Photochemical synthesis method of fluorine-containing tertiary amine
The photochemical method for synthesizing fluorinated tertiary amines solves the problems of multiple steps and complex purification in traditional synthesis methods, achieving a highly efficient and concise synthesis process with high yield and purity, making it suitable for the biomedical field.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUIZHOU MEDICAL UNIV
- Filing Date
- 2026-01-29
- Publication Date
- 2026-05-12
AI Technical Summary
The synthesis of fluorinated tertiary amine compounds in the current technology requires multiple synthesis steps and cumbersome purification steps, which hinders the progress of drug development.
A photochemical method was used to carry out a photocatalytic reaction of (2,2-difluoroethylene-1,1-diyl)diphenyl, dibenzylamine, 3-phenylpropanal, catalyst, Lewis acid, and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate under a nitrogen atmosphere and at room temperature, followed by vacuum distillation and purification by silica gel column chromatography.
A high-yield (77%) and high-purity (99%) synthesis of fluorinated tertiary amines was achieved, providing a synthetic method under mild conditions with promising prospects for biomedical applications.
Smart Images
Figure CN122010747A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis. Background Technology
[0002] Fluorinated tertiary amines have wide applications in pharmaceuticals, pesticides, and functional materials due to their unique biological and chemical properties. Drugs such as posaconazole, fluoroerythromycin, and fluoxetine exhibit good biological activity in antibacterial, antidepressant, antifungal, anticancer, and diabetes treatment. Studies have shown that introducing fluorine atoms or fluorine-containing groups into drug molecules can significantly improve their metabolic stability, lipophilicity, and biological activity. Traditional reductive amination and substitution reactions have significant limitations in the synthesis of branched tertiary amines. Furthermore, the hydroamination of amines and alkenes requires substrate molecules with specific structures, necessitating multi-step synthesis and cumbersome purification processes, which severely hinders drug development. Summary of the Invention
[0003] This invention aims to solve the problem that the existing technology requires multiple synthesis steps and cumbersome purification steps to obtain fluorinated tertiary amine compounds, and thus provides a photochemical synthesis method for fluorinated tertiary amines.
[0004] A photochemical synthesis method for a fluorinated tertiary amine, comprising the following steps:
[0005] Under nitrogen atmosphere, room temperature, and stirring conditions, (2,2-difluoroethylene-1,1-diyl)diphenyl, dibenzylamine, 3-phenylpropanal, catalyst, Lewis acid, diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, and organic solvent were mixed evenly to obtain a mixture. Then, under nitrogen atmosphere, room temperature, blue light irradiation at a wavelength of 450 nm, and stirring conditions, the mixture was subjected to a photocatalytic reaction. After the reaction, the solvent was removed by vacuum distillation, and then purified by silica gel column chromatography to obtain a fluorinated tertiary amine, thus completing the photochemical synthesis method of the fluorinated tertiary amine.
[0006] The structural formula of (2,2-difluoroethylene-1,1-diyl)diphenyl is as follows: ;
[0007] The molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to dibenzylamine is 1:(1.0~1.5); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to 3-phenylpropanal is 1:(1.0~1.5); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to the catalyst is 1:(0.01~0.03); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to Lewis acid is 1:(0.3~0.5); and the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 1:(1.5~2.0).
[0008] The beneficial effects of this invention are:
[0009] This invention provides a photochemical synthesis method for fluorinated tertiary amines under mild conditions. This method has good application prospects in biopharmaceutical synthesis. The reaction conditions of this invention are simple and mild, the raw materials are readily available, the yield can reach 77%, and the purity can reach 99%. It is an ideal and practical photochemical synthesis method for fluorinated tertiary amines. Attached Figure Description
[0010] Figure 1 The 1H NMR spectrum of the fluorinated tertiary amine prepared in Example 1;
[0011] Figure 2 The 13C NMR spectrum of the fluorinated tertiary amine prepared in Example 1;
[0012] Figure 3 The image shows the 19F NMR spectrum of the fluorinated tertiary amine prepared in Example 1. Detailed Implementation
[0013] Specific Implementation Method 1: This embodiment describes a photochemical synthesis method for a fluorinated tertiary amine, which is carried out according to the following steps:
[0014] Under nitrogen atmosphere, room temperature, and stirring conditions, (2,2-difluoroethylene-1,1-diyl)diphenyl, dibenzylamine, 3-phenylpropanal, catalyst, Lewis acid, diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, and organic solvent were mixed evenly to obtain a mixture. Then, under nitrogen atmosphere, room temperature, blue light irradiation at a wavelength of 450 nm, and stirring conditions, the mixture was subjected to a photocatalytic reaction. After the reaction, the solvent was removed by vacuum distillation, and then purified by silica gel column chromatography to obtain a fluorinated tertiary amine, thus completing the photochemical synthesis method of the fluorinated tertiary amine.
