Water-soluble thiourea ligand as well as preparation method and application thereof

Abstract

The invention discloses a water-soluble thiourea ligand as well as a preparation method and application thereof, and compared with the prior art, the water-soluble thiourea ligand has the following advantages that a designed and synthesized hydrophilic functional group is not directly connected to a substituted aromatic ring of thiourea any more, but is bridged through a carbon chain; the water solubility of the synthesized aliphatic carboxylic acid functionalized water-soluble thiourea is better than that of the previous aromatic carboxylic acid functionalized water-soluble thiourea, so that the recovery efficiency of the ligand and the catalyst is higher; the novel water-soluble thiourea ligand disclosed by the invention is efficient and simple in synthesis and mild in condition, arylamine only needs to react with halogenated alkane carboxylate, then thiourea is formed through ring closing by using sulfur phosgene, finally hydrolysis is performed, the target product aliphatic carboxylic acid functionalized water-soluble cyclic thiourea is prepared through a three-step method, strict anhydrous and anaerobic operation is not needed, additional reduction operation is also not needed, and the method is suitable for industrial production. The post-treatment is simple, safe, green and environment-friendly.

Description

Technical Field

[0001] The invention relates to the technical field of thiourea ligands, and in particular to a water-soluble thiourea ligand and a preparation method and application thereof. Background Art

[0002] The coupling reaction catalyzed by transition metals (palladium, nickel, ruthenium, rhodium, etc.) is one of the most important methods in organic synthesis and drug synthesis. In recent years, especially in the development of new anticancer drugs, many active entities with excellent anticancer effects and prospects have been obtained through coupling reactions catalyzed by ligand transition metal complexes (Suzuki reaction, Heck reaction, Sonogashira reaction, Buchwald-Hartwig amination reaction, etc.). According to research statistics, in the 40 years from 1976 to 2015, among the drug synthesis patents reported in US patents, cross-coupling reactions such as C–C (such as Suzuki reaction, as shown below) and C–N (such as Buchwald-Hartwig amination reaction) are one of the most widely used synthesis tools.

[0003]

[0004] The use of transition metal-bound ligands is becoming increasingly frequent in catalytic reactions. The metal center is affected by the ligand, the catalyst activity changes, and then affects the selectivity of the reaction, making the chemical reaction more varied. Transition metal catalysts are mainly affected by the ligand's stereo effect, steric effect and electronic effect. Therefore, the design, synthesis and catalytic reaction research of ligands have become an important research field. In particular, the research on organic phosphine ligands and N-containing ligands (including diamine ligands, bipyridine ligands, oxazole ligands, NHC ligands, etc.) has also achieved fruitful results. However, these traditional ligands such as organic phosphine ligands and organic N-containing ligands have more or less defects such as unstable properties, difficult synthesis, high price and easy residue, which greatly affects the product quality and limits the promotion and application.

[0005] In recent years, thiourea derivatives have been applied as ligands and catalysts in the field of organometallic catalytic synthesis. This research group synthesized many different types of thiourea ligands (see: Chen, W.; Lu, X.-Y.; Xu, B.-H.; Yu, W.-G.; Zhou, Z.-N.; Hu, Y. [J]. Synthesis, 2018, 50 (7), 1499–1510. Yang, D.; Chen, Y.-C.; Zhu, N.-Y. [J]. Org. Lett. 2004, 6, 1577-1580. Yang, M.; Yip, K.-T.; Pan, J.-H.; Chen, Y.-C.; Zhu, N.-Y.; Yang, D. [J]. Synlett 2006, 3057-3060. Chen, W.; Li, R.; Han, B.; Li, B.-J.; Chen, Y.-C.; Wu Y.; Ding L.-S.;Yang,D.[J].Eur.J.Org.Chem.2006,1177-1184.Chen,W.;Li,R.;WuY.;Ding L.-S.;Chen,Y.-C.[J].Synthesis,2006,3058-3062.Li,R.;Chen,W.;Shi,J.-Y.;Chen,L.-J.;Chen,Y.-C.;Ding L.-S.;Wei,Y.-Q.[J].J Mass Spectrom.2008,43,542–546.). Although thiourea can be used as a good ligand for transition metals, most of the catalytic systems are not recyclable, and the reported thiourea ligand-transition metal and catalytic reaction types are relatively few. Since thiourea is very stable to heat, air and water, and can even catalyze oxidation reactions, it has great potential in catalyzing recyclable coupling reactions. However, there are few related studies, and it is necessary to synthesize thiourea compounds with more structures.

