Preparation method and purification method of mono-benzyl-substituted triazacyclononane and derivative of mono-benzyl-substituted triazacyclononane

Abstract

The invention provides a preparation method, a purification method and a derivative of monobenzyl-substituted triazacyclononane, and belongs to the field of organic synthesis. The invention provides a preparation method of mono-benzyl-substituted triazacyclononane, which comprises the following steps: in the presence of lithium hydroxide or hydrate thereof and a solvent, triazacyclononane reacts with benzyl halide to form a reaction solution, and post-treatment is performed to obtain the mono-benzyl-substituted triazacyclononane. Under the condition that other exposed amino groups are not protected, a benzyl group can be selectively formed on triazacyclononane, so that the production efficiency is greatly improved.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a preparation method, a purification method and a derivative of a monobenzyl-substituted triazacyclononane. Background Art

[0002] CN110944676A discloses a type of iron (III) contrast agent, which uses 1,4,7-triazacyclononane or its derivatives as macrocyclic ligands. 1-Benzyl-1,4,7-triazacyclononane is an important intermediate for synthesizing such macrocyclic ligands.

[0003] Exo-Diastereoisomer of 10-aryl-1,4,7-triazabicyclo[5.2.1]decane as intermediary in specific derivatisation of triazacyclononane (Tetrahedron, 68 (2012), 5637-5643) discloses a method for preparing 1-benzyl-1,4,7-triazacyclononane, and the synthesis route is as follows:

[0004]

[0005] That is, the two nitrogen atoms in 1,4,7-triazanonane are first protected, and then a benzyl group is added to the remaining nitrogen atom, and finally the protection is removed to obtain the target compound.

[0006] However, this route is slow, time-consuming, and requires more materials. In addition, due to the lack of technical solutions for further purifying the compound in the prior art, the final product is also doped with inorganic salts such as potassium bromide, resulting in a low content of the final product. Summary of the invention

[0007] The present invention is made to solve the above-mentioned problem, and aims to provide a method for preparing a monobenzyl-substituted triazacyclononane without protecting the excess amino group in advance, a method for purifying the monobenzyl-substituted triazacyclononane prepared by the above method, and a monobenzyl-substituted triazacyclononane derivative formed in the purification process.

[0008] The present invention provides a method for preparing a monobenzyl-substituted triazacyclononane, which has the following characteristics:

[0009]

[0010] In the above formula, BnX is a benzyl halide,

[0011] The steps include:

[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 post-treated to obtain compound 2.

[0013] The method for preparing the monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: wherein the solvent is a mixed solvent composed of ethanol and water in a volume ratio of (2-5):1.

[0014] In the preparation method of the monobenzyl-substituted triazacyclononane provided by the present invention, the method may also have the following characteristics: wherein the benzyl halide is benzyl bromide, and the molar ratio of the benzyl halide to the compound 1 is (0.8-1.2):1.

[0015] The method for preparing the monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: wherein the molar ratio of lithium hydroxide or its hydrate to compound 1 is (0.8-1.2):1.

[0016] In the preparation method of the monobenzyl-substituted triazacyclononane provided by the present invention, the following characteristics may also be present: wherein the post-treatment step comprises:

[0017] The ethanol in the reaction solution was removed, and dichloromethane and water were added for extraction. The organic phase was taken, washed with a sodium chloride aqueous solution, dried, filtered, and concentrated to obtain compound 2.

[0018] The method for preparing the monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: comprising the following steps:

[0019] Compound 1 is dissolved in ethanol, an aqueous solution of lithium hydroxide or its hydrate is added, stirred at 30-60°C for 0.2-1.0h, an ethanol solution of benzyl bromide is added, reacted at 70-90°C for 2-5h to obtain a reaction solution, ethanol in the reaction solution is removed, dichloromethane and water are added for extraction, the organic phase is taken, washed with an aqueous solution of sodium chloride, dried, filtered, and concentrated to obtain compound 2. Preferably, the concentration of the aqueous solution of lithium hydroxide or its hydrate is 40-50g / L, and the concentration of the ethanol solution of benzyl bromide is 160-180g / L.

