Synthesis method of 5-(aryl propyl) furoic acid compound

Abstract

The invention discloses a synthesis method of a 5-(aryl propyl) furoic acid compound, which comprises the following steps: in a nitrogen atmosphere, adding 5-(acetoxymethyl) furan-2-carboxylic acid ethyl ester, an initiator, Lewis base-borane, mercaptan, an additive and olefin into a solvent 1, and heating and reacting while stirring to obtain a 5-(aryl propyl) furoic acid ethyl ester compound; adding the obtained 5-(aryl propyl) ethyl furoate compound and alkali into a solvent 2, heating and reacting while stirring, extracting to remove organic phase impurities after the reaction is finished, then adjusting the pH value of a water phase solution, extracting with dichloromethane again, concentrating and collecting the obtained organic phase; and adding a protecting group removing reagent into the concentrated product for deprotection to obtain a target product. The 5-(aryl propyl) furoic acid compound is a novel furan bio-based polymeric monomer, and the polymer is prepared by using the monomer, so that the research and development of the novel bio-based polymer are realized.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing 5-(arylpropyl)furoic acid compounds. Background Art

[0002] Polyamide and polyester are polymer materials containing repeated amide and ester groups in their molecules. These two types of materials are widely used in the automotive industry, textile industry, electrical industry, medical industry and other fields. In recent years, with the continuous development of society and the continuous advancement of science and technology, the demand for polyamide and polyester with various functions has been growing. Therefore, developing new methods to realize the development of new functional polyamide and polyester is an important direction of synthetic chemistry and polymer chemistry research.

[0003] Bio-platform molecules have the advantages of being environmentally friendly and widely available. In recent years, synthesizers have used chemical synthesis to transform bio-platform molecules into polymer monomers with diverse structures, thereby achieving the synthesis of polymers with various functions. These research results have promoted the process of bio-based materials replacing traditional petrochemical raw materials. For example, fructose and glucose are transformed into dimethyl furandicarboxylate or furandicarboxylic acid, and further polycondensed with ethylene glycol to synthesize polyethylene 2,5-furandicarboxylate (PEF). This type of polymer exhibits the advantages of biodegradability, excellent barrier properties, and high mechanical strength (Zhou Qiao, Wang Haonan, Shi Yafei, et al. Research progress of bio-based polyester PEF [J]. Engineering Plastics Application, 2023, 51 (01): 139-145.). In addition, the polycondensation of furan dicarboxylic acid with various types of diamines can realize the synthesis of various types of furan dicarboxylic acid polyamide materials. These polymers can be used in membrane separation, heat-resistant materials and other fields (Li Zhenhuan, Yang Xueqing, Su Kunmei, et al. Preparation and properties of environmentally friendly furan-based polyamide materials [J]. Journal of Tianjin Polytechnic University, 2022, 41 (04): 1-7.). The polymerization monomers of the above-mentioned bio-based polyesters and polyamides are all furan dicarboxylic acid. Although this compound has shown a wide range of application value, the types of bio-based monomers are far less than those derived from petrochemical raw materials, and the application potential of bio-based materials has not been fully developed. Therefore, using readily available bio-platform molecules as raw materials and using efficient synthesis methods to achieve the development of new bio-based polymerization monomers is still a long-term goal in this field.

[0004]

[0005] 5-Hydroxymethyl furoic acid is an intermediate in the synthesis of furandicarboxylic acid. The compound contains a carboxyl group and a hydroxyl functional group. Developing an efficient method to achieve the dehydroxylation of 5-Hydroxymethyl furoic acid and introduce amino and hydroxyl functional groups on the side chain of furan methylene is an effective way to transform it into a variety of bio-based polymerization monomers, which is conducive to the realization of a variety of bio-based polymers. In addition, the development of this method can also achieve the high value of bio-platform molecules.

[0006] Summary of the invention

[0007] The object of the present invention is to provide a method for synthesizing 5-(arylpropyl)furoic acid compounds to overcome the above-mentioned defects in the prior art.