[0006] It can be seen that the present invention develops a new type of ligand transition metal catalyst, which can not only efficiently catalyze organic synthesis reactions but also easily separate and recycle the catalyst, and has very important scientific significance and application value in improving the selectivity and efficiency of transition metal catalysis and green chemistry. Summary of the invention

[0007] The purpose of the present invention is to provide a water-soluble thiourea ligand. The water-soluble thiourea functionalized with aliphatic carboxylic acid synthesized by bridging with a carbon chain has better water solubility than the previous water-soluble thiourea functionalized with aromatic carboxylic acid, so the recovery efficiency of the ligand and the catalyst is higher.

[0008] To achieve the above object, the present invention provides a water-soluble thiourea ligand, the structural formula of which is selected from one of I-III:

[0009]

[0010] Wherein, R is selected from one of H, Alkyl, OMe, and CO2H, and n is a natural number.

[0011] Compared with traditional NHC ligands, the water-soluble thiourea ligands and metal complexes of the present invention not only have the advantages of easy availability of raw materials, simple synthesis, high catalytic activity, and extremely stable to air, water, and heat, but also thiourea and its derivatives have long been used as drugs or active pharmaceutical intermediates, and there are a large number of literature reports on their physicochemical properties, biological activity, toxicity tests, and toxicological properties. However, the biological activity and toxicity tests of NHC structure compounds are rarely reported. Therefore, the thiourea structure with clearer biological activity and toxicological properties as a ligand will have more advantages than the NHC structure compound with unknown toxicological properties in the future industrial large-scale catalytic reaction. In summary, in the design of the ligand structure, the toxicity and safety of the catalyst in future applications are considered from the top-level design, and the thiourea ligand skeleton with stable properties and clearer biological activity is selected for self-assembly transformation to obtain a new type of recyclable nanoreactor catalytic system that conforms to the trend of green chemistry development. This is the core innovation of the present invention.

[0012] The second object of the present invention is to provide a preparation method of structural formula I, which specifically comprises the following steps:

[0013] S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction;

[0014] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0015] S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B;

[0016] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I;

[0017] Among them, the structural formula of reactant A is:

[0018] The structural formula of reactant B is:

[0019] The structural formula of product A is:

[0020] The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

[0021] The third object of the present invention is to provide a preparation method of structural formula II, which specifically comprises the following steps:

[0022] S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction;

[0023] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0024] S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B;

[0025] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula II;

[0026] Among them, the structural formula of reactant A is:

[0027] The structural formula of reactant B is:

[0028] The structural formula of product A is:

[0029] The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

[0030] The fourth object of the present invention is to provide a preparation method of structural formula III, which specifically comprises the following steps:

[0031] S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction;

[0032] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0033] S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B;

[0034] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula III;

[0035] Among them, the structural formula of reactant A is:

[0036] The structural formula of reactant B is:

[0037] The structural formula of product A is:

[0038] The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

[0039] The present invention optimizes the design of multiple sites of the catalyst structure. Based on the second-generation water-soluble thiourea ligand that we have successfully prepared in the early stage, we conduct a comprehensive exploration of the thiourea ligand structure. The experimental results of the third-generation new water-soluble thiourea ligand catalyzing the Suzuki reaction show that the improved third-generation new water-soluble thiourea ligand is not only simpler to synthesize, but also has excellent catalytic activity and recyclability (after five cycles of catalysis, the product is still obtained with a yield of up to 92%). The advantages of converting thiourea into water-soluble thiourea are mainly: making the thiourea ligand recyclable and reducing the ligand residue in the product, thereby reducing the transition metal residue, directly improving the product quality and safety.

