A method for synthesizing substituted nitrogen heterocyclic compounds
By using a nitrogen heterocyclic amide compound in combination with 4,4,5,5-tetramethyl-1,3,2-diaxopentane and a base through a halogen substitution reaction, the problem of the high toxicity limitation of diborane was solved, and a high-yield synthesis of nitrogen heterocyclic compounds was achieved, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SUZHOU EMMART BIOTECHNOLOGY CO LTD
- Filing Date
- 2023-09-21
- Publication Date
- 2026-05-29
AI Technical Summary
In the prior art, the high toxicity and hazards of diborane limit the industrial production of nitrogen heterocyclic compounds, and the yield of existing synthetic methods is low.
Using nitrogen-containing heterocyclic amides as starting materials, the reaction proceeds after halogen substitution with 4,4,5,5-tetramethyl-1,3,2-diaxopentaborane and a specific base. High-yield substituted nitrogen-containing heterocyclic compounds are obtained by avoiding the use of highly toxic substances and employing organic solvents such as diethyl ether or tetrahydrofuran, while controlling the reaction temperature and time.
A safe and efficient synthesis of nitrogen heterocyclic compounds was achieved, with a product yield of over 77%, making it suitable for industrial production.
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Figure CN117263839B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic compound synthesis technology, and specifically relates to a method for synthesizing substituted nitrogen heterocyclic compounds. Background Technology
[0002] Nitrogen-containing heterocycles with tiny structures are an ideal structural module and an important pharmaceutical precursor, widely used in the fields of synthesis and medicinal chemistry, such as in the synthesis of antitumor drugs.
[0003] Currently, one publicly disclosed method for synthesizing such compounds is the reduction of 2-azacyclobutane-2-carboxylate from diborane (B2H6) to 2-azacyclobutane methylamine (Synthesis and antitumor activities of platinum complexes of unsymmetrical alicyclic diamines as carrier ligands. Kazumi Morikawa. Journal of Pharmaceutical Sciences. 1990).
[0004]
[0005] However, diborane is highly toxic and is a colorless gas at room temperature. It can form explosive mixtures with air and spontaneously combusts in humid air, posing an extremely high risk and low safety profile, making it unsuitable for industrial production. Summary of the Invention
[0006] The technical problem to be solved by the present invention is to provide a safe and efficient method for synthesizing substituted nitrogen heterocyclic compounds, which has a high yield and is more suitable for industrial production, in order to address the shortcomings of the prior art.
[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0008] A method for synthesizing a substituted nitrogen heterocyclic compound as shown in formula (I) or formula (II),
[0009]
[0010] In formulas (I) and (II), R1 is a C1 to C6 alkyl group;
[0011] The synthesis method includes the following steps:
[0012] Step S1, make The compound represented by formula (III) was prepared by reacting with R1X. Or the compound represented by formula (IV) Where X is a halogen;
[0013] Step S2: React the compound shown in formula (III) and the compound shown in formula (IV) in the presence of 4,4,5,5-tetramethyl-1,3,2-diaxopentane and an organic solvent to obtain the substituted nitrogen heterocyclic compound shown in formula (I) or formula (II), wherein the base is one or a combination of sodium carbonate, sodium hydroxide, potassium carbonate, and potassium tert-butoxide.
[0014] In this invention, the substituted nitrogen heterocyclic compounds shown in formula (I) or formula (II) are three- or four-membered rings, which have greater ring strain and are more unstable than five- or six-membered rings. The inventors of this application attempted to use five- or six-membered ring reaction conditions: heating and stirring under reflux for several hours in the presence of lithium aluminum hydride and tetrahydrofuran, but the yield was extremely low.
[0015] According to some embodiments of the present invention, R1 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or isobutyl. Preferably, R1 is methyl, ethyl, propyl, or isopropyl.
[0016] According to some embodiments of the invention, X is F, Cl, Br or I.
[0017] According to some embodiments of the present invention, in step S2, the organic solvent is one or a combination of several of diethyl ether, tetrahydrofuran, methanol, and 1,4-dioxane.
[0018] Preferably, in step S2, the alkali is one or a combination of sodium carbonate and potassium carbonate, and the organic solvent is diethyl ether.
[0019] According to some embodiments of the present invention, in step S2, the reaction is carried out at 15–45°C for 6–10 h.
[0020] According to some embodiments of the present invention, in step S2, the molar ratio of the 4,4,5,5-tetramethyl-1,3,2-diaxopentane to the compounds shown in formula (III) and (IV) is 2 to 4:1; the molar ratio of the base to the compounds shown in formula (III) and (IV) is 0.8 to 1.2:1.
[0021] In some specific embodiments, in step S2, after the reaction is completed, water is added to the reaction solution, ethyl acetate is used for extraction, the organic phases are combined, washed with saturated saline solution, dried, and column chromatography is performed to obtain the substituted nitrogen heterocyclic compound shown in formula (I) or formula (II).
[0022] According to some embodiments of the present invention, in step S1, the reaction is carried out in the presence of a base and an organic solvent.
[0023] In some specific embodiments, in step S1, the alkali is one or a combination of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; the organic solvent is one or a combination of acetonitrile, acetone, and N,N-dimethylformamide; the reaction temperature is 40–60°C; and the reaction time is 6–10 h.
[0024] In some specific embodiments, in step S1, after the reaction is completed, the organic solvent in the reaction solution is evaporated, water is added, and then the solution is extracted with ethyl acetate and recrystallized to obtain the compound shown in formula (III) or the compound shown in formula (IV).
[0025] Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art:
[0026] The synthesis method of this invention uses nitrogen-containing heterocyclic amide compounds as starting materials. First, a substitution reaction is carried out on the nitrogen-containing heterocycle. Then, under the action of a specific reducing agent 4,4,5,5-tetramethyl-1,3,2-diaxopentaborane and in combination with a specific base, the substituted nitrogen-containing heterocyclic compounds are obtained in the presence of an organic solvent. The reaction does not require the use of highly toxic substances, has high safety, and the product yield is as high as 77% or more, making it more suitable for industrial production. Attached Figure Description
[0027] Figure 1 The NMR spectrum of (1-methylazacyclobutane-3-yl)methylamine from Example 1;
[0028] Figure 2 The NMR spectrum of (1-ethylazacyclobutane-3-yl)methylamine in Example 2 is shown. Detailed Implementation
[0029] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.
[0030] The raw materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.
[0031] The structure of the compound was determined by nuclear magnetic resonance (¹H-NMR). NMR determination was performed using an ACF-400BRUKER NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated dimethyl sulfoxide (DMSO-D₆), or heavy water (D₂O), with TMS as an internal standard. Column chromatography was performed using 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).
[0032] Example 1
[0033] This embodiment provides the synthesis of (1-methylazacyclobutane-3-yl)methylamine.
[0034]
[0035] The synthesis steps include:
[0036] In a 50 mL flask, 2 g (20 mmol) of aziridine-3-carboxamide, 4.8 g (34 mmol) of iodomethane, 4.1 g (30 mmol) of potassium carbonate, and 20 mL of acetonitrile were added, and the mixture was stirred at 50 °C for 8 h. After the reaction was complete, the acetonitrile was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate and recrystallized to give 2.2 g of 1-methylaziridine-3-carboxamide, with a yield of 97%.
[0037] In a 25 mL flask, 1-methylazacyclobutane-3-carboxamide (1.1 g, 10 mmol), 4,4,5,5-tetramethyl-1,3,2-diaxopentaborane (HBpin) (3.8 g, 30 mmol), sodium carbonate (1.06 g, 10 mmol), and 15 mL of diethyl ether were added, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, the mixture was poured into pure water, extracted multiple times with ethyl acetate, and the organic phases were combined, washed once with saturated saline solution, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.03 g of (1-methylazacyclobutane-3-yl)methylamine, with a yield of 96.9%.
[0038] The NMR spectrum of the product in this example is as follows: Figure 1 As shown.
[0039] 1 H NMR(400MHz,D2O)δ3.10(dd,2H),3.02(dd,2H),2.77(dt,2H),2.29(s,3H),2.02(hept,1H).
[0040] Example 2
[0041] This embodiment provides the synthesis of (1-ethylazacyclobutane-3-yl)methylamine.
[0042]
[0043] The synthesis steps include:
[0044] In a 50 mL flask, 2 g (20 mmol) of aziridine-3-carboxamide, 5.3 g (34 mmol) of iodoethane, 4.1 g (30 mmol) of potassium carbonate, and 20 mL of acetonitrile were added, and the mixture was stirred at 50 °C for 8 h. After the reaction was complete, the acetonitrile was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate and recrystallized to give 2.47 g of 1-ethylaziridine-3-carboxamide, with a yield of 96.3%.
[0045] In a 25 mL flask, 1-ethylazacyclobutane-3-carboxamide (1.3 g, 10 mmol), 4,4,5,5-tetramethyl-1,3,2-diazepineborane (HBpin) (3.8 g, 30 mmol), sodium carbonate (10 mmol), and 15 mL of diethyl ether were added, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, the mixture was poured into pure water, extracted multiple times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1.11 g of (1-ethylazacyclobutane-3-yl)methylamine, with a yield of 97.1%.
[0046] The NMR spectrum of the product in this example is as follows: Figure 2 As shown.
[0047] 1 H NMR(400MHz,D2O)δ2.98(m,4H),2.77(dt,2H),2.64(q,2H),1.99(t,1H),1.06(t,3H).
[0048] Example 3
[0049] This embodiment provides the synthesis of (1-methylaziridin-2-yl)methylamine.
[0050]
[0051] In this example, aziridin-2-carboxamide (20 mmol) was used instead of aziridine-3-carboxamide, otherwise the same as in Example 1. The final product was (1-methylaziridin-2-yl)methylamine. Overall yield: 92.3%.
[0052] The NMR data are as follows:
[0053] 1 H NMR (400MHz, D2O) δ2.90 (m, 4H), 2.23 (d, 3H), 1.66 (td, 1H).
[0054] Example 4
[0055] This embodiment provides the synthesis of (1-methylazacyclobutane-2-yl)methylamine.
[0056]
[0057] In this example, aziridine-2-carboxamide (20 mmol) was used instead of aziridine-3-carboxamide, otherwise the same as in Example 1. The final product was (1-methylaziridine-2-yl)methylamine. Overall yield: 94.0%.
[0058] The NMR data are as follows:
[0059] 1 H NMR (400MHz, D2O) δ3.04(m,2H),2.89(d,3H),2.30(d,3H),1.87(d,2H).
[0060] Example 5
[0061] This embodiment provides the synthesis of (1-ethylazacyclobutane-2-yl)methylamine.
[0062]
[0063] In this example, aziridine-2-carboxamide (20 mmol) was used instead of aziridine-3-carboxamide, otherwise the same as in Example 2. The final product was (1-ethylaziridine-2-yl)methylamine. Overall yield: 93.9%.
[0064] The NMR data are as follows:
[0065] 1 H NMR(400MHz,D2O)δ3.03(m,1H),2.92(m,4H),2.60(m,2H),1.85(m,2H),1.08(t,3H).
[0066] Example 6
[0067] This embodiment provides the synthesis of (1-ethylaziridin-2-yl)methylamine.
[0068]
[0069] In this example, aziridine-2-carboxamide (20 mmol) was used instead of aziridine-3-carboxamide, otherwise the same as in Example 2. The final product was (1-ethylaziridin-2-yl)methylamine. Overall yield: 92.6%.
[0070] The NMR data are as follows:
[0071] 1H NMR (400MHz, D2O) δ3.34(p,1H),3.06(dd,1H),3.00(dd,1H),2.88(m,2H),2.59(m,1H),2.53(m,1H),1.11(t,3H).
[0072] Example 7
[0073] This example provides the synthesis of (1-methylazacyclobutane-3-yl)methylamine, which is basically the same as in Example 1, except that potassium tert-butoxide is used instead of sodium carbonate in the second step of the reaction, specifically:
[0074] In a 25 mL flask, 1-methylazacyclobutane-3-carboxamide (1.1 g, 10 mmol), 4,4,5,5-tetramethyl-1,3,2-diazepineborane (HBpin) (3.8 g, 30 mmol), potassium tert-butoxide (10 mmol), and 15 mL of diethyl ether were added, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, the mixture was poured into pure water, extracted multiple times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.91 g of (1-methylazacyclobutane-3-yl)methylamine, with a yield of 86.0%.
[0075] Example 8
[0076] This example provides the synthesis of (1-methylazacyclobutane-3-yl)methylamine, which is basically the same as in Example 1, except that tetrahydrofuran is used instead of diethyl ether in the second step of the reaction, specifically:
[0077] In a 25 mL flask, 1-methylazacyclobutane-3-carboxamide (1.1 g, 10 mmol), 4,4,5,5-tetramethyl-1,3,2-diaxopentaborane (HBpin) (3.8 g, 30 mmol), sodium carbonate (10 mmol), and 15 mL of tetrahydrofuran were added, and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, the mixture was poured into pure water, extracted multiple times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.85 g of (1-methylazacyclobutane-3-yl)methylamine, with a yield of 80.1%.
[0078] Comparative Example 1
[0079]
[0080] This example provides the synthesis of (1-methylazacyclobutane-3-yl)methylamine, which is basically the same as in Example 1, except that the reaction conditions for the second step are different, specifically:
[0081] In a 25 mL flask, 1.1 g (10 mmol) of 1-methylazacyclobutane-3-carboxamide, 0.76 g (20 mmol) of lithium aluminum hydride (LAH), and 15 mL of tetrahydrofuran were added, and the mixture was stirred under reflux for 12 hours. After the reaction was completed and cooled, excess LAH was decomposed by stepwise addition of H₂O, 1N NaOH, H₂O, and Na₂SO₄ (v / v / v / v = 1:1:3:12.5, based on 1 g LAH). After stirring for 10 minutes, the solid was filtered and washed with EtOAc. The solvent was removed by rotary evaporation, dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.28 g of (1-methylazacyclobutane-3-yl)methylamine, in 26.0% yield.
[0082] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.
[0083] The endpoints and any values of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
Claims
1. A method for synthesizing a substituted nitrogen heterocyclic compound represented by formula (I) or formula (II), ； In formulas (I) and (II), R1 is a C1 to C6 alkyl group; Its features are, The synthesis method includes the following steps: Step S1, make The compound represented by formula (III) was prepared by reacting with R1X. Or the compound represented by formula (IV) Where X is a halogen; Step S2: The compound shown in formula (III) or formula (IV) is reacted in the presence of 4,4,5,5-tetramethyl-1,3,2-dihexaoxoborane and a base and an organic solvent to prepare the substituted nitrogen heterocyclic compound shown in formula (I) or formula (II), wherein the base is one or a combination of sodium carbonate, sodium hydroxide, potassium carbonate, and potassium tert-butoxide; the molar ratio of 4,4,5,5-tetramethyl-1,3,2-dihexaoxoborane to the compound shown in formula (III) or formula (IV) is 2 to 4:1; the molar ratio of the base to the compound shown in formula (III) or formula (IV) is 0.8 to 1.2:
1.
2. The synthesis method according to claim 1, characterized in that: R1 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or isobutyl; and / or X is F, Cl, Br, or I.
3. The synthesis method according to claim 1, characterized in that: In step S2, the organic solvent is one or a combination of several of the following: diethyl ether, tetrahydrofuran, methanol, and 1,4-dioxane.
4. The synthesis method according to claim 1, characterized in that: In step S2, the alkali is one or a combination of potassium carbonate and sodium carbonate, and the organic solvent is diethyl ether.
5. The synthesis method according to any one of claims 1 to 4, characterized in that: In step S2, the reaction is carried out at 15–45°C for 6–10 hours.
6. The synthesis method according to any one of claims 1 to 4, characterized in that: In step S2, after the reaction is completed, water is added to the reaction solution, ethyl acetate is used for extraction, the organic phases are combined, washed with saturated saline solution, dried, and column chromatography is performed to obtain the substituted nitrogen heterocyclic compound shown in formula (I) or formula (II).
7. The synthesis method according to claim 1, characterized in that: In step S1, the reaction is carried out in the presence of a base and an organic solvent.
8. The synthesis method according to claim 7, characterized in that: In step S1, the alkali is one or a combination of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; the organic solvent is one or a combination of acetonitrile, acetone, and N,N-dimethylformamide; the reaction temperature is 40–60°C; and the reaction time is 6–10 h.
9. The synthesis method according to claim 7, characterized in that: In step S1, after the reaction is completed, the organic solvent in the reaction solution is evaporated, water is added, and then the solution is extracted with ethyl acetate and recrystallized to obtain the compound shown in formula (III) or the compound shown in formula (IV).