[0008] The method for synthesizing 5-(arylpropyl)furoic acid compounds of the present invention comprises the following steps: Step 1: Under a nitrogen atmosphere, ethyl 5-(acetoxymethyl)furan-2-carboxylate, an initiator, a Lewis base-borane, a thiol, an additive and an olefin are added to solvent 1, and the mixture is heated to react under stirring. The reaction endpoint is determined by thin layer chromatography, and then a mixture of petroleum ether and ethyl acetate in a volume ratio of 50:1 is used as an eluent, and the mixture is separated by a silica gel column to obtain ethyl 5-(arylpropyl)furoate compounds.

[0009] In step 1, the initiator is di-tert-butyl peroxide (DTBP), the Lewis base-borane is p-dimethylaminopyridine-borane (DMAP-BH3), the thiol is 2-methoxythiophenol, and the additive is sodium dihydrogen phosphate dihydrate.

[0010] The structure of the olefin is shown below:

[0011] Furthermore, the molar ratio of ethyl 5-(acetoxymethyl)furan-2-carboxylate, initiator, Lewis base-borane, thiol, additive and olefin is 1.0: 1.0: 2.0: 0.2: 1.2: 5.0.

[0012] In step 1, the solvent 1 is acetonitrile.

[0013] Furthermore, in the reaction system, the concentration of ethyl 5-(acetoxymethyl)furan-2-carboxylate is controlled at 0.067-0.1 mol / L.

[0014] In step 1, the heating reaction temperature is 120°C.

[0015] Step 2: Add the 5-(arylpropyl)furoic acid ethyl ester compound obtained in step 1 and a base to solvent 2, heat and react under stirring, and determine the reaction endpoint by thin layer chromatography (TLC) spot plate. First, extract with dichloromethane to remove impurities in the organic phase, then add 1.0 M hydrochloric acid solution to the aqueous phase to adjust the pH of the reaction solution to 1-2, extract with dichloromethane again, and concentrate and collect the obtained organic phase; the concentrated product does not need to be purified, and a deprotection reagent is directly added for deprotection to obtain the target product.

[0016] In step 2, the base is potassium hydroxide; the molar ratio of 5-(arylpropyl)furoic acid ethyl ester compound to the base is 1.0:2.0-4.0.

[0017] In step 2, the solvent 2 is composed of methanol and water in a volume ratio of 4:1.

[0018] Furthermore, the concentration of 5-(arylpropyl)furoic acid ethyl ester compounds in the reaction system is controlled at 0.10-0.20 mol / L.

[0019] In step 2, the heating reaction temperature is 60°C.

[0020] In step 2, the deprotection process is divided into two routes according to the different R groups: Route 1: When the R group is methoxy (R = OMe), the 5-(arylpropyl)furoic acid intermediate is added to solvent 3, and 5 equivalents of boron tribromide are added at a reaction temperature of 3. The reaction endpoint is determined by thin layer chromatography (TLC) spot plate. After the reaction is completed, water is added to quench the reaction, and the reaction is extracted with dichloromethane. The collected organic phase is concentrated by rotary evaporation to obtain 5-(3-(4-hydroxyphenyl)propyl)furan-2-carboxylic acid. Route 2: When the R group is tert-butyloxycarbonylamino (R = NHBoc), the 5-(arylpropyl)furoic acid intermediate is added to solvent 4, 20 equivalents of trifluoroacetic acid are added at reaction temperature 4, the reaction endpoint is determined by thin layer chromatography (TLC) spot plate, and then the solvent is removed by rotary evaporator to obtain 5-(3-(4-aminophenyl)propyl)furan-2-carboxylic acid.

[0021] In route 1, the solvent 3 is dichloromethane, and the reaction temperature 3 is from -78°C to room temperature.

[0022] In route 2, the solvent 4 is dichloromethane, and the reaction temperature 4 is room temperature.

[0023] The synthetic route is as follows:

[0024] The above process can be expressed by the reaction formula: Synthesis of 5-(3-(4-hydroxyphenyl)propyl)furan-2-carboxylic acid:

[0025] Synthesis of 5-(3-(4-aminophenyl)propyl)furan-2-carboxylic acid:

[0026] The method of the present invention was used for the first time to develop efficient dehydroxylation and alkylation of ethyl 5-(acetoxymethyl)furan-2-carboxylate, which not only completed the development of bio-based polymerization monomers, but also realized the conversion of cheap and readily available furan bio-based molecules into high value-added products. DETAILED DESCRIPTION

[0027] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Embodiment 1:

[0028] The synthesis steps of ethyl 5-(3-(4-methoxyphenyl)propyl)furan-2-carboxylate in this embodiment are as follows:

[0029] Under nitrogen atmosphere, 5-(acetoxymethyl)furan-2-carboxylic acid ethyl ester (0.2 mmol), dimethylaminopyridine-borane (2 equivalents), sodium dihydrogen phosphate dihydrate (1.2 equivalents) were added to a 10 mL Schlenk reaction tube, and then acetonitrile (3 mL) was added, followed by p-methoxystyrene (5 equivalents), di-tert-butyl peroxide (1 equivalent), and 2-methoxythiophenol (0.2 equivalents). Finally, the reaction vessel was vented to maintain a nitrogen environment, and the reaction bottle was placed in an oil bath pot at 120°C for 12 hours. The reaction endpoint was determined by thin layer chromatography (TLC) spot plate, and then petroleum ether / ethyl acetate was mixed in a volume ratio of 50:1 as the eluent, and separated by silica gel column to obtain 5-(3-(4-methoxyphenyl)propyl)furan-2-carboxylic acid ethyl ester.

[0030] The product yield was 51%, white liquid; 1 H NMR (400 MHz, CDCl3) δ 1.36 (3H, t, J = 7.2Hz), 1.94-2.01 (2H, m), 2.61 (2H, t, J = 8.0 Hz), 2.70 (2H, t,J = 8.0 Hz), 3.79(3H, s), 4.34 (2H, q, J = 7.2 Hz), 6.11-6.13 (1H, m), 6.81-6.85 (2H, m), 7.08-7.11 (3H, m); 13 C NMR (100 MHz, CDCl3) δ 14.4, 27.6, 29.5, 34.2, 55.2, 60.7,107.6, 113.7, 119.0, 129.3, 133.5, 143.2, 157.8, 158.9, 161.0.

[0031] The synthesis steps of (3-(4-hydroxyphenyl)propyl)furan-2-carboxylic acid in this embodiment are as follows:

[0032] Under nitrogen atmosphere, ethyl 5-(3-(4-methoxyphenyl)propyl)furan-2-carboxylate (1.0mmol), potassium hydroxide (4 equivalents), methanol (4mL) and water (1mL) were added to the reaction vessel, and the reaction mixture was stirred at 60°C for 18h. After the reaction was completed, the reaction solution was extracted three times with dichloromethane to remove impurities in the organic phase, and then 1.0 M hydrochloric acid solution was added to the aqueous phase to adjust the pH of the solution to 1-2, and then extracted with dichloromethane again to obtain the ester hydrolysis product. Under nitrogen atmosphere, the product was added to the reaction bottle, the reaction mixture was stirred at -78°C for 30 minutes, and then boron tribromide (5 equivalents) was added dropwise. After the addition was completed, the reaction was continued at -78°C for 2h, and then the temperature was raised to room temperature to continue the reaction. After 6h, water was slowly added to quench, and the filtrate was extracted with dichloromethane three times. The collected organic phase was concentrated by rotary evaporation to obtain (3-(4-hydroxyphenyl)propyl)furan-2-carboxylic acid.

[0033] The product yield was 83%, white solid; 1 H NMR(400 MHz, CDCl3)δ 1.95-2.02 (2H, m), 2.61(2H, t, J = 7.6 Hz), 2.72 (2H, t, J = 7.6 Hz), 6.18 (1H, d, J = 3.6 Hz), 6.76 (2H,d, J = 7.6 Hz), 7.05 (2H, d, J = 7.6 Hz), 7.23 (1H, d, J = 3.6 Hz);13 C NMR (100 MHz, (CD3)2SO) δ 27.0, 29.4, 33.6, 108.0, 115.1, 118.9, 129.2, 131.4, 143.3, 155.4,159.3, 160.3. Embodiment 2:

[0034] The synthesis steps of ethyl 5-(3-(4-(tert-butoxycarbonyl)amino)phenyl)propyl)furan-2-carboxylate in this embodiment are as follows:

[0035] Under nitrogen atmosphere, ethyl 5-(acetoxymethyl)furan-2-carboxylate (0.2 mmol), dimethylaminopyridine-borane (2 equivalents), sodium dihydrogen phosphate dihydrate (1.2 equivalents), acetonitrile (3 mL), and then tert-butyl (4-vinylphenyl) carbamate (5 equivalents), di-tert-butyl peroxide (1 equivalent), 2-methoxythiophenol (0.2 equivalents) were added to a 10 mL Schlenk reaction tube. Finally, the reaction vessel was vented to maintain a nitrogen environment, and the reaction bottle was placed in an oil bath pot at 120°C for 12 h. The reaction endpoint was determined by thin layer chromatography (TLC) spot plate, and then petroleum ether / ethyl acetate was mixed in a volume ratio of 50:1 as the eluent, and separated by silica gel column to obtain ethyl 5-(3-(4-(tert-butyloxycarbonyl)amino)phenyl)propyl)furan-2-carboxylate.

[0036] The product yield was 39%, white liquid; 1 H NMR (400 MHz, CDCl3) 1.36 (3H, t, J = 7.2 Hz),1.50 (9H, s), 1.92-2.00 (2H, m), 2.60 (2H, t, J = 7.6 Hz), 2.68 (2H, t, J = 7.6Hz), 4.34 (2H, q, J = 7.2 Hz), 6.11 (1H, d, J = 3.2 Hz), 6.53 (1H, s), 7.07-7.09(3H, m), 7.28 (2H, d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 14.3, 27.6, 28.3,29.3, 34.4, 60.7, 80.3, 107.7, 118.7, 119.0, 128.9, 136.1, 136.3, 143.2,152.8, 158.9, 160.8.

[0037] The synthesis steps of 5-(3-(4-aminophenyl)propyl)furan-2-carboxylic acid in this embodiment are as follows:

[0038] Under nitrogen atmosphere, ethyl 5-(3-(4-(tert-butoxycarbonyl)amino)phenyl)propyl)furan-2-carboxylate (1.0 mmol), potassium hydroxide (4 equivalents), methanol (4 mL) and water (1 mL) were added to the reaction vessel, and the reaction mixture was stirred at 60 °C for 18 h. After the reaction, the reaction solution was extracted with dichloromethane to remove impurities in the organic phase, and then 1.0 M hydrochloric acid solution was added to the aqueous phase to adjust the pH of the solution to 1-2, and then extracted with dichloromethane again to obtain the ester hydrolysis product. The product was then dissolved in a dichloromethane solution and stirred, and trifluoroacetic acid (20 equivalents) was added and stirred for two hours. After the reaction was completed, 5-(3-(4-aminophenyl)propyl)furan-2-carboxylic acid was obtained by rotary evaporation and concentration.

[0039] The product yield was 91%, yellow solid; 1 H NMR(500 MHz, CD3OD)δ 1.85-1.91 (2H, m), 2.57-2.60 (4H, m), 6.13 (1H, d, J = 2.5 Hz), 7.04 (1H, d, J = 2.5 Hz), 7.22-7.24(2H, m), 7.26-7.30 (2H, m); 13 C NMR (125 MHz, CD3OD) δ 28.4, 30.5, 35.5, 109.1, 120.4, 123.6, 130.8, 131.3, 143.8, 144.8, 162.0, 162.1.

[0040] There are many reports on furan polyesters and furan polyamides. As a type of bio-based polymer, they can be widely used in packaging materials, organic semiconductors, self-healing repair materials and other fields, and have become a research hotspot in polymer materials today. For example, 2,5-furandicarboxylic acid, which is currently being studied more, is a typical representative of biomass furan monomers. It can be polycondensed with different types of alcohol compounds such as ethylene glycol, neopentyl glycol, 1,4-cyclohexanediol, etc. to obtain polyester products. The obtained polymers have good ductility, barrier properties and tensile strength. Bio-based furan polyamides have better solubility than petroleum-based polyamides and have been widely studied. The introduction of furan carboxylic acid into amide polymers usually forms amorphous or low-crystallinity materials. Intramolecular hydrogen bonds are formed between the oxygen heteroatoms in the furan ring and the hydrogen of the amide bond. These intramolecular hydrogen bonds usually reduce the thermodynamic and mechanical properties of furan polyamides (Fang Yonggan, Yang Chongling, Lin Jianyun, et al. Research Progress on Synthesis and Application of Bio-based Polyfuran Polymers [J]. Polymer Bulletin, 2022, (05): 38-54.). Robert's research group in Germany used long-chain 1,10-decanediol to synthesize long-chain furan-based polyamides, successfully inhibiting the formation of intramolecular hydrogen bonds, thereby improving its crystallinity (Robert T. ACS Sustain Chem Eng, 2020, 8 , 10812-10821). The monomers reported in the present invention have some similarities with the above-mentioned literature, and also contain long methylene chains as well as carboxyl and hydroxyl functional groups, and thus can be used to prepare long-chain furan polyesters and polyamides with similar properties.

[0041] When other conditions remain unchanged, any one of the olefins in the above-mentioned embodiments can be used to obtain the corresponding new furan-based bio-based polymerization monomer, and the yield varies depending on the use of different olefins. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can still be made without departing from the concept of the present invention, which are all within the scope of protection of the present invention.

Claims

1. A method for synthesizing 5-(arylpropyl)furoic acid compounds, characterized in that The steps include: Step 1: under nitrogen atmosphere, ethyl 5-(acetoxymethyl)furan-2-carboxylate, initiator, Lewis base-borane, thiol, additive and olefin are added to solvent 1, heated to react under stirring, the reaction end point is determined by thin layer chromatography, and separated by silica gel column to obtain ethyl 5-(arylpropyl)furoate compounds; Step 2: Add the 5-(arylpropyl)furoic acid ethyl ester compound obtained in step 1 and a base to solvent 2, heat and react under stirring, determine the reaction endpoint by thin layer chromatography, first extract with dichloromethane to remove organic phase impurities, then adjust the pH of the aqueous phase solution to 1-2, extract with dichloromethane again, and concentrate and collect the obtained organic phase; add a deprotecting group reagent to the concentrated product for deprotection to obtain the target product.

2. The synthesis method according to claim 1, characterized in that: In step 1, the initiator is di-tert-butyl peroxide, the Lewis base-borane is p-dimethylaminopyridine-borane, the thiol is 2-methoxythiophenol, and the additive is sodium dihydrogen phosphate dihydrate; The structure of the olefin is shown below: 。 3. The synthesis method according to claim 2, characterized in that: The molar ratio of ethyl 5-(acetoxymethyl)furan-2-carboxylate, initiator, Lewis base-borane, thiol, additive and olefin is 1.0: 1.0: 2.0: 0.2: 1.2: 5.

0.

4. The synthesis method according to claim 1, characterized in that: The solvent 1 is acetonitrile.

5. The synthesis method according to claim 1, characterized in that: In step 1, the heating reaction temperature is 120°C.

6. The synthesis method according to claim 1, characterized in that: In step 2, the base is potassium hydroxide; the molar ratio of 5-(arylpropyl)furoic acid ethyl ester compound to the base is 1.0:2.0-4.

0.

7. The synthesis method according to claim 1, characterized in that: In step 2, the solvent 2 is composed of methanol and water in a volume ratio of 4:

1.

8. The synthesis method according to claim 1, characterized in that: In step 2, the heating reaction temperature is 60°C.

9. The synthesis method according to claim 1, characterized in that: In step 2, the deprotection process is divided into two routes according to the different R groups: Route 1: When R = OMe, add 5-(arylpropyl)furoic acid intermediate to solvent 3, and add 5 equivalents of boron tribromide at reaction temperature 3, and determine the reaction endpoint by TLC spot plate. After the reaction is completed, add water to quench, extract with dichloromethane, collect the organic phase, and concentrate by rotary evaporation to obtain 5-(3-(4-hydroxyphenyl)propyl)furan-2-carboxylic acid; Route 2: When R = NHBoc, add the 5-(arylpropyl)furoic acid intermediate to solvent 4, add 20 equivalents of trifluoroacetic acid at reaction temperature 4, determine the reaction endpoint by TLC spot plate, and then remove the solvent by rotary evaporator to obtain 5-(3-(4-aminophenyl)propyl)furan-2-carboxylic acid; The synthetic route is as follows: 。 10. The synthesis method according to claim 9, characterized in that: In route 1, the solvent 3 is dichloromethane, and the reaction temperature 3 is -78°C to room temperature; In route 2, the solvent 4 is dichloromethane, and the reaction temperature 4 is room temperature.

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