[0015] The structural formula of (2,2-difluoroethylene-1,1-diyl)diphenyl is as follows: ;
[0016] The molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to dibenzylamine is 1:(1.0~1.5); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to 3-phenylpropanal is 1:(1.0~1.5); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to the catalyst is 1:(0.01~0.03); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to Lewis acid is 1:(0.3~0.5); and the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 1:(1.5~2.0).
[0017] In this specific embodiment, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester is used as a reducing agent.
[0018] The (2,2-difluoroethylene-1,1-diyl)diphenyl described in this specific embodiment was prepared with reference to the following literature: Hu M, Ni C, Li L, et al. gem-Difluoroolefination of diazo compounds with TMSCF3 or TMSCF2Br: transition-metal-free cross-coupling of two carbene precursors[J]. Journal of the American Chemical Society, 2015, 137(45): 14496-14501.
[0019] The (2,2-difluoroethylene-1,1-diyl)diphenyl of this invention is a fluorinating agent with good functional group tolerance.
[0020] The beneficial effects of this embodiment are:
[0021] This specific embodiment provides a photochemical synthesis method for fluorinated tertiary amines under mild conditions. This method has good application prospects in biopharmaceutical synthesis. The reaction conditions of this specific embodiment are simple and mild, the raw materials are readily available, the yield can reach 77%, and the purity can reach 99%. It is an ideal and practical photochemical synthesis method for fluorinated tertiary amines.
[0022] Specific Implementation Method Two: This implementation method differs from Specific Implementation Method One in that the organic solvent used is acetonitrile, anhydrous acetonitrile, anhydrous dichloroethane, toluene, N,N-dimethylformamide, or anhydrous dimethyl sulfoxide. Everything else is the same as in Specific Implementation Method One.
[0023] Specific Implementation Method Three: This implementation method differs from Specific Implementation Method One or Two in that the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to the volume ratio of the organic solvent is 1 mmol:(5~10) mL. Everything else is the same as in Specific Implementation Method One or Two.
[0024] Specific Implementation Method Four: This implementation method differs from Specific Implementation Methods One to Three in that the catalyst is 4Cz-IPN, Ir(dFCF3ppy)2dtbpyPF6, Ir(dFppy)2bpyPF6, Ir(dFCF3ppy)2bpyPF6, or Ir(dFppy)2dtbpyPF6. Everything else is the same as in Specific Implementation Methods One to Three.
[0025] The Ir(dFCF3ppy)2dtbpyPF6 described in this specific embodiment is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), CAS number 870987-63-6.
[0026] Specific Implementation Method Five: This implementation method differs from Specific Implementation Methods One to Four in that the Lewis acid is trifluoroacetic acid, boron trifluoride ether, lithium chloride, sodium trifluoromethanesulfonate, sodium tetrafluoroborate, or p-toluenesulfonic acid. Everything else is the same as in Specific Implementation Methods One to Four.
[0027] Specific Implementation Method Six: This implementation method differs from Specific Implementation Methods One to Five in that the solvent used for silica gel column chromatography separation and purification is a mixed solvent of petroleum ether and ethyl acetate. Everything else is the same as in Specific Implementation Methods One to Five.
[0028] Specific Implementation Method Seven: This implementation method differs from Specific Implementation Methods One to Six in that the volume ratio of petroleum ether to ethyl acetate is (100~110):1. Everything else is the same as in Specific Implementation Methods One to Six.
[0029] Specific Implementation Method Eight: This implementation method differs from Specific Implementation Methods One to Seven in that: under a nitrogen atmosphere, at room temperature, and with a stirring speed of 200 r / min to 300 r / min, (2,2-difluoroethylene-1,1-diyl)diphenyl, dibenzylamine, 3-phenylpropanal, a catalyst, a Lewis acid, diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, and an organic solvent are mixed for 20 h to 24 h to obtain a mixture. Everything else is the same as in Specific Implementation Methods One to Seven.
[0030] Specific Implementation Method Nine: This implementation method differs from Specific Implementation Methods One to Eight in that the mixture is subjected to a photocatalytic reaction for 70 to 74 hours under the conditions of nitrogen atmosphere, room temperature, irradiation with a blue light lamp at a wavelength of 450 nm and a power of 10W to 14W, and a stirring speed of 200 r / min to 300 r / min. All other conditions are the same as in Specific Implementation Methods One to Eight.
[0031] Specific Implementation Method Ten: This implementation method differs from Specific Implementation Methods One through Nine in that the fluorinated tertiary amine is N,N-dibenzyl-2-fluoro-1,1,5-triphenylpent-1-ene-3-amine, with the structural formula […]. The rest is the same as in specific implementation methods one through nine.
[0032] The beneficial effects of the present invention are verified using the following embodiments:
[0033] Example 1:
[0034] A photochemical synthesis method for a fluorinated tertiary amine, comprising the following steps:
[0035] Under a nitrogen atmosphere, at room temperature and with a stirring speed of 300 r / min, 21.6 mg (0.1 mmol) of (2,2-difluoroethylene-1,1-diyl)diphenyl, 29.6 mg (0.15 mmol) of dibenzylamine, 20.1 mg (0.15 mmol) of 3-phenylpropanal, 1 mg (0.001 mol) of catalyst, 4.4 mg (0.04 mmol) of Lewis acid, 37.95 mg (0.15 mmol) of diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, and 1 mL of organic solvent were mixed for 24 h to obtain a mixture. Then, under a nitrogen atmosphere, at room temperature, irradiated with a blue light lamp with a wavelength of 450 nm and a power of 12 W, and with a stirring speed of 300 r / min, the mixture was subjected to a photocatalytic reaction for 72 h. After the reaction, the solvent was removed by vacuum distillation, and then purified by silica gel column chromatography to obtain a fluorinated tertiary amine.
[0036] The structural formula of (2,2-difluoroethylene-1,1-diyl)diphenyl is as follows: ;
[0037] The organic solvent is anhydrous dimethyl sulfoxide.
[0038] The catalyst is Ir(dFCF3ppy)2dtbpyPF6.
[0039] The Lewis acid mentioned is sodium tetrafluoroborate.
[0040] The solvent used for silica gel column chromatography separation and purification is a mixture of petroleum ether and ethyl acetate.
[0041] The volume ratio of petroleum ether to ethyl acetate is 100:1.
[0042] The fluorinated tertiary amine is N,N-dibenzyl-2-fluoro-1,1,5-triphenylpent-1-ene-3-amine, with the structural formula: .
[0043] The preparation route of the fluorinated tertiary amine in this embodiment is as follows:
[0044]
[0045] The fluorinated tertiary amine prepared in Example 1 had a yield of 77% and a purity of 99%.
[0046] Figure 1 The 1H NMR spectrum of the fluorinated tertiary amine prepared in Example 1; Figure 2 The 13C NMR spectrum of the fluorinated tertiary amine prepared in Example 1; Figure 3 The 19F NMR spectrum of the fluorinated tertiary amine prepared in Example 1; NMR data analysis:
[0047] 1H NMR (400 MHz, CDCl3): δH 7.37-7.22 (m, 5H), 7.22 – 7.12 (m, 10H), 7.07 (t, J = 7.6 Hz, 2H), 6.98 (dd, J = 4.0, 1.4 Hz, 4H), 6.91-6.76 (m, 4H), 3.97 (d, J = 13.9 Hz, 2H), 3.74 (ddd, J = 35.0, 8.7, 5.6 Hz, 1H), 3.45 (d, J= 13.9 Hz, 2H), 2.79 (dt, J = 13.7, 6.8 Hz, 1H), 2.67-2.55 (m, 1H), 2.35-2.22(m, 1H), 2.04 (td, J = 13.8, 7.7 Hz, 1H).
[0048] 13C NMR (101 MHz, CDCl3): δC 157.3 (d, J = 268.3 Hz), 142.0 , 140.2,138.3 (d, J = 7.8 Hz), 138.2, 130.7 (d, J = 2.6 Hz), 130.1 (d, J = 4.1 Hz),128.9, 128.7, 128.6, 128.5, 128.14, 128.11, 127.4, 127.2, 126.7, 125.8, 125.0(d, J = 15.5 Hz), 55.4 (d, J = 23.0 Hz), 54.7, 32.1, 31.7.
[0049] 19F NMR (376 MHz, CDCl3): δF -111.49 (d, J = 34.9 Hz).
Claims
1. A photochemical synthesis method for a fluorine-containing tertiary amine, characterized in that... It is done in the following steps: Under nitrogen atmosphere, room temperature, and stirring conditions, (2,2-difluoroethylene-1,1-diyl)diphenyl, dibenzylamine, 3-phenylpropanal, catalyst, Lewis acid, diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, and organic solvent were mixed evenly to obtain a mixture. Then, under nitrogen atmosphere, room temperature, blue light irradiation at a wavelength of 450 nm, and stirring conditions, the mixture was subjected to a photocatalytic reaction. After the reaction, the solvent was removed by vacuum distillation, and then purified by silica gel column chromatography to obtain a fluorinated tertiary amine, thus completing the photochemical synthesis method of the fluorinated tertiary amine. The structural formula of (2,2-difluoroethylene-1,1-diyl)diphenyl is as follows: ; The molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to dibenzylamine is 1:(1.0~1.5); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to 3-phenylpropanal is 1:(1.0~1.5); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to the catalyst is 1:(0.01~0.03); the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to Lewis acid is 1:(0.3~0.5); and the molar ratio of (2,2-difluoroethylene-1,1-diyl)dibenzene to diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 1:(1.5~2.0).
2. The photochemical synthesis method for a fluorine-containing tertiary amine according to claim 1, characterized in that... The organic solvent is acetonitrile, anhydrous acetonitrile, anhydrous dichloroethane, toluene, N,N-dimethylformamide, or anhydrous dimethyl sulfoxide.
3. The photochemical synthesis method for a fluorinated tertiary amine according to claim 1, characterized in that... The molar ratio of (2,2-difluoroethylene-1,1-diyl)diphenyl to the volume ratio of the organic solvent is 1 mmol: (5~10) mL.
4. The photochemical synthesis method for a fluorine-containing tertiary amine according to claim 1, characterized in that... The catalyst is 4Cz-IPN, Ir(dFCF3ppy)2dtbpyPF6, Ir(dFppy)2bpyPF6, Ir(dFCF3ppy)2bpyPF6 or Ir(dFppy)2dtbpyPF6.
5. The photochemical synthesis method for a fluorinated tertiary amine according to claim 1, characterized in that... The Lewis acid is trifluoroacetic acid, boron trifluoride ether, lithium chloride, sodium trifluoromethanesulfonate, sodium tetrafluoroborate, or p-toluenesulfonic acid.
6. The photochemical synthesis method for a fluorinated tertiary amine according to claim 1, characterized in that... The solvent used for silica gel column chromatography separation and purification is a mixture of petroleum ether and ethyl acetate.
7. The photochemical synthesis method for a fluorinated tertiary amine according to claim 6, characterized in that... The volume ratio of petroleum ether to ethyl acetate is (100~110):
1.
8. The photochemical synthesis method for a fluorinated tertiary amine according to claim 1, characterized in that... Under nitrogen atmosphere, at room temperature and with a stirring speed of 200 r / min to 300 r / min, (2,2-difluoroethylene-1,1-diyl)diphenyl, dibenzylamine, 3-phenylpropanal, catalyst, Lewis acid, diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate and organic solvent were mixed for 20 h to 24 h to obtain a mixture.
9. The photochemical synthesis method for a fluorinated tertiary amine according to claim 1, characterized in that... The mixture was subjected to photocatalytic reaction for 70-74 hours under nitrogen atmosphere, room temperature, irradiation with a blue light lamp with a wavelength of 450 nm and a power of 10 W to 14 W, and a stirring speed of 200 r / min to 300 r / min.
10. The photochemical synthesis method for a fluorinated tertiary amine according to claim 1, characterized in that... The fluorinated tertiary amine is N,N-dibenzyl-2-fluoro-1,1,5-triphenylpent-1-ene-3-amine, with the structural formula: .