[0040] Preferably, in step S1, the molar ratio of reactant A to reactant B is 1:(2-6).

[0041] Preferably, in step S1, the heating and stirring temperature is 80-180° C., and the heating and stirring time is 5-7 h.

[0042] Preferably, in step S3, the molar ratio of product A to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of product A to thiophosgene is 1:(1-2).

[0043] Preferably, in step S3, the time for adding thiophosgene dropwise is 10-14 hours, and the time for stirring after the addition is 10-14 hours.

[0044] Preferably, in step S4, the molar ratio of the intermediate product B to sodium hydroxide is 1:(8-12), and the pH is adjusted to 1 after hydrochloric acid is added dropwise.

[0045] A fifth object of the present invention is to provide an application of a water-soluble thiourea ligand in a Suzuki reaction catalyzed by aqueous recyclable palladium.

[0046] The catalytic Suzuki reaction involving water-soluble thiourea is carried out in pure water. After the reaction is completed, only a small amount of organic solvent needs to be added to extract the product into the organic layer. In the water layer, only the raw materials need to be added to continue the reaction to enter the next catalytic cycle. When using a water-soluble thiourea catalyst, this new water-soluble catalyst containing a hydrophilic structure can extract and purify the product by extracting organic matter with a simple organic solvent. Because the catalyst is highly water-soluble, it will not cause the catalyst to be lost or remain in the product when dissolved in water. Because the water layer contains water-soluble thiourea ligands and transition metal palladium complexes, the catalyst can be recovered and recycled by directly adding the reaction raw materials required for the next cycle without any treatment. This lays a good foundation for achieving highly selective, easy to recover, low-toxic and efficient catalysis of other coupling reactions, and provides green and efficient excellent catalysts for the pharmaceutical industry.

[0047] Compared with the prior art, the present invention has the following advantages:

[0048] 1. The hydrophilic functional group designed and synthesized by the present invention is no longer directly connected to the substituted aromatic ring of the thiourea, but is bridged by a carbon chain. The water-soluble thiourea functionalized with aliphatic carboxylic acid synthesized by the present invention has better water solubility than the water-soluble thiourea functionalized with aromatic carboxylic acid in the past, so the recovery efficiency of the ligand and the catalyst is higher;

[0049] 2. The synthesis of the novel water-soluble thiourea ligand of the present invention is efficient and simple, and the conditions are mild. The aromatic amine only needs to react with the halogenated alkane carboxylic acid ester and then use thiophosgene to close the ring to form thiourea, and finally hydrolyze. The target product, the water-soluble cyclic thiourea functionalized with fatty carboxylic acid, is obtained by the three-step method. Strict anhydrous and oxygen-free operation and additional reduction operation are not required, and the post-treatment is simple, safe and environmentally friendly.

[0050] 3. Compared with the defects of water-soluble organic phosphine ligands that are sensitive to air and water, easily oxidized and lose coordination ability, and produce oxidation and decomposition residues, the water-soluble thiourea ligand of the present invention is very stable to air, water, and heat. The Suzuki reaction catalyzed by it can be carried out in pure water. The separation of the product and the catalyst only requires the addition of a small amount of organic solvent for extraction. There will be no catalyst residue or loss in the extraction organic solvent. After the product is concentrated by vacuum distillation, the extraction organic solvent can be very conveniently used for the next cycle of catalytic reaction. The water-soluble thiourea and the metal palladium complex are dissolved in the aqueous phase, and the reaction raw materials are continuously added to start the next catalytic cycle. Therefore, the entire catalytic reaction system, ligand synthesis and catalytic cycle of the present invention have a series of advantages such as economy, greenness, safety, and environmental protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 Schematic diagram of the reuse of the water-soluble thiourea ligand of the present invention. DETAILED DESCRIPTION

[0052] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0053] A water-soluble thiourea ligand, characterized in that the structural formula is selected from one of I-III:

[0054]

[0055] Wherein, R is selected from one of H, Alkyl, OMe, and CO2H, and n is a natural number.

[0056] Compared with traditional NHC ligands, the water-soluble thiourea ligands and metal complexes of the present invention not only have the advantages of easy availability of raw materials, simple synthesis, high catalytic activity, and extremely stable to air, water, and heat, but also thiourea and its derivatives have long been used as drugs or active pharmaceutical intermediates, and there are a large number of literature reports on their physicochemical properties, biological activity, toxicity tests, and toxicological properties. However, the biological activity and toxicity tests of NHC structure compounds are rarely reported. Therefore, the thiourea structure with clearer biological activity and toxicological properties as a ligand will have more advantages than the NHC structure compound with unknown toxicological properties in the future industrial large-scale catalytic reaction. In summary, in the design of the ligand structure, the toxicity and safety of the catalyst in future applications are considered from the top-level design, and the thiourea ligand skeleton with stable properties and clearer biological activity is selected for self-assembly transformation to obtain a new type of recyclable nanoreactor catalytic system that conforms to the trend of green chemistry development. This is the core innovation of the present invention.

[0057] The specific embodiment of the present invention also provides a preparation method of the above structural formula I, which specifically comprises the following steps:

[0058] S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath at 80-180°C for 5-7h. The molar ratio of reactant A to reactant B is 1:(2-6);

[0059] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0060] S3, after mixing product A with a tetrahydrofuran solution of anhydrous sodium carbonate, adding a tetrahydrofuran solution of thiophosgene, stirring after completion of the dropwise addition and removing tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and the organic layer is washed with saturated brine in turn, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatography to obtain intermediate product B, the molar ratio of product A to anhydrous sodium carbonate is 1: (1-2), the molar ratio of product A to thiophosgene is 1: (1-2), the time for dropping thiophosgene is 10-14h, and the time for stirring after completion of the dropwise addition is 10-14h;

[0061] S4, after mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, the molar ratio of the intermediate product B to the sodium hydroxide is 1: (8-12), stirring and rotary evaporating to remove tetrahydrofuran, and dripping hydrochloric acid under stirring in an ice bath to adjust the pH to 1, until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I;

[0062] Among them, the structural formula of reactant A is:

[0063] The structural formula of reactant B is:

[0064] The structural formula of product A is:

[0065] The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

[0066] The specific embodiment of the present invention also provides a preparation method of structural formula II, which specifically comprises the following steps:

[0067] S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath at 80-180°C for 5-7h. The molar ratio of reactant A to reactant B is 1:(2-6);

[0068] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0069] S3, after mixing product A with a tetrahydrofuran solution of anhydrous sodium carbonate, adding a tetrahydrofuran solution of thiophosgene, stirring after completion of the dropwise addition and removing tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and the organic layer is washed with saturated brine in turn, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatography to obtain intermediate product B, the molar ratio of product A to anhydrous sodium carbonate is 1: (1-2), the molar ratio of product A to thiophosgene is 1: (1-2), the time for dropping thiophosgene is 10-14h, and the time for stirring after completion of the dropwise addition is 10-14h;

[0070] S4, after mixing the intermediate product B with sodium hydroxide, water and tetrahydrofuran are added, the molar ratio of the intermediate product B to the sodium hydroxide is 1: (8-12), the tetrahydrofuran is removed after stirring and rotary evaporation, and hydrochloric acid is added dropwise under stirring in an ice bath to adjust the pH to 1, and after the reaction is completed, the product is filtered, washed and dried to obtain the product structural formula II;

[0071] Among them, the structural formula of reactant A is:

[0072] The structural formula of reactant B is:

[0073] The structural formula of product A is:

[0074] The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

[0075] The specific embodiment of the present invention also provides a preparation method of structural formula III, which specifically comprises the following steps:

[0076] S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath at 80-180°C for 5-7h. The molar ratio of reactant A to reactant B is 1:(2-6);

[0077] S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A;

[0078] S3, after mixing product A with a tetrahydrofuran solution of anhydrous sodium carbonate, adding a tetrahydrofuran solution of thiophosgene, stirring after completion of the dropwise addition and removing tetrahydrofuran by rotary evaporation, then adding ethyl acetate and water and stirring, and the organic layer is washed with saturated brine in turn, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatography to obtain intermediate product B, the molar ratio of product A to anhydrous sodium carbonate is 1: (1-2), the molar ratio of product A to thiophosgene is 1: (1-2), the time for dropping thiophosgene is 10-14h, and the time for stirring after completion of the dropwise addition is 10-14h;

[0079] S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, the molar ratio of the intermediate product B to the sodium hydroxide is 1: (8-12), stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH to 1, filtering, washing, and drying after the reaction is completed to obtain a product of structural formula III;

[0080] Among them, the structural formula of reactant A is:

[0081] The structural formula of reactant B is:

[0082] The structural formula of product A is:

[0083] The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

[0084] The present invention optimizes the design of multiple sites of the catalyst structure. Based on the second-generation water-soluble thiourea ligand that we have successfully prepared in the early stage, we conduct a comprehensive exploration of the thiourea ligand structure. The experimental results of the third-generation new water-soluble thiourea ligand catalyzing the Suzuki reaction show that the improved third-generation new water-soluble thiourea ligand is not only simpler to synthesize, but also has excellent catalytic activity and recyclability (after five cycles of catalysis, the product is still obtained with a yield of up to 92%). The advantages of converting thiourea into water-soluble thiourea are mainly: making the thiourea ligand recyclable and reducing the ligand residue in the product, thereby reducing the transition metal residue, directly improving the product quality and safety.

[0085] The specific embodiment of the present invention also provides an application of a water-soluble thiourea ligand in a Suzuki reaction catalyzed by aqueous recyclable palladium.

[0086] The catalytic Suzuki reaction involving water-soluble thiourea is carried out in pure water. After the reaction is completed, only a small amount of organic solvent needs to be added to extract the product into the organic layer. In the water layer, only the raw materials need to be added to continue the reaction to enter the next catalytic cycle. When using a water-soluble thiourea catalyst, this new water-soluble catalyst containing a hydrophilic structure can extract and purify the product by extracting organic matter with a simple organic solvent. Because the catalyst is highly water-soluble, it will not cause the catalyst to be lost or remain in the product when dissolved in water. Because the water layer contains water-soluble thiourea ligands and transition metal palladium complexes, the catalyst can be recovered and recycled by directly adding the reaction raw materials required for the next cycle without any treatment. This lays a good foundation for achieving highly selective, easy to recover, low-toxic and efficient catalysis of other coupling reactions, and provides green and efficient excellent catalysts for the pharmaceutical industry.

[0087] The following is a full description with reference to specific embodiments.

[0088] Example 1

[0089] Synthesis of methyl 3,4-bis(4-ethoxy-4-oxybutylamino)benzoate:

[0090]

[0091] Synthesis steps of 3,4-bis(4-ethoxy-4-oxybutylamino)benzoic acid methyl ester:

[0092] Reactant A: 3,4-diaminobenzoic acid methyl ester (3.324g, 20mmol), reactant B: bromobutyric acid ethyl ester (15.604g, 80mmol) and N,N-diisopropylethylamine solution (13.2ml) were mixed in a round-bottom flask, and 369.4mg tetrabutylammonium iodide was added. The reaction was stopped after heating and stirring at 130°C in an oil bath for 6 hours. After the reaction solution was cooled to room temperature, 50ml ethyl acetate and 50ml water were added and stirred, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30ml x 2), and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and subjected to silica gel flash column chromatography (eluent: petroleum ether: ethyl acetate = 3:1). The crude product of 3,4-bis(4-ethoxy-4-oxobutylamino)benzoic acid methyl ester was obtained as a pale yellow oily substance, 5.126g, with a yield of 65%. The crude product was used directly in the next step without further purification.

[0093] Synthesis of thiourea intermediates:

[0094]

[0095] Synthesis steps of thiourea intermediates:

[0096] In a fume hood, in a round-bottom flask containing crude methyl 3,4-bis(4-ethoxy-4-oxobutylamino)benzoate (1.183 g, 3 mmol) and anhydrous sodium carbonate (382 mg, 3.6 mmol) in 30 ml of tetrahydrofuran, very slowly dropwise thiophosgene (414 mg, 3.6

[0097] mmol,) in 10 ml tetrahydrofuran solution. The addition was completed in about 12 hours, and stirring was continued at room temperature for 12 hours. The tetrahydrofuran was removed by rotary evaporation, and 30 ml ethyl acetate and 30 ml water were added and stirred. The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and then subjected to silica gel rapid column chromatography (eluent: petroleum ether: ethyl acetate = 3:1), and evaporated to dryness on a rotary evaporator to obtain 873 mg of a white solid with a yield of 67%.

[0098] Synthesis of new water-soluble thiourea:

[0099]

[0100] Synthesis steps of new water-soluble thiourea:

[0101] Thiourea intermediate (873mg, 2mmol) and sodium hydroxide (800mg, 20mmol) were mixed in a round-bottom flask, and water (20mL) and tetrahydrofuran (20mL) were added. Stirring was carried out at room temperature for 24 hours, and tetrahydrofuran was removed by rotary evaporation. Under ice bath cooling and stirring, hydrochloric acid was carefully added dropwise to adjust the pH to 1. A large amount of white solid precipitated from the solution. Stirring was continued in ice bath for 30 minutes. The white solid obtained by suction filtration was washed with water (10ml x 3) and dried to obtain 696mg of white solid, with a yield of 95%.

[0102] The inventors performed performance tests on the intermediate product and the product obtained in Example 1, and the test results are as follows:

[0103]

[0104] White solid; melting point: 86–87°C.

[0105] 1 H NMR (400MHz, CDCl3) δ7.96(dd,J=8.4,1.5Hz,1H),7.90(d,J=1.1Hz,1H),7.30(d,J=8.4Hz,1H),4.40(dd,J=14.6,7.1Hz,4H ), 4.15 (qd, J=7.1, 1.9Hz, 4H), 3.95 (d, J=6.0Hz, 3H), 2.44 (t, J=7.0Hz, 4H), 2.25–2.08 (m, 4H), 1.27 (td, J=7.1, 1.5Hz, 6H).

[0106] 13 C NMR (100MHz, CDCl3) δ172.6,172.4,171.1,166.5,135.2,131.8,125.1,125.0,110.3,108.6,60.8,52.5,52.4,44.1,31.4,31.1,23.3,23.1,14.5.

[0107]

[0108] White solid; melting point: 269–271°C.

[0109] 1 H NMR (400MHz, DMSO) δ12.40(s,3H),8.02(d,J=1.3Hz,1H),7.88(dd,J=8.4,1.4Hz,1H),7.5 6(d,J=8.4Hz,1H), 4.34(dd,J=14.8,8.2Hz,4H), 2.34(q,J=7.2Hz,4H), 2.02–1.88(m,4H).

[0110] 13 C NMR (100MHz, DMSO) δ173.5,173.4,169.83,166.85,134.49,131.15,125.14,124.31,110.28,108.95,43.5,43.4,30.6,30.5,22.9.

[0111] Example 2

[0112] The only difference from Example 1 is that the reactant A in this example is Reactant B is: The rest is the same as Example 1 and will not be described again here.

[0113] The inventors tested the performance of the intermediate product and the product obtained in Example 2. The test results are as follows: Intermediate product:

[0114] White solid; melting point: 113–115°C.

[0115] 1 H NMR (400MHz, CDCl3) δ7.04 (s, 2H), 4.53 (t, J = 7.2Hz, 4H), 4.11 (q, J = 7.1Hz, 4H), 2.88 (t, J = 7.2Hz, 4H), 2.34 (s, 6H), 1.21 (t, J = 7.1Hz, 6H).

[0116] 13 C NMR (100MHz, CDCl3) δ171.1,168.0,131.9,130.1,110.1,61.1,40.6,32.7,20.5,14.4.

[0117] product: White solid; melting point: 235–237°C.

[0118] 1 H NMR (400MHz, DMSO) δ 12.39 (s, 2H), 7.30 (s, 2H), 4.40 (t, J = 7.4Hz, 4H), 2.69 (t, J = 7.4Hz, 4H), 2.29 (s, 6H).

[0119] 13 C NMR (100MHz, DMSO) δ171.8,166.7,130.9,129.3,110.1,40.0,31.9,19.7.

[0120] Example 3

[0121] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:2, and the rest is the same as Example 1 and will not be repeated here.

[0122] Example 4

[0123] The only difference from Example 1 is that the molar ratio of reactant A to reactant B in this example is 1:6, and the rest is the same as that in the example, which will not be repeated here.

[0124] Example 5

[0125] The only difference from Example 1 is that in this example, reactant A is The rest is the same as Example 1 and will not be described again here.

[0126] Example 6

[0127] The only difference from Example 5 is that in this example, reactant B is The rest is the same as Example 5 and will not be described again here.

[0128] Example 7

[0129] The only difference from Example 1 is that in this example, reactant A is The rest is the same as Example 1 and will not be described again here.

[0130] Example 8

[0131] The only difference from Example 7 is that in this example, reactant B is The rest is the same as Example 7 and will not be described again here.

[0132] The water-soluble thiourea ligand palladium complex prepared in Example 1 can be recycled in the aqueous phase to catalyze the Suzuki reaction.

[0133]

[0134] At room temperature, in air, water-soluble thiourea ligand (0.2 mol%, 4.6 mg), Na2PdCl4 (0.1 mol%, 1.5 mg), arylbenzene boronic acid (7.5 mmol), potassium hydroxide (561 mg, 10.0 mmol), TBAB (5 mmol, 1.61 g), bromoaryl hydrocarbon (5.0 mmol) and water (5 mL) were added to a round-bottom flask containing a stirring bar. The mixture was stirred in a round-bottom flask at 25°C or 100°C until the reaction was completed. The resulting reaction mixture was extracted with ether (3×10 mL), the organic layers were combined, concentrated by rotary evaporation, and then subjected to silica gel flash column chromatography to obtain the cross-coupling product. The coupling product was then 1 H NMR and 13 C NMR detection, the data obtained are consistent with the nuclear magnetic data reported in the literature. The same reaction starting materials arylphenylboronic acid (7.5mmol) and bromoaryl hydrocarbon (5.0mmol) were added to the water layer again, and potassium hydroxide (561mg, 10.0mmol) was added to start the next round of catalytic reaction. After five cycles of catalysis, the activity of the new water-soluble thiourea ligand palladium catalyst did not decrease significantly.

[0135] The experimental results of the Suzuki reaction catalyzed by water-soluble thiourea ligands show that the improved third-generation new water-soluble thiourea ligand is not only simpler to synthesize, but also has excellent catalytic activity and recyclability (after five cycles of catalysis, the product can still be obtained with a yield of up to 92%, such as Figure 1 The advantages of converting thiourea into water-soluble thiourea are mainly: making the thiourea ligand recyclable and reducing the ligand residue in the product, thereby reducing the transition metal residue, which directly improves the product quality and safety. The catalytic Suzuki reaction involving water-soluble thiourea is carried out in pure water. After the reaction is completed, only a small amount of organic solvent needs to be added to extract the product into the organic layer. In the water layer, only the raw material needs to be added to continue the reaction to enter the next catalytic cycle. The catalyst can be reused, such as Figure 1As shown. When a water-soluble thiourea catalyst is used, this new water-soluble catalyst with a hydrophilic structure can be used to extract and purify the product by extracting organic matter with a simple organic solvent. Because the catalyst is highly water-soluble, it will not cause the catalyst to be lost or remain in the product even if it is dissolved in water. Because the water layer contains water-soluble thiourea ligands and transition metal palladium complexes, the catalyst can be recovered and recycled by directly adding the reaction raw materials required for the next cycle without any treatment. This lays a good foundation for achieving highly selective, easy-to-recover, low-toxic and efficient catalysis of other coupling reactions, and provides the pharmaceutical industry with green and efficient excellent catalysts.

[0136] Although the disclosure is disclosed as above, the protection scope of the disclosure is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the disclosure, and these changes and modifications will fall within the protection scope of the present invention.

Claims

1. A water-soluble thiourea ligand, characterized in that The structural formula is selected from one of I-III: Wherein, R is selected from one of H, Alkyl, OMe, and CO2H, and n is a natural number.

2. A method for preparing a water-soluble thiourea ligand as claimed in claim 1, characterized in that: The preparation method of the structural formula I specifically comprises the following steps: S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B; S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula I; Among them, the structural formula of reactant A is: The structural formula of reactant B is: The structural formula of product A is: The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, I.

3. A method for preparing a water-soluble thiourea ligand as claimed in claim 1, characterized in that: The preparation method of the structural formula II specifically comprises the following steps: S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B; S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula II; Among them, the structural formula of reactant A is: The structural formula of reactant B is: The structural formula of product A is: The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, and I.

4. A method for preparing a water-soluble thiourea ligand as claimed in claim 1, characterized in that: The preparation method of the structural formula III specifically comprises the following steps: S1. After reactant A, reactant B and N,N-diisopropylethylamine solution are mixed, tetrabutylammonium iodide is added, and the mixture is heated and stirred in an oil bath for reaction; S2. After the reaction is completed, the reaction solution is cooled to room temperature, ethyl acetate and water are added, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, the organic layers are combined, and the mixture is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, chromatographed, and evaporated to dryness using a rotary evaporator to obtain product A; S3, product A and anhydrous sodium carbonate tetrahydrofuran solution were mixed, and then thiophosgene tetrahydrofuran solution was added, and after the dropwise addition was completed, the tetrahydrofuran was removed by stirring and rotary evaporation, and then ethyl acetate and water were added and stirred, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated by rotary evaporation and chromatographed to obtain intermediate product B; S4, mixing the intermediate product B with sodium hydroxide, adding water and tetrahydrofuran, stirring and rotary evaporating to remove tetrahydrofuran, adding hydrochloric acid dropwise under stirring in an ice bath to adjust the pH until the reaction is completed, filtering, washing, and drying to obtain a product of structural formula III; Among them, the structural formula of reactant A is: The structural formula of reactant B is: The structural formula of product A is: The structural formula of intermediate product B is: Wherein, R is selected from one of H, Alkyl, OMe, CO2H, n is a natural number, and X is one of Br, Cl, and I.

5. The method for preparing a water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In the step S1, the molar ratio of reactant A to reactant B is 1:(2-6).

6. The method for preparing a water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In the step S1, the temperature of heating and stirring is 80-180° C., and the time of heating and stirring is 5-7 hours.

7. The method for preparing a water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In step S3, the molar ratio of product A to anhydrous sodium carbonate is 1:(1-2), and the molar ratio of product A to thiophosgene is 1:(1-2).

8. The method for preparing a water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In step S3, the time for adding thiophosgene dropwise is 10-14 hours, and the time for stirring after the addition is 10-14 hours.

9. The method for preparing a water-soluble thiourea ligand according to any one of claims 2 to 4, characterized in that: In the step S4, the molar ratio of the intermediate product B to sodium hydroxide is 1:(8-12), and the pH is adjusted to 1 after hydrochloric acid is added dropwise.

10. An application of a water-soluble thiourea ligand, characterized in that: The application comprises applying the water-soluble thiourea ligand according to claim 1 to a Suzuki reaction catalyzed by aqueous phase recyclable palladium.

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