A method for preparing, purifying and derivatives of a monobenzyl substituted triazacyclononane
Monobenzyl-substituted triazacyclononanes were prepared by reacting lithium hydroxide with benzyl halide and then purified using Boc2O. This method solves the problems of long processing time and insufficient purification in existing technologies, and achieves efficient and high-purity preparation of triazacyclononanes.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI LINKCHEM TECHNOLOGY CO LTD
- Filing Date
- 2024-12-05
- Publication Date
- 2026-06-19
AI Technical Summary
The existing synthetic route for 1-benzyl-1,4,7-triazacyclononane is time-consuming, consumes a lot of materials, and the final product is doped with inorganic salts. The purification technology is insufficient, resulting in low product content.
Monobenzyl-substituted triazacyclononanes were prepared by reacting lithium hydroxide or its hydrate with benzyl halide in a specific solvent. Subsequently, Boc2O was used for substitution and purification to remove the protecting groups.
It improved production efficiency, enabled the preparation of high-purity monobenzyl-substituted triazacyclononane, overcame the difficulties of separating highly polar and inorganic salt impurities, and achieved a product purity of over 96%.
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Figure CN119735561B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing, purifying, and reproducing monobenzyl-substituted triazacyclononane. Background Technology
[0002] CN110944676A discloses a class of iron(III) contrast agents that use 1,4,7-triazacyclononane or its derivatives as macrocyclic ligands. 1-Benzyl-1,4,7-triazacyclononane is an important intermediate in the synthesis of this type of macrocyclic ligand.
[0003] The paper "Exo-Diastereoisomer of 10-aryl-1,4,7-triazabicyclo[5.2.1]decane asintermediary in specific derivatisation of triazacyclononane" (Tetrahedron, 68 (2012), 5637-5643) discloses a method for preparing 1-benzyl-1,4,7-triazacyclononane, the synthetic route of which is as follows:
[0004]
[0005] The process involves first protecting two nitrogen atoms in 1,4,7-triazanonane, then adding a benzyl group to the remaining nitrogen atom, and finally removing the protection to obtain the target compound.
[0006] However, this route is slow, time-consuming, and requires a large amount of materials. Furthermore, due to the lack of existing technologies for further purification of the compound, the final product is often contaminated with inorganic salts such as potassium bromide, resulting in a low purity. Summary of the Invention
[0007] This invention is made to solve the above-mentioned problems, and aims to provide a method for preparing monobenzyl-substituted triazacyclononane without prior protection of excess amino groups, a method for purifying the monobenzyl-substituted triazacyclononane prepared by the above method, and a monobenzyl-substituted triazacyclononane derivative formed during the purification process.
[0008] This invention provides a method for preparing a monobenzyl-substituted triazacyclononane, characterized by the following reaction formula:
[0009]
[0010] In the above formula, BnX represents benzyl halide.
[0011] Includes the following steps:
[0012] In the presence of lithium hydroxide or its hydrate and a solvent, compound 1 reacts with benzyl halide to form a reaction solution, which is then post-processed to obtain compound 2.
[0013] The method for preparing monobenzyl-substituted triazacyclononane provided by the present invention may also have the following feature: wherein the solvent is a mixed solvent composed of ethanol and water in a volume ratio of (2-5):1.
[0014] The method for preparing monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: wherein the benzyl halide is benzyl bromide, and the molar ratio of benzyl halide to compound 1 is (0.8-1.2):1.
[0015] The method for preparing monobenzyl-substituted triazacyclononane provided by the present invention may also have the following feature: wherein the molar ratio of lithium hydroxide or its hydrate to compound 1 is (0.8-1.2):1.
[0016] The method for preparing monobenzyl-substituted triazacyclononane provided by this invention may also have the following feature: the post-processing step includes:
[0017] Remove the ethanol from the reaction solution, add dichloromethane and water for extraction, take the organic phase, wash with sodium chloride aqueous solution, dry, filter, concentrate, and obtain compound 2.
[0018] The method for preparing monobenzyl-substituted triazacyclononane provided by this invention may also have the following features: including the following steps:
[0019] Compound 1 is dissolved in ethanol, and an aqueous solution of lithium hydroxide or its hydrate is added. The mixture is stirred at 30-60°C for 0.2-1.0 h, and an ethanol solution of benzyl bromide is added. The mixture is reacted at 70-90°C for 2-5 h to obtain a reaction solution. The ethanol in the reaction solution is removed, and the mixture is extracted with dichloromethane and water. The organic phase is collected, washed with an aqueous sodium chloride solution, dried, filtered, and concentrated to obtain compound 2. Preferably, the concentration of the aqueous solution of lithium hydroxide or its hydrate is 40-50 g / L, and the concentration of the ethanol solution of benzyl bromide is 160-180 g / L.
[0020] This invention also provides a method for purifying monobenzyl-substituted triazacyclononane, characterized by the following steps:
[0021] In the presence of alkali and solvent, the crude compound 2 was reacted with Boc2O and purified to obtain compound 3;
[0022] Compound 3 reacts with an acid, and after purification, compound 2 or its salt is obtained in pure form.
[0023] The structural formula of compound 3 is as follows:
[0024]
[0025] The purification method for monobenzyl-substituted triazacyclononane provided by this invention may also include the following steps:
[0026] In the presence of triethylamine and dichloromethane, the crude compound 2 was reacted with Boc2O and purified to obtain compound 3;
[0027] Compound 3 was reacted with hydrogen chloride solution and purified to obtain pure compound 2.
[0028] The purification method for monobenzyl-substituted triazacyclononane provided by this invention may also include the following steps:
[0029] The crude compound 2 was dissolved in dichloromethane, triethylamine and Boc2O were added, and the mixture was stirred at 20-30°C for 2-4 hours. Dichloromethane and water were added for extraction, and the mixture was dried and concentrated to obtain compound 3.
[0030] Compound 3 was dissolved in ethyl acetate, and an ethyl acetate solution of hydrogen chloride was added. The mixture was reacted at 20-30°C for 1-5 hours, concentrated under reduced pressure, and then released through an alkaline ion exchange resin to obtain pure compound 2.
[0031] The purification method for monobenzyl-substituted triazacyclononane provided by this invention may also include the following steps:
[0032] The crude compound 2 was dissolved in dichloromethane, triethylamine and Boc2O were added, and the mixture was stirred at 20-30℃ for 2-4 h. Dichloromethane and water were added for extraction, and the mixture was dried, concentrated, and subjected to column chromatography to obtain compound 3.
[0033] Compound 3 was dissolved in ethyl acetate, and an ethyl acetate solution of hydrogen chloride was added. The mixture was reacted at 20-30°C for 1-5 hours, concentrated under reduced pressure, and washed with ethyl acetate to obtain pure compound 2 hydrochloride.
[0034] Preferably, the molar ratio of crude compound 2 to triethylamine is 1:(2-5), the molar ratio of compound 2 to Boc2O is 1:(2-5), and the molar volume ratio of crude compound 2 to dichloromethane is 1g:(10-30)mL.
[0035] Preferably, the concentration of the ethyl acetate solution of hydrogen chloride is 2-5 mol / L.
[0036] The present invention also provides a triazacyclononane derivative having the following structural formula:
[0037]
[0038] The role and effect of invention
[0039] According to the method for preparing monobenzyl-substituted triazacyclononane of the present invention, since lithium hydroxide or its hydrate is used as a base, the present invention can selectively attach a benzyl group to triazacyclononane without protecting other exposed amino groups, thus greatly improving production efficiency.
[0040] The purification method for monobenzyl-substituted triazacyclononane and a triazacyclononane derivative of the present invention overcomes the disadvantages of monobenzyl-substituted triazacyclononane, which are difficult to separate by column chromatography due to its high polarity and difficulty in separating inorganic salt impurities, by first using Boc2O to further substitute the monobenzyl-substituted triazacyclononane to obtain a triazacyclononane derivative, and then purifying the triazacyclononane derivative and finally removing the Boc group. Attached Figure Description
[0041] Figure 1 This is the proton spectrum of compound 3 in Example 2 of the present invention;
[0042] Figure 2 This is the HPLC spectrum of the pure free compound 2 in Example 2 of the present invention;
[0043] Figure 3 This is the hydrogen spectrum of the pure free compound 2 in Example 2 of the present invention. Detailed Implementation
[0044] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.
[0045] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.
[0046] In the following examples, LiOH·H2O is lithium hydroxide monohydrate; BnBr is benzyl bromide.
[0047] <Example 1>
[0048] A method for preparing monobenzyl-substituted triazacyclononane
[0049] This embodiment provides a method for preparing monobenzyl-substituted triazacyclononane, the reaction formula of which is as follows:
[0050]
[0051] Includes the following steps:
[0052] 20 g of compound 1 (154.8 mmol, 1.0 eq) was dissolved in 450 mL of ethanol. 150 mL of an aqueous solution of 6.49 g LiOH·H₂O (154.8 mmol, 1.0 eq) was added. The mixture was heated to 50 °C and stirred for 30 min. 150 mL of an ethanol solution of 26.5 g BnBr (154.8 mmol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was refluxed at 80 °C for 3 h to obtain the reaction solution. The ethanol in the reaction solution was removed by vacuum concentration. Extraction was performed with 200 mL of dichloromethane and 500 mL of water. The organic phase was collected, washed once with 500 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 27.2 g of crude compound 2, a pale yellow liquid. The yield of the crude product was 80.1%, and the HPLC purity was 90%.
[0053] <Comparative Example 1>
[0054] A method for preparing monobenzyl-substituted triazacyclononane
[0055] This comparative example provides a method for preparing monobenzyl-substituted triazacyclononane, the reaction formula of which is as follows:
[0056]
[0057] Includes the following steps:
[0058] 20 g of compound 1 (154.8 mmol, 1.0 eq) was dissolved in 450 mL of ethanol. A 150 mL aqueous solution of 21.4 g potassium carbonate (154.8 mmol, 1.0 eq) was added. The mixture was heated to 50 °C and stirred for 30 min. A 150 mL ethanol solution of 26.5 g BnBr (154.8 mmol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was refluxed at 80 °C for 3 h to obtain the reaction solution. The ethanol in the reaction solution was removed by vacuum concentration. Extraction was performed with 200 mL of dichloromethane and 500 mL of water. The organic phase was collected and washed once with 500 mL of saturated sodium chloride aqueous solution. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of 8.8 g of compounds 2 and 2'. According to the HPLC chromatogram, the ratio of compound 2 to compound 2' in the obtained mixture was 1:1.2.
[0059] <Example 2>
[0060] A purification method for monobenzyl-substituted triazacyclononane
[0061] This embodiment provides a method for purifying monobenzyl-substituted triazacyclononane, the reaction formula of which is as follows:
[0062]
[0063] Includes the following steps:
[0064] Step 1: Dissolve 1.3g of crude compound 2 (90% purity, 5.33mmol, 1.0eq) obtained in Example 1 in 26mL of dichloromethane, add 1.62g of triethylamine (16.0mmol, 3.0eq) and 3.49g of Boc2O (16.0mmol, 3.0eq), and stir at 25°C for 3h to obtain a reaction solution. Add 20mL of dichloromethane and 40mL of water to the reaction solution for extraction, take the organic phase, wash with 50mL of saturated sodium chloride aqueous solution, take the organic phase, dry with sodium sulfate, filter, concentrate, and obtain 1.93g of intermediate compound 3;
[0065] The proton NMR spectrum of compound 3 is as follows: Figure 1 As shown.
[0066] Step 2: Dissolve 1.93g of intermediate compound 3 in 20mL of ethyl acetate, add 20mL of 4mol / L ethyl hydrochloride solution, stir at 25℃ for 3h, filter the reaction solution, wash the solid with ethyl acetate, liberate with basic ion exchange resin, dry, and obtain 1.2g of free pure compound 2, a yellow oily liquid with HPLC purity of 96.1% and a two-step yield of 98.2%.
[0067] The HPLC chromatogram of the free compound 2 obtained in this embodiment is shown below. Figure 2 As shown, the proton spectrum is as follows Figure 3 As shown.
[0068] The role and effect of the embodiments
[0069] According to the preparation method of monobenzyl-substituted triazacyclononane involved in the above embodiments, since lithium hydroxide monohydrate is used as the base, the technical solution provided in Example 1 can selectively attach a benzyl group to triazacyclononane without protecting other exposed amino groups, which greatly improves the production efficiency.
[0070] According to the purification method of monobenzyl-substituted triazacyclononane and a triazacyclononane derivative involved in the above embodiments, since the monobenzyl-substituted triazacyclononane is first further substituted with Boc2O to obtain a triazacyclononane derivative, and then the triazacyclononane derivative is purified and finally the Boc group is removed, it is possible to obtain a free product with a purity of over 96% without causing a significant loss in yield, overcoming the disadvantages of monobenzyl-substituted triazacyclononane being difficult to separate by column chromatography due to its high polarity and the difficulty in separating inorganic salt impurities.
[0071] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention.
Claims
1. A process for the preparation of a mono-benzyl substituted triazacyclononane, characterized in that, The reaction formula is as follows: In the above formula, BnX represents benzyl halide. Includes the following steps: In the presence of lithium hydroxide or its hydrate and a solvent, compound 1 reacts with benzyl halide to form a reaction solution, which, after post-treatment, yields compound 2. The solvent is a mixed solvent composed of ethanol and water in a volume ratio of (2-5):
1. The benzyl halide is benzyl bromide.
2. The method for preparing monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: wherein The molar ratio of the benzyl halide to compound 1 is (0.8-1.2):
1.
3. The method for preparing monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: wherein, The molar ratio of the lithium hydroxide or its hydrate to compound 1 is (0.8-1.2):
1.
4. The method for preparing monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: in, The post-processing steps include: Remove the ethanol from the reaction solution, add dichloromethane and water for extraction, take the organic phase, wash with sodium chloride aqueous solution, dry, filter, concentrate, and obtain compound 2.
5. The method for preparing monobenzyl-substituted triazacyclononane according to claim 1, characterized in that, Includes the following steps: Compound 1 was dissolved in ethanol, and an aqueous solution of lithium hydroxide or its hydrate was added. The mixture was stirred at 30-60°C for 0.2-1.0 h, and an ethanol solution of benzyl bromide was added. The mixture was reacted at 70-90°C for 2-5 h to obtain a reaction solution. The ethanol in the reaction solution was removed, and the mixture was extracted with dichloromethane and water. The organic phase was taken, washed with an aqueous solution of sodium chloride, dried, filtered, and concentrated to obtain compound 2.
6. The method for preparing monobenzyl-substituted triazacyclononane according to claim 1, characterized in that, The purification method includes the following steps: In the presence of alkali and solvent, the crude compound 2 was reacted with Boc2O and purified to obtain compound 3; Compound 3 reacts with an acid, and after purification, compound 2 is obtained in its pure form. The structural formula of compound 3 is as follows:
7. The method for preparing monobenzyl-substituted triazacyclononane according to claim 6, characterized in that, The purification method includes the following steps: In the presence of triethylamine and dichloromethane, the crude compound 2 was reacted with Boc2O and purified to obtain compound 3; Compound 3 was reacted with hydrogen chloride solution and purified to obtain pure compound 2 or its salt.
8. The method for preparing monobenzyl-substituted triazacyclononane according to claim 6, characterized in that, The purification method includes the following steps: The crude compound 2 was dissolved in dichloromethane, triethylamine and Boc2O were added, and the mixture was stirred at 20-30℃ for 2-4 hours. Dichloromethane and water were added for extraction, and the mixture was dried and concentrated to obtain compound 3. Compound 3 was dissolved in ethyl acetate, and an ethyl acetate solution of hydrogen chloride was added. The mixture was reacted at 20-30°C for 1-5 hours, concentrated under reduced pressure, and then released through an alkaline ion exchange resin to obtain pure compound 2.