[0020] The present invention also provides a method for purifying a monobenzyl-substituted triazacyclononane, which has the following characteristics and comprises the following steps:

[0021] In the presence of a base and a solvent, the crude compound 2 is reacted with Boc 2 O contact reaction, purification, to obtain compound 3;

[0022] Compound 3 is contacted with an acid for reaction and purified to obtain a pure product of compound 2 or its salt.

[0023] Among them, the structural formula of compound 3 is:

[0024]

[0025] The purification method of the monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: comprising the following steps:

[0026] In the presence of triethylamine and dichloromethane, the crude compound 2 was reacted with Boc 2 O contact reaction, purification, to obtain compound 3;

[0027] Compound 3 is contacted with hydrogen chloride solution for reaction and purified to obtain pure compound 2.

[0028] The purification method of the monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: comprising the following steps:

[0029] The crude compound 2 was dissolved in dichloromethane, and triethylamine and Boc 2 O, stir the reaction at 20-30°C for 2-4h, add dichloromethane and water for extraction, dry and concentrate to obtain compound 3;

[0030] Compound 3 was dissolved in ethyl acetate, and a solution of hydrogen chloride in ethyl acetate was added. The mixture was reacted at 20-30° C. for 1-5 h, and concentrated under reduced pressure. The alkaline ion exchange resin was freed to obtain a pure product of compound 2.

[0031] The purification method of the monobenzyl-substituted triazacyclononane provided by the present invention may also have the following characteristics: comprising the following steps:

[0032] The crude compound 2 was dissolved in dichloromethane, and triethylamine and Boc 2 O, stir the reaction at 20-30°C for 2-4h, add dichloromethane and water for extraction, dry, concentrate, and perform column chromatography to obtain compound 3;

[0033] Dissolve compound 3 in ethyl acetate, add a solution of hydrogen chloride in ethyl acetate, react at 20-30°C for 1-5h, concentrate under reduced pressure, and wash with ethyl acetate to obtain a pure product of compound 2 hydrochloride.

[0034] Preferably, the molar ratio of the crude compound 2 to triethylamine is 1:(2-5), and the molar ratio of the crude compound 2 to Boc 2 The molar ratio of O is 1:(2-5), and the molar volume ratio of the crude compound 2 to dichloromethane is 1 g:(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 characteristics:

[0037]

[0038] Functions and Effects of the Invention

[0039] According to the method for preparing the monobenzyl-substituted triazacyclononane involved in the present invention, since lithium hydroxide or its hydrate is used as a base, the present invention can selectively add a benzyl group to the triazacyclononane without protecting other exposed amino groups, thereby greatly improving the production efficiency.

[0040] According to the purification method of the monobenzyl-substituted triazacyclononane and a triazacyclononane derivative involved in the present invention, because Boc 2 O is further substituted on the monobenzyl-substituted triazacyclononane to obtain a triazacyclononane derivative, which is then purified and finally the Boc group is removed, thereby overcoming the shortcomings of the monobenzyl-substituted triazacyclononane that is difficult to separate by column chromatography due to its high polarity and difficult to separate inorganic salt impurities, and effectively improving the purity of the target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 is the hydrogen spectrum of compound 3 in Example 2 of the present invention;

[0042] Figure 2 is the HPLC spectrum of the pure product of free compound 2 in Example 2 of the present invention;

[0043] Figure 3 It is the hydrogen spectrum of the pure product of free compound 2 in Example 2 of the present invention. DETAILED DESCRIPTION

[0044] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below in conjunction with embodiments and drawings.

[0045] In the following examples, unless otherwise specified, all raw materials are commercially available products.

[0046] In the following examples, LiOH·H 2 O 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 a monobenzyl-substituted triazacyclononane, and the reaction formula is as follows:

[0050]

[0051] The steps include:

[0052] 20 g of compound 1 (154.8 mmol, 1.0 eq) was dissolved in 450 mL of ethanol and 6.49 g of LiOH·H was added. 2 O (154.8mmol, 1.0eq) in 150mL aqueous solution, heated to 50°C, stirred for 30min, and 26.5g BnBr (154.8mmol, 1.0eq) in 150mL ethanol solution was added dropwise. After the addition was complete, the temperature was raised to 80°C and refluxed for 3h to obtain a reaction solution. The ethanol in the reaction solution was removed by vacuum concentration, and 200mL of dichloromethane and 500mL of water were added for extraction. The organic phase was taken and washed once with 500mL of saturated sodium chloride aqueous solution. The organic phase was taken and dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 27.2g of crude compound 2, a light yellow liquid, with a crude yield of 80.1% and a HPLC purity of 90%.

[0053] <Comparative Example 1>

[0054] A method for preparing monobenzyl-substituted triazacyclononane

[0055] This comparative example provides a method for preparing a monobenzyl-substituted triazacyclononane, and the reaction formula is as follows:

[0056]

[0057] The steps include:

[0058] 20g of compound 1 (154.8mmol, 1.0eq) was dissolved in 450mL of ethanol, 21.4g of potassium carbonate (154.8mmol, 1.0eq) in 150mL of aqueous solution was added, the temperature was raised to 50°C, stirred for 30min, 26.5g of BnBr (154.8mmol, 1.0eq) in 150mL of ethanol solution was added dropwise, and after the addition was completed, the temperature was raised to 80°C and refluxed for 3h to obtain a reaction solution. The ethanol in the reaction solution was removed by vacuum concentration, 200mL of dichloromethane and 500mL of water were added for extraction, the organic phase was taken, and washed once with 500mL of saturated sodium chloride aqueous solution, the organic phase was taken, anhydrous sodium sulfate was added for drying, filtered, and concentrated to obtain 8.8g of a mixture of compound 2 and compound 2'. According to the HPLC spectrum, the ratio of compound 2 to compound 2' in the obtained mixture was 1:1.2.

[0059] <Example 2>

[0060] A method for purifying monobenzyl-substituted triazacyclononane

[0061] This embodiment provides a method for purifying a monobenzyl-substituted triazacyclononane, and the reaction formula is as follows:

[0062]

[0063] The steps include:

[0064] Step 1, 1.3 g of the crude compound 2 prepared in Example 1 (purity 90%, 5.33 mmol, 1.0 eq) was dissolved in 26 mL of dichloromethane, and 1.62 g of triethylamine (16.0 mmol, 3.0 eq) and 3.49 g of Boc 2 O (16.0 mmol, 3.0 eq), stirred at 25 ° C for 3 h to obtain a reaction solution. 20 mL of dichloromethane and 40 mL of water were added to the reaction solution for extraction, and the organic phase was taken and washed with 50 mL of saturated sodium chloride aqueous solution. The organic phase was taken and dried with sodium sulfate, filtered, and concentrated to obtain 1.93 g of intermediate compound 3;

[0065] The hydrogen spectrum of compound 3 is as follows Figure 1 shown.

[0066] Step 2, dissolve 1.93 g of the intermediate compound 3 in 20 mL of ethyl acetate, add 20 mL of 4 mol / L hydrogen chloride ethyl acetate solution, stir at 25 ° C for 3 h, filter the reaction solution, wash the solid with ethyl acetate, free it using an alkaline ion exchange resin, and dry it to obtain 1.2 g 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 spectrum of the free pure compound 2 obtained in this example is as follows: Figure 2 As shown, the hydrogen spectrum is Figure 3 shown.

[0068] Functions and Effects of the Embodiments

[0069] According to the preparation method of the monobenzyl-substituted triazacyclononane involved in the above embodiment, because lithium hydroxide monohydrate is used as a base, the technical solution provided in Example 1 can selectively add a benzyl group to the triazacyclononane without protecting other exposed amino groups, thereby greatly improving the production efficiency.

[0070] According to the purification method of the monobenzyl-substituted triazacyclononane and a triazