A method for deuterium substitution at the gamma position of a fatty amine compound
A palladium catalytic system assisted by heavy water and aldehyde directing groups was used to achieve γ-position selective deuteration of aliphatic amines, solving the problems of high cost and poor selectivity in existing methods and providing an efficient and low-cost deuteration solution.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
- Filing Date
- 2024-05-24
- Publication Date
- 2026-07-21
AI Technical Summary
Existing deuteration methods for aliphatic amines mainly focus on α-position or full deuteration, making it difficult to achieve selective deuteration at specific sites such as β and γ positions. Furthermore, traditional methods are costly and have poor selectivity, making it difficult to meet the needs of practical applications.
Using heavy water as the deuterium source and employing an aldehyde-directing group to assist in the transition metal palladium catalysis, the γ-position deuteration of aliphatic amine compounds is achieved through the combination of catalyst, directing group, ligand, and silver salt. The reaction conditions are mild, the operation is simple, the cost is low, and the degree of deuteration is high.
This method achieves efficient γ-position deuteration of aliphatic amine compounds, with high deuteration degree, high yield, simple operation, low cost, and environmentally friendly reagents, and is applicable to the preparation of a variety of aliphatic amine compounds.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of deuterated compound synthesis technology, and particularly to a method for γ-position deuteration of aliphatic amine compounds. Background Technology
[0002] Deuterated organic compounds have wide applications in NMR solvents, mechanical probes in chemical and biological processes, bioactive compounds, and pharmaceuticals, especially in the pharmaceutical field. When drug metabolism involves the breaking of CH bonds, the deuteration of these covalently bound hydrogen atoms can provide improved metabolomics characterization and prevent the formation of toxic metabolites. Deuteration of drugs often results in significantly improved stability and longer half-lives. Furthermore, isotope-labeled drug candidates play a crucial role in understanding the metabolic characteristics of drug molecules and assessing their toxicity. Therefore, deuterated compounds play an important role in medicinal chemistry. With the development of the chemical industry and the continuous growth of market demand, the application of deuterated drugs will also gain enormous potential.
[0003] Approximately 92% of drug candidates are nitrogen-containing compounds. Introducing deuterium into readily metabolizable sites of amines can improve drug absorption and distribution. Conversely, introducing deuterium into some non-metabolizable sites of amines has wide applications in studying their metabolic and excretion characteristics. From this perspective, the deuteration of aliphatic amines is of great significance. In particular, the development of selective deuteration methods for specific sites is an urgent task.
[0004] Traditional methods for synthesizing deuterated aliphatic amines involve reducing nitriles with deuterating reagents such as LiAlD4. However, these methods are impractical due to their low atom economy, high cost, limited functional group tolerance, and difficulty in controlling selectivity. With the rapid growth in demand for deuterated amine compounds, various research groups have developed deuteration methods for various amines in recent years, but most are limited to the α-position and full deuteration of amines. For example, Lillian and colleagues achieved selective deuteration of the α-position of primary amines using ruthenium complexes and D2O pairs in 2016 (J. Am. Chem. Soc. 2016, 138, 13489-13492); in 2018, Kerr and his team reported a method for the α-position deuteration of amino groups via iridium catalysis. 3 Hydrogen isotope exchange method for C(sp)-H bonds (ACS Catal. 2018, 8, 10895-10900); In 2017, MacMillan and his team used D2O as a source of hydrogen isotopes to efficiently realize the transfer of hydrogen atoms in aliphatic amines C(sp) bonds via photoredox-mediated hydrogen atom transfer. 3The full deuteration of the β-H bond is an example (Science. 2017, 358, 1182–1187). In contrast, deuteration methods at specific sites (such as β and γ-positions) in amine compounds are rarely reported. In 2019, Zhang et al. completed the deuteration of the β-position of amines in various alkylamine drug molecules through the synergistic catalysis of B(C6F5)3 and the n-alkylamine system (ACS Catalysis, 2019, 141: 14570-14575); in the same year, Ellen et al. reported the deuteration of the β-H bond. 10 - Tert-butanol as a deuterium source, Pd catalyzes deuteration at the γ-position of cyclic aliphatic amines (Organometallics, 2019, 38, 138-143).
[0005] As seen in the methods described above, most current deuteration methods for aliphatic amines involve α-position or full deuteration. However, in practical applications, α-position deuteration of aliphatic amines is not stable enough and often fails to achieve the desired results; full deuteration methods are difficult to apply clinically due to their inability to precisely target a specific site. In contrast, γ-position targeted deuteration is clearly more advantageous and can meet the needs of many clinical applications. This application develops a method for γ-position hydrogen-deuterium exchange of aliphatic amines using cheaper heavy water as the deuterium source and an aldehyde-directing group-assisted transition metal palladium catalysis. The catalysts, directing groups, ligands, and other reagents used are all safe and inexpensive, and the deuterated product has a high degree of deuteration and a fixed deuteration site, demonstrating potential application value. Summary of the Invention
[0006] The purpose of this invention is to provide a method for the γ-position deuteration of aliphatic amine compounds, which requires less catalyst, is simple to operate, has high degree of deuteration and yield, is easy to separate, has low cost, and uses environmentally friendly reagents.
[0007] The technical solution adopted by this invention to solve its technical problem is:
[0008] A method for the γ-position deuteration of aliphatic amine compounds.
[0009]
[0010] Using the aliphatic amine compound shown in Formula I as a raw material, under normal pressure, it undergoes a deuteration reaction with a deuterium source reagent through a catalytic system. The reaction product is then separated and purified to obtain the γ-deuterated product of the aliphatic amine compound shown in Formula I.
[0011] The catalytic system includes a metal catalyst, a directing group, a ligand, a silver salt for maintaining the valence state of palladium, and a solvent;
[0012] R1, R2, R3, and R4 are all selected from one or more of hydrogen atoms, C1-C10 alkyl groups, hydroxyl groups, and C1-C10 alkoxy groups. The C1-C10 alkyl groups can be straight-chain or branched, and the C1-C10 alkoxy groups can be straight-chain or branched. Preferably, during preparation, a Boc protecting group is added to the amino group of the aliphatic amine compound represented by Formula I to facilitate separation and purification.
[0013] This invention utilizes highly active 2-hydroxynicotinaldehyde as the aldehyde directing group, a small amount of palladium acetate as a metal catalyst, and ligand-assisted hydrocarbon activation. Simultaneously, heavy water is used as the deuterium source for the γ-deuteration of aliphatic amine substrates. This method requires minimal catalyst, is simple to operate, achieves high deuteration degree and yield, simplifies separation, reduces cost, and uses environmentally friendly reagents. The aliphatic amines are derivatives of 3-pentaneamine.
[0014] The molar ratio of each material in the reaction is: aliphatic amine compound: metal catalyst: directing group: ligand: silver salt: solvent: deuterium source reagent = 1 mmol: 0.1~0.2 mmol: 0.5~1.0 mmol: 0.5~1.0 mmol: 1.0~2.0 mmol: 1.0~2.0 mL: 1.0~2.0 mL.
[0015] The metal catalyst is palladium acetate.
[0016] The directing group is 2-hydroxynicotinaldehyde.
[0017] The ligand is one of 2-hydroxy-5-nitropyridine, 2-hydroxy-3-methyl-5-nitropyridine, 2-hydroxy-3-nitro-5-trifluoromethylpyridine, 2-hydroxy-3-trifluoromethyl-5-nitropyridine, and 2-hydroxy-5-trifluoromethyl.
[0018] The silver salt is silver trifluoroacetate.
[0019] The deuterium source reagent is heavy water.
[0020] The solvent is one of hexafluoroisopropanol, ethyl acetate, dichloromethane, dioxane, and tetrahydrofuran.
[0021] The deuteration reaction temperature is 120–150℃, and the reaction time is 24–48 hours.
[0022] The beneficial effects of this invention are: the one-pot reaction does not require solvent replacement during the process, and the reaction is highly operable with good deuteration effect; the process method has good universality and can be used to prepare deuterated products of various aliphatic amine compounds; it is safe, environmentally friendly, and inexpensive. Attached Figure Description
[0023] Figure 1 This is the NMR spectrum of the product from Example 1. Detailed Implementation
[0024] The technical solution of the present invention will be further described in detail below through specific embodiments.
[0025] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available or commonly used in the field. The methods described in the following embodiments are conventional methods in the field, unless otherwise specified.
[0026] Because aliphatic amines have low boiling points, the amino group Boc is included as a protecting group in the examples to facilitate the separation and purification of the product. The final product will be deprotected. Boc can be removed directly under normal acidic conditions without affecting the degree of deuteration.
[0027] In the following examples, 10 mol% and 50 mol% are both molar percentages of 1 mmol of raw material.
[0028] Example 1: Synthesis of deuterated 2-aminobutane
[0029]
[0030] In a 15 mL dry sealed tube, 1 mmol (73.14 mg) of 2-aminobutane, 10 mol% (22.4 mg) of palladium acetate, 50 mol% (61.5 mg) of 2-hydroxynicotinaldehyde, 50 mol% (70.05 mg) of 2-hydroxy-5-nitropyridine, 1.0 eq. (220.0 mg) of silver trifluoroacetate, 1.0 mL of hexafluoroisopropanol, and 1.0 mL of D2O (99.9%) were added sequentially. The mixture was stirred at 120 °C and reacted under normal pressure for 24 hours.
[0031] After the reaction was complete, stirring was stopped, and the mixture was quenched with cold water. The reaction solution was washed with a mixture of dichloromethane and methanol (4:1) and filtered through diatomaceous earth to remove palladium and silver salts. 2 mL of 4M hydrochloric acid aqueous solution was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The pH was checked with pH paper to ensure that the pH was <3. Then, 5 mL of 15% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for another hour. The pH was checked with pH paper to ensure that the pH was >10. The organic phase was separated using a separatory funnel, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, and 3 mL of 15% sodium hydroxide aqueous solution and 3 mL of Boc anhydride were added. The mixture was stirred at 50°C for 4 hours. After the reaction was complete, the organic phase was separated and rotary evaporated to obtain a crude product protected by aminoBoc. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 129.3 mg of the target compound, with a yield of 74.7% and a degree of deuteration of 85%. 1H NMR (400MHz, CDCl3) δ4.30 (s, 1H), 3.55 (s, 1H), 1.44 (s, 9H), 1.40 (d, J = 7.2Hz, 2H), 1.09 (d, J = 6.6Hz, 3H), 0.86 ( t,0.45H (Appendix) Figure 1 ).
[0032] Example 2: Synthesis of deuterated 2-aminopentane
[0033]
[0034] In a 15 mL dry sealed tube, 1 mmol (87.16 mg) of 2-aminopentane, 10 mol% (22.4 mg) of palladium acetate, 50 mol% (61.5 mg) of 2-hydroxynicotinaldehyde, 50 mol% (70.05 mg) of 2-hydroxy-5-nitropyridine, 1.0 eq. (220.0 mg) of silver trifluoroacetate, 1.0 mL of hexafluoroisopropanol, and 1.0 mL of D2O (99.9%) were added sequentially. The mixture was stirred at 150 °C and reacted under normal pressure for 24 hours.
[0035] After the reaction was complete, stirring was stopped, and the reaction mixture was quenched with cold water. The reaction solution was washed with a mixture of dichloromethane and methanol (4:1) and filtered through diatomaceous earth to remove palladium and silver salts. 2 mL of 4M hydrochloric acid aqueous solution was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The pH was checked with pH paper to ensure that the pH was <3. Then, 5 mL of 15% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for another hour. The pH was checked with pH paper to ensure that the pH was >10. The organic phase was separated using a separatory funnel, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, and 3 mL of 15% sodium hydroxide aqueous solution and 3 mL of Boc anhydride were added. The mixture was stirred at 50°C for 4 hours. After the reaction was complete, the organic phase was separated and rotary evaporated to obtain a crude product protected by aminoBoc. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 126.0 mg of the target compound, with a yield of 67.3% and a degree of deuteration of 72%. 1 H NMR (400MHz, CDCl3) δ4.29(s,1H),3.63(s,1H),1.44(s,9H),1.39–1.26( m, 2.55H ), 1.09 (d, J = 6.6Hz, 3H), 0.89 (d, J = 6.0Hz, 3H).
[0036] Example 3 Synthesis of 1,2-Dimethylpropylamine
[0037]
[0038] In a 15 mL dry sealed tube, 1 mmol (87.16 mg) of 1,2-dimethylpropylamine, 10 mol% (22.4 mg) of palladium acetate, 50 mol% (61.5 mg) of 2-hydroxynicotinaldehyde, 50 mol% (70.05 mg) of 2-hydroxy-5-nitropyridine, 1.0 eq. (220.0 mg) of silver trifluoroacetate, 1.0 mL of hexafluoroisopropanol, and 1.0 mL of D2O (99.9%) were added sequentially. The mixture was stirred at 120 °C and reacted under normal pressure for 48 hours.
[0039] After the reaction was complete, stirring was stopped, and the mixture was quenched with cold water. The reaction solution was washed with a mixture of dichloromethane and methanol (4:1) and filtered through diatomaceous earth to remove palladium and silver salts. 2 mL of 4M hydrochloric acid aqueous solution was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The pH was checked with pH paper to ensure it was <3. Then, 5 mL of 15% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for another hour. The pH was checked again with pH paper to ensure it was >10. The organic phase was separated using a separatory funnel, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, and 3 mL of 15% sodium hydroxide aqueous solution and 3 mL of Boc anhydride were added. The mixture was stirred at 50°C for 4 hours. After the reaction was complete, the organic phase was separated and rotary evaporated to obtain a crude product protected by aminoBoc. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 169.8 mg of the target compound, with a yield of 90.8% and a degree of deuteration of 80%. 1 H NMR (400MHz, CDCl3) δ4.35 (s, 1H), 3.52 (s, 1H), 1.58 (s, 1H), 1.44 (s, 9H), 1.05 (d, J = 6.7Hz, 3H), 0.85 (ddt, J = 7.9, 5.7, 2.5Hz, 1.18H ).
[0040] Starting from γ-aliphatic amine derivatives, γ-deuterated aliphatic amine products were obtained under the conditions of Example 1, and the results are shown in the table below:
[0041] Compound numbering Deuteration degree (%D) Yield (%) 4-d 83 79 5-d 81 46 6-d 83 45 7-d 83 46 8-d 74 64 9-d 74 63 10-d 69 63 11-d 70 58 12-d 56 83 13-d 80 65
[0042] γ-Deuterated 3-pentanamine (4-d) 1 H NMR (400MHz, CDCl3) δ4.25(s,1H),3.40(s,1H),1.43(s,9H),1.62–1.20(m,4H),0.86(m,0.98H).
[0043]
[0044] γ-Deuterated 2-amino-1-methoxybutane (tert-butyl(1-methoxybutan-2-yl-4,4,4)carbamate)(5-d) 1 H NMR (400MHz, CDCl3) δ4.66(s,1H),3.59(s,1H),3.44–3.34(m,2H),1.56(dt,J=13.5,6.3Hz,2H),1.44(s,9H),1.00–0.77( m, 0.5H) .
[0045]
[0046] γ-Deuterated 2-amino-1-butanol (6-d) 1 H NMR (400MHz, CDCl3) δ4.60 (s, 1H), 3.68 (t, J = 6.9Hz, 1H), 3.55 (dq, J = 8.7, 5. 2Hz,2H),2.38(s,1H),1.54(dd,J=13.6,5.8Hz,2H),1.45(s,9H),1.02–0.84( m, 0.51H ).
[0047]
[0048] γ-Deuterated 2-amino-3-methyl-1-butanol (7-d) 1 H NMR (400MHz, CDCl3) δ4.66 (s, 1H), 3.79–3.53 (m, 2H), 3.42 (s, 1H), 2.25 (s, 1H), 1.79 (t, J = 6.5Hz, 1H), 1.44 (s, 9H), 0.90 ( q,J=7.4Hz,1.01H ).
[0049]
[0050] γ-Deuterated isobutylamine (2-methylpropan-1-amine)(8-d) 1 H NMR (400MHz, CDCl3) δ4.58 (s, 1H), 2.92 (d, J = 6.1Hz, 2H), 1.68 (q, J = 6.5Hz, 1H), 1.43 (s, 9H), 1.03–0.73 (m, 1.56H).
[0051]
[0052] γ-Deuterated neopentylcarbamate (9-d) 1 H NMR (400MHz, Chloroform-d) δ4.57 (s, 1H), 2.90 (d, J = 6.0Hz, 2H), 1.44 (s, 9H), 0.89–0.81 (m, 2.28H).
[0053]
[0054] γ-Deuterated 2-methyl-n-butylamine (tert-butyl(2-methylbutyl)carbamate)(10-d) 1 H NMR (400MHz, CDCl3) δ4.55(s,1H),3.14–2.82(m,2H),1.43(m,11H),1.11(m,0.76H),0.93–0.67(m,3.93H).
[0055]
[0056] γ-Deuterated 6-amino-2-methyl-2-heptano (11-d) 1 H NMR(400MHz, CDCl3)δ4.30(s,1H),3.67(s,1H),1.42( d, J = 16.5 Hz, 13.60 H ),1.19(dd,J=12.1,5.7Hz,6H),1.12(d,J=6.6Hz,3H).
[0057]
[0058] γ-Deuterated 1,3-dimethylamylamine (12-d) 11 H NMR (400MHz, CDCl3) δ4.25 (d, J = 23.3Hz, 1H), 3.71 (s, 1H), 1.44 (s, 9H), 1.41–1.23 ( m, 3.44H ),1.21–1.13(m,1H),1.09(t,J=6.9Hz,3H),0.92–0.82(m,6H).
[0059]
[0060] γ-Deuterated tert-butylcarbamate (13-d)1 H NMR (400MHz, CDCl3) δ5.38 (d, J=8.5Hz, 1H), 4.53 (td, J=8.0, 5.0Hz, 1H), 3. 05(s,3H),2.93(s,3H),1.70(m,1H),1.60–1.46(m,1H),1.40(s,9H),0.90( t,J= 7.4Hz, 0.60H ).
[0061]
[0062] Under the same conditions as in Example 1, but with a different ligand, the results are shown in the table below:
[0063] ligands Yield (%) Deuteration degree (%D) 2-Hydroxy-3-methyl-5-nitropyridine 67 85 2-Hydroxy-3-nitro-5-trifluoromethylpyridine 65 84 2-Hydroxy-3-trifluoromethyl-5-nitropyridine 68 84 2-Hydroxy-5-trifluoromethyl 70 85 .
[0064] Under the same conditions as Example 1, but with a different solvent, the results are shown in the table below:
[0065] solvent Yield (%) Deuteration degree (%D) Ethyl acetate 72 85 dichloromethane 58 84 Dioxane 56 84 Tetrahydrofuran 63 85 .
[0066] Under the same conditions as Example 1, but with different proportions, the results are shown in the table below:
[0067]
[0068] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.
Claims
1. A method for the γ-position deuteration of aliphatic amine compounds, characterized in that, Using aliphatic amine compounds as raw materials, under normal pressure, a deuteration reaction is carried out with a deuterium source reagent through a catalytic system. The reaction products are separated and purified to obtain γ-deuterated products of aliphatic amine compounds. The aliphatic amine compounds specifically include 2-aminobutane, 2-aminopentane, 1,2-dimethylpropylamine, 3-aminopentane, 2-amino-1-methoxybutane, 2-amino-1-butanol, 2-amino-3-methyl-1-butanol, isobutylamine, tert-pentylamine, 2-methyl-n-butylamine, 6-amino-2-methyl-2-heptanol, or 1,3-dimethylpentylamine. The specific γ-deuterated products corresponding to the above-mentioned aliphatic amine compounds are as follows: , , , , , , , , , , , ; The catalytic system consists of a metal catalyst, a directing group, a ligand, a silver salt for maintaining the valence state of palladium, and a solvent. The metal catalyst is palladium acetate; the directing group is 2-hydroxynicotinaldehyde; the ligand is one of 2-hydroxy-5-nitropyridine, 2-hydroxy-3-methyl-5-nitropyridine, 2-hydroxy-3-nitro-5-trifluoromethylpyridine, and 2-hydroxy-3-trifluoromethyl-5-nitropyridine; the silver salt is silver trifluoroacetate; and the solvent is one of hexafluoroisopropanol, ethyl acetate, dichloromethane, dioxane, and tetrahydrofuran.
2. The γ-position deuteration method according to claim 1, characterized in that, The molar ratio of each material in the reaction is: aliphatic amine compound: metal catalyst: directing group: ligand: silver salt: solvent: deuterium source reagent = 1 mmol : 0.1~0.2 mmol : 0.5~1.0 mmol : 0.5~1.0 mmol : 1.0~2.0 mmol : 1.0~2.0 mL : 1.0~2.0 mL.
3. The γ-position deuteration method according to claim 1, characterized in that, The deuterium source reagent is heavy water.
4. The γ-position deuteration method according to claim 1, characterized in that, The deuteration reaction temperature is 120~150℃, and the reaction time is 24~48 hours.