvent to the substrate is 5:1-15:1; The molar ratio of phosphorus oxybromide to substrate is 2-4:1; The reaction temperature is 50-100°C.

[0012] Further, in step (6), the reaction solvent includes a mixture of one or more of 1,4-dioxane, acetonitrile, tetrahydrofuran, and water; The base includes one of potassium acetate, potassium carbonate, sodium carbonate and cesium carbonate; The catalyst comprises one of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex, tetrakis(triphenylphosphine)palladium, and bis(triphenylphosphine)palladium dichloride; The weight ratio of the reaction solvent to the substrate is 5:1-25:1; The molar ratio of the base to the substrate is 5-20:1; The weight ratio of the catalyst to the substrate is 5%-30%:1; The reaction temperature is 50-100°C.

[0013] Furthermore, in step (7), the reaction solvent includes one of trifluoroacetic acid, hydrochloric acid, aqueous sulfuric acid, and trifluoromethanesulfonic acid; The weight ratio of the reaction solvent to the substrate is 5:1-20:1; The reaction temperature is 20-100°C.

[0014] Furthermore, in step (8), the reaction solvent includes one of water, methanol, ethanol, and isopropanol; The base includes one of sodium hydroxide, sodium methoxide, sodium tert-butoxide and sodium ethoxide; The weight ratio of the reaction solvent to the substrate is 5:1-20:1; The molar ratio of the base to the substrate is 2-10:1; The reaction temperature is 20-50°C.

[0015] The beneficial effects of the present invention are: The invention uses 4-bromobenzenesulfonyl chloride and o-phenylenediamine as raw materials: 4-pinacolylbenzenesulfonyl chloride is substituted and coupled to obtain 4-pinacolylbenzenesulfonate neopentyl alcohol ester; o-phenylenediamine is substituted, ring-closed and brominated to obtain 4,7-dibromo-1,10-o-phenanthroline; two intermediates are coupled, hydrolyzed and salt-formed, and a total of eight steps of reaction are carried out to obtain the target product 4,4'-(1,10-o-phenanthroline-4,7-diyl) sodium dibenzenesulfonate. The synthetic method has simple and safe operation of each step of reaction, a yield of up to 75%, good repeatability, and is a synthetic method suitable for industrialized scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0017] Figure 1The reaction flow chart of preparing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to the present invention; Figure 2 This is the NMR spectrum of IM1 prepared by the present invention; Figure 3 This is the NMR spectrum of IM2 prepared by the present invention; Figure 4 This is the nuclear magnetic spectrum of IM3 prepared by the present invention; Figure 5 This is the NMR spectrum of IM4 prepared by the present invention; Figure 6 The NMR spectrum of IM5 prepared by the present invention; Figure 7 This is the nuclear magnetic spectrum of IM6 prepared by the present invention; Figure 8 The NMR spectrum of IM7 prepared by the present invention; Fig. 9 This is the nuclear magnetic spectrum of sodium 4,4'-(1,10-o-phenanthroline-4,7-diyl)dibenzenesulfonate prepared by the present invention. DETAILED DESCRIPTION

[0018] The embodiments of the present invention are described in detail below, and the embodiments are intended to explain the present invention and should not be construed as limiting the present invention. If specific techniques or conditions are not specified in the embodiments, they are carried out according to the techniques or conditions described in the literature in this area or according to the product specifications. If the manufacturers of reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0019] In order to have a clearer understanding of the technical features, purposes and effects of the present invention, the specific implementation methods of the present invention are now described.

[0020] The synthesis method of sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate in the present invention is carried out in 8 steps, and the reaction flow chart thereof is as follows: Figure 1 As shown, the specific steps include: (1) Mix 4-bromobenzenesulfonyl chloride and a reaction solvent, add 2,2-dimethylpropanol and the reaction solvent at room temperature; after the addition, stir at room temperature overnight, then add a base, separate the liquids, wash the organic phase with hydrochloric acid 4 times, concentrate the organic phase to dryness, and crystallize it with acetonitrile and water to obtain IM1; The reaction solvent includes one of dichloromethane, toluene, tetrahydrofuran and pyridine; the base includes one of pyridine, triethylamine, 4-dimethylaminopyridine and sodium bicarbonate; the weight ratio of the reaction solvent to the substrate is 5:1-15:1, the molar ratio of the base to the substrate is 1.1-3.5:1, and the molar ratio of 2,2-dimethylpropanol to the substrate is 2-4:1.

[0021] (2) IM1 and the reaction solvent were mixed, and then a base and bipinacol diborane were added, and the atmosphere was replaced with nitrogen three times, and a catalyst was added. The temperature was raised to 60-65°C and the reaction was carried out overnight, and then the temperature was lowered to room temperature, and ethyl acetate and water were added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate; the organic phases were combined, washed with saturated brine, and dried and decolorized with anhydrous sodium sulfate and activated carbon. After filtering and concentration, the crude product was crystallized with acetonitrile and water, dried, and then slurried with petroleum ether, filtered and dried to obtain IM2; The reaction solvent comprises one of 1,4-dioxane, acetonitrile, toluene and tetrahydrofuran; the base comprises one of potassium acetate, potassium carbonate, sodium carbonate and cesium carbonate; the catalyst comprises one of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) dichloromethane complex, tetrakis(triphenylphosphine)palladium and bis(triphenylphosphine)palladium dichloride; the weight ratio of the reaction solvent to the substrate is 5:1-25:1, the molar ratio of the base to the substrate is 1.5-5:1, the molar ratio of the bis-pinacol diborane to the substrate is 1-2:1, and the weight ratio of the catalyst to the substrate is 2.5%-10%:1; and the reaction temperature is 50-100°C.

[0022] (3) Mix trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione, raise the temperature to 85-90°C, and stir for 2-3 hours; cool to 40-45°C, add o-phenylenediamine in batches, raise the temperature to 75-85°C, stir for 1-2 hours, then cool to room temperature, add methyl tert-butyl ether, stir for 1-2 hours, filter, and dry to obtain IM3.

[0023] (4) The reaction solvent was heated, IM3 was added in batches, and the reaction was continued for 10 minutes, and then the temperature was lowered to 60-65°C and filtered; the filtered solid was heated to reflux with methanol, slurried for 1-2 hours, cooled to room temperature, filtered and dried to obtain IM4; The reaction solvent includes one of diphenyl ether, N-methylpyrrolidone, xylene and N,N-dimethylformamide; the weight ratio of the reaction solvent to the substrate is 5:1-25:1; and the reaction temperature is 150-230°C.

[0024] (5) Mix the reaction solvent and IM4, add phosphorus oxybromide, heat to reflux, react overnight, cool to room temperature, add methyl tert-butyl ether, stir for 1 hour, and filter; dissolve the solid in ammonia water in batches, add dichloromethane and methanol to filter and extract; filter the solid and then dissolve and filter with dichloromethane and methanol, and combine the organic phases; dry and decolorize the organic phase with activated carbon and anhydrous sodium sulfate; filter and concentrate, and beat with acetonitrile overnight, filter and dry the material to obtain IM5; The reaction solvent includes one of acetonitrile, chloroform, toluene and phosphorus oxybromide; the weight ratio of the reaction solvent to the substrate is 5:1-15:1; the molar ratio of phosphorus oxybromide to the substrate is 2-4:1; and the reaction temperature is 50-100°C.

[0025] (6) Mix the reaction solvent with water, add IM5 and IM2 and a base, replace the atmosphere with nitrogen three times, add a catalyst, heat to 85-90°C, react overnight, then cool to 40-50°C, concentrate, add dichloromethane and water to filter and extract, extract the aqueous phase with dichloromethane, combine the organic phases, wash once, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and pass the crude product through a column with dichloromethane and methanol. After concentration, dissolve the crude product in tetrahydrofuran and add activated carbon for decolorization. After filtering and concentration, slurry the crude product with methyl tert-butyl ether, filter and dry to obtain IM6. The reaction solvent includes one or more mixtures of 1,4-dioxane, acetonitrile, tetrahydrofuran and water; the base includes one of potassium acetate, potassium carbonate, sodium carbonate and cesium carbonate; the catalyst includes one of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex, tetrakis(triphenylphosphine)palladium and bis(triphenylphosphine)palladium dichloride; the weight ratio of the reaction solvent to the substrate is 5:1-25:1, the molar ratio of the base to the substrate is 5-20:1, and the weight ratio of the catalyst to the substrate is 5%-30%:1; and the reaction temperature is 50-100°C.

[0026] (7) Add the reaction solvent and IM6, raise the temperature to reflux and react overnight, then cool the reaction solution to room temperature, add isopropyl acetate dropwise, stir for 2-4 hours, and filter; beat the filter cake with isopropyl acetate, filter and dry to obtain the crude IM7, which is directly used in the next step; The reaction solvent includes one of trifluoroacetic acid, hydrochloric acid, sulfuric acid aqueous solution and trifluoromethanesulfonic acid, the weight ratio of the reaction solvent to the substrate is 5:1-20:1; and the reaction temperature is 20-100°C.

[0027] (8) Add the reaction solvent and IM7, cool to 10°C, add the base in batches, stir at room temperature overnight, filter, dissolve the filter cake with water, stir for 0.5-1 hour, add acetone dropwise, stir for 3-5 hours, filter, slurry the filter cake with acetone, filter and dry to obtain sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate; The reaction solvent includes one of water, methanol, ethanol and isopropanol; the base includes one of sodium hydroxide, sodium methoxide, sodium tert-butoxide and sodium ethoxide; the weight ratio of the reaction solvent to the substrate is 5:1-20:1; the molar ratio of the base to the substrate is 2-10:1; and the reaction temperature is 20-50°C.

[0028] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention.

[0029] Example 1 The synthesis method of sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate in Example 1 of the present invention comprises the following steps: (1) Add 100.0 g of p-bromobenzenesulfonyl chloride and 1500 mL of dichloromethane to a 3 L three-necked flask. Then, add 100.0 g of 2,2-dimethylpropanol and 60.0 g of pyridine at room temperature. After the addition, stir at room temperature overnight. Then, add 500 ml of saturated sodium bicarbonate aqueous solution. Separate the liquids. Wash the organic phase with 500 ml of 0.5 N hydrochloric acid four times. Concentrate the organic phase to dryness and crystallize it with 100 ml of acetonitrile and 750 ml of water to obtain 110.0 g of IM1 with a yield of 90% and a purity of 97%.

[0030] 1 H-NMR (400MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8Hz, 2H), 3.69 (s, 2H), 0.91 (s, 9H). Analysis method: The reaction endpoint and product purity were determined by gas chromatography (GC, Agilent 8860). The specific chromatographic conditions were: HP-50+ column (30m×0.32mm ID×0.25μm), inlet temperature 280°C, detector FID temperature 280°C, and gradient: 100°C for 1 minute, then heated to 280°C at 20°C / min and held for 3 minutes.

[0031] (2) In a 3 L three-necked flask, 100.0 g IM1 and 1000 mL 1,4-dioxane were added, followed by 100.0 g potassium acetate and 120.0 g bis-pinacol diborane. The atmosphere was replaced with nitrogen three times, and 5.0 g 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex was added. The temperature was raised to 60-65 °C for overnight reaction, then the temperature was lowered to room temperature, and 500 mL ethyl acetate and 500 mL water were added. The layers were separated and the aqueous phase was extracted with 500 mL ethyl acetate. The organic phases were combined and washed with 500 mL saturated brine, and 100.0 g anhydrous sodium sulfate and 20.0 g activated carbon were added for drying and decolorization. After filtration and concentration, the crude product was crystallized with 300 mL acetonitrile and 900 mL water. After drying, the product was slurried with 500 mL petroleum ether, filtered and dried to obtain 105.0 g IM2 with a yield of 90%.

[0032] 1H-NMR (400MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4Hz, 2H), 3.66 (s, 2H), 1.36 (s, 12H), 0.89 (s, 9H). Analysis method: The reaction endpoint and product purity were determined by gas chromatography (GC, Agilent 8860). The specific chromatographic conditions were: HP-50+ column (30m×0.32mm ID×0.25μm), inlet temperature 280°C, detector temperature 280°C, gradient: 100°C for 1 minute, then heated to 280°C at 20°C / min and held for 3 minutes.

[0033] (3) Add 1700 mL of trimethyl orthoformate and 238.0 g of 2,2-dimethyl-1,3-dioxane-4,6-dione to a 5 L three-necked flask, raise the temperature to 85-90 °C, and stir for 2-3 hours; cool to 40-45 °C, add 85.0 g of o-phenylenediamine in batches, raise the temperature to 75-85 °C, and stir for 1-2 hours. Then cool to room temperature, add 1700 mL of methyl tert-butyl ether, stir for 1-2 hours, filter, and dry to obtain 237.0 g of IM3 with a yield of 72%.

[0034] 1H-NMR (400MHz, CDCl3): δ 11.34 (brd, J = 13.2 Hz, 2H), 8.51 (d, J =13.6 Hz, 2H), 7.42 (s, 4H), 1.76 (s, 12H). Analytical method: The reaction endpoint and product purity were measured by high performance liquid chromatography (HPLC, Agilent) internal standard method. The specific chromatographic conditions were as follows: HC-C18 column (4.6*150mm, 5um or equivalent column (with pre-column)), mobile phase A was 0.1% trifluoroacetic acid-water solution, mobile phase B was acetonitrile, mobile phase flow rate was 1.0 mL / min, injection volume was 1 μL, detection wavelength was 214 nm, column temperature was 25°C; the yield was mass yield.

[0035] (4) Add 1400 mL of diphenyl ether to a 3 L three-necked flask and heat it to 230 °C. Add 280.0 g of IM3 in batches and react for 10 minutes. Then cool it to 60-65 °C and filter. Add 560 mL of methanol to reflux, beat for 1-2 hours, cool to room temperature, filter and dry to obtain 119.0 g of IM4 with a yield of 83%.

[0036] 1 H-NMR (400MHz, CDCl3): δ 8.00 (d, J = 6.0 Hz, 2H), 7.66 (s, 2H), 6.38(d, J = 6.0 Hz, 2H). Analytical method: The reaction endpoint and product purity were measured by high performance liquid chromatography (HPLC, Agilent) internal standard method. The specific chromatographic conditions were as follows: HC-C18 column (4.6*150mm, 5um or equivalent column (with pre-column)), mobile phase A was 0.1% trifluoroacetic acid-water solution, mobile phase B was acetonitrile, mobile phase flow rate was 1.0 mL / min, injection volume was 1 μL, detection wavelength was 214 nm, column temperature was 25°C; the yield was mass yield.

[0037] (5) Add 1500 mL of acetonitrile and 100.0 g of IM4 to a 5 L three-necked flask, then add 405.0 g of phosphorus oxybromide, heat to reflux, react overnight, then cool to room temperature, add 1500 mL of methyl tert-butyl ether, stir for 1 hour, and filter; dissolve the solid in 1500 mL of ammonia water in batches, add 3000 mL of dichloromethane and 300 mL of methanol, filter and extract; dissolve the filtered solid in 3000 mL of dichloromethane and 300 mL of methanol, filter, and combine the organic phases; dry and decolorize the organic phase with 40.0 g of activated carbon and 100.0 g of anhydrous sodium sulfate; filter and concentrate, then beat with 500 mL of acetonitrile overnight, filter and dry to obtain 75.0 g of IM5, with a yield of 47%.

[0038] 1 H-NMR (400MHz, CDCl3): δ 8.98 (d, J = 4.8 Hz, 2H), 8.31 (s, 2H), 7.95(d, J = 4.8 Hz, 2H). Analytical method: The reaction endpoint and product purity were measured by high performance liquid chromatography (HPLC, Agilent) internal standard method. The specific chromatographic conditions were as follows: HC-C18 column (4.6*150mm, 5um or equivalent column (with pre-column)), mobile phase A was water, mobile phase B was acetonitrile, mobile phase flow rate was 1.0 mL / min, injection volume was 1 μL, detection wavelength was 214 nm, column temperature was 25°C; the yield was mass yield.

[0039] (6) Add 6400 mL of 1,4-dioxane and 1600 mL of water to a 10 L three-necked flask, then add 100.0 g of IM5, 262.0 g of IM2 and 613.4 g of potassium carbonate. Replace the atmosphere with nitrogen three times and add 24.0 g of 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride dichloromethane complex was heated to 85-90°C, reacted overnight, then cooled to 40-50°C, concentrated, added 2000mL of dichloromethane and 2000mL of water, filtered, extracted and separated, the aqueous phase was extracted with 1000mL of dichloromethane, the organic phases were combined, washed once with 1000mL of water, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was column-filtered with dichloromethane and methanol (50 / 1). After concentration, the crude product was dissolved in 3000mL of tetrahydrofuran and activated carbon was added for decolorization. After filtration and concentration, it was slurried with 2000mL of methyl tert-butyl ether, filtered and dried to obtain 100.0g IM6 with a yield of 53%.

[0040] 1 H-NMR (400MHz, CDCl3): δ 9.32 (d, J = 4.4 Hz, 2H), 8.10 (d, J = 8.4Hz, 4H), 7.77 (s, 2H), 7.73 (d, J = 8.4 Hz, 4H), 7.63 (d, J = 4.4 Hz, 2H), 3.82 (s, 4H), 0.97 (s, 18H). Analytical method: The reaction endpoint and product purity were measured by high performance liquid chromatography (HPLC, Agilent) internal standard method. The specific chromatographic conditions were as follows: HC-C18 column (4.6*150mm, 5um or equivalent column (with pre-column)), mobile phase A was 0.1% trifluoroacetic acid aqueous solution, mobile phase B was acetonitrile, mobile phase flow rate was 1.0 mL / min, injection volume was 1 μL, detection wavelength was 214 nm, column temperature was 25°C; the yield was mass yield.

[0041] (7) Add 1900 mL of trifluoroacetic acid and 127.0 g of IM6. After the addition is complete, heat the mixture to reflux and react overnight. Then cool the reaction mixture to room temperature and add 3800 mL of isopropyl acetate dropwise. After the addition is complete, stir for 2 to 4 hours and filter. The filter cake is slurried with 1300 mL of isopropyl acetate, filtered and dried to obtain 100.0 g of crude IM7, which is directly used in the next step. 1 H-NMR (400MHz, D2O): δ 9.04 (d, J= 5.2 Hz, 2H), 7.80 (d, J = 5.2 Hz,2H), 7.60 (d, J = 8.0 Hz, 4H), 7.46 (s, 2H), 7.31 (d, J = 8.0 Hz, 4H). Analytical method: The reaction endpoint and product purity were measured by high performance liquid chromatography (HPLC, Agilent) internal standard method. The specific chromatographic conditions were as follows: HC-C18 column (4.6*150mm, 5um or equivalent column (with pre-column)), mobile phase A was 0.1% trifluoroacetic acid aqueous solution, mobile phase B was acetonitrile, mobile phase flow rate was 1.0 mL / min, injection volume was 1 μL, detection wavelength was 214 nm, column temperature was 25°C; the yield was mass yield.

[0042] (8) Add 1900 mL of methanol and 100.0 g of IM7. After the addition is complete, cool to 10 °C and add 86.4 g of sodium methoxide in batches. Stir at room temperature overnight and filter. Dissolve the filter cake with 2000 mL of water and stir for 0.5 to 1 hour. Add 8000 mL of acetone dropwise and stir for 3 to 5 hours. Filter. Slurry the filter cake with 1300 ml of acetone. After filtering and drying, obtain 80.9 g of sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate with a yield of 75%.

[0043] 1 H-NMR (400MHz, DMSO): δ 9.19 (d, J = 4.4 Hz, 2H), 7.89 (s, 2H), 7.83(d, J = 8.0 Hz, 4H), 7.75 (d, J = 4.4 Hz, 2H), 7.58 (d, J = 8.0 Hz, 4H). Analytical method: The reaction endpoint and product purity were measured by high performance liquid chromatography (HPLC, Agilent) internal standard method. The specific chromatographic conditions were as follows: HC-C18 column (4.6*150mm, 5um or equivalent column (with pre-column)), mobile phase A was 0.1% trifluoroacetic acid aqueous solution, mobile phase B was acetonitrile, mobile phase flow rate was 1.0 mL / min, injection volume was 1 μL, detection wavelength was 214 nm, column temperature was 25°C; the yield was mass yield.

[0044] The final NMR spectrum of IM1-7 is as follows Figure 2-8As shown, the nuclear magnetic spectrum of the finally obtained sodium 4,4'-(1,10-o-phenanthroline-4,7-diyl) dibenzenesulfonate is as follows Fig. 9 shown.

[0045] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be covered by the scope of the claims of the present invention.

Claims

1. A method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate, characterized in that: The following steps are involved: (1) Mix 4-bromobenzenesulfonyl chloride and a reaction solvent, add 2,2-dimethylpropanol and the reaction solvent at room temperature; after the addition, stir at room temperature overnight, then add a base, separate the liquids, wash the organic phase with hydrochloric acid 4 times, concentrate the organic phase to dryness, and crystallize it with acetonitrile and water to obtain IM1; (2) IM1 and the reaction solvent were mixed, and then a base and bipinacol diborane were added, and the atmosphere was replaced with nitrogen three times, and a catalyst was added. The temperature was raised to 60-65°C and the reaction was carried out overnight, and then the temperature was lowered to room temperature, and ethyl acetate and water were added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate; the organic phases were combined, washed with saturated brine, and dried and decolorized with anhydrous sodium sulfate and activated carbon. After filtering and concentration, the crude product was crystallized with acetonitrile and water, dried, and then slurried with petroleum ether, filtered and dried to obtain IM2; (3) Mix trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione, heat to 85-90°C, and stir for 2-3 hours; cool to 40-45°C, add o-phenylenediamine in batches, heat to 75-85°C, stir for 1-2 hours, cool to room temperature, add methyl tert-butyl ether, stir for 1-2 hours, filter, and dry to obtain IM3; (4) The reaction solvent was heated, IM3 was added in batches, and the reaction was continued for 10 minutes, and then the temperature was lowered to 60-65°C and filtered; the filtered solid was heated to reflux with methanol, slurried for 1-2 hours, cooled to room temperature, filtered and dried to obtain IM4; (5) Mix the reaction solvent and IM4, add phosphorus oxybromide, heat to reflux, react overnight, cool to room temperature, add methyl tert-butyl ether, stir for 1 hour, and filter; dissolve the solid in ammonia water in batches, add dichloromethane and methanol to filter and extract; filter the solid and then dissolve and filter with dichloromethane and methanol, and combine the organic phases; dry and decolorize the organic phase with activated carbon and anhydrous sodium sulfate; filter and concentrate, and beat with acetonitrile overnight, filter and dry the material to obtain IM5; (6) Mix the reaction solvent with water, add IM5 and IM2 and a base, replace the atmosphere with nitrogen three times, add a catalyst, heat to 85-90°C, react overnight, then cool to 40-50°C, concentrate, add dichloromethane and water to filter and extract, extract the aqueous phase with dichloromethane, combine the organic phases, wash once, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and pass the crude product through a column with dichloromethane and methanol. After concentration, dissolve the crude product in tetrahydrofuran and add activated carbon for decolorization. After filtering and concentration, slurry the crude product with methyl tert-butyl ether, filter and dry to obtain IM6. (7) Add the reaction solvent and IM6, raise the temperature to reflux and react overnight, then cool the reaction solution to room temperature, add isopropyl acetate dropwise, stir for 2-4 hours, and filter; beat the filter cake with isopropyl acetate, filter and dry to obtain the crude IM7, which is directly used in the next step; (8) Add the reaction solvent and IM7, cool to 10°C, add the base in batches, stir at room temperature overnight, filter, dissolve the filter cake in water, stir for 0.5-1 hour, add acetone dropwise, stir for 3-5 hours, filter, slurry the filter cake with acetone, filter and dry to obtain sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate.

2. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (1), the reaction solvent includes one of dichloromethane, toluene, tetrahydrofuran, and pyridine; The base includes one of pyridine, triethylamine, 4-dimethylaminopyridine and sodium bicarbonate; The weight ratio of the reaction solvent to the substrate is 5:1-15:1; The molar ratio of the base to the substrate is 1.1-3.5:1; The molar ratio of the 2,2-dimethylpropanol to the substrate is 2-4:

1.

3. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (2), the reaction solvent includes one of 1,4-dioxane, acetonitrile, toluene, and tetrahydrofuran; The base includes one of potassium acetate, potassium carbonate, sodium carbonate and cesium carbonate; The catalyst comprises one of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex, tetrakis(triphenylphosphine)palladium, and bis(triphenylphosphine)palladium dichloride; The weight ratio of the reaction solvent to the substrate is 5:1-25:1; The molar ratio of the base to the substrate is 1.5-5:1; The molar ratio of the bis-pinacol diborane to the substrate is 1-2:1; The weight ratio of the catalyst to the substrate is 2.5%-10%:1; The reaction temperature is 50-100°C.

4. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (4), the reaction solvent includes one of diphenyl ether, N-methylpyrrolidone, xylene, and N,N-dimethylformamide; The weight ratio of the reaction solvent to the substrate is 5:1-25:1; The reaction temperature is 150-230°C.

5. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (5), the reaction solvent includes one of acetonitrile, chloroform, toluene, and phosphorus oxybromide; The weight ratio of the reaction solvent to the substrate is 5:1-15:1; The molar ratio of phosphorus oxybromide to substrate is 2-4:1; The reaction temperature is 50-100°C.

6. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (6), the reaction solvent includes a mixture of one or more of 1,4-dioxane, acetonitrile, tetrahydrofuran, and water; The base includes one of potassium acetate, potassium carbonate, sodium carbonate and cesium carbonate; The catalyst comprises one of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex, tetrakis(triphenylphosphine)palladium, and bis(triphenylphosphine)palladium dichloride; The weight ratio of the reaction solvent to the substrate is 5:1-25:1; The molar ratio of the base to the substrate is 5-20:1; The weight ratio of the catalyst to the substrate is 5%-30%:1; The reaction temperature is 50-100°C.

7. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (7), the reaction solvent includes one of trifluoroacetic acid, hydrochloric acid, aqueous sulfuric acid, and trifluoromethanesulfonic acid; The weight ratio of the reaction solvent to the substrate is 5:1-20:1; The reaction temperature is 20-100°C.

8. The method for synthesizing sodium 4,4'-(1,10-phenanthroline-4,7-diyl)dibenzenesulfonate according to claim 1, characterized in that: In step (8), the reaction solvent includes one of water, methanol, ethanol, and isopropanol; The base includes one of sodium hydroxide, sodium methoxide, sodium tert-butoxide and sodium ethoxide; The weight ratio of the reaction solvent to the substrate is 5:1-20:1; The molar ratio of the base to the substrate is 2-10:1; The reaction temperature is 20-50°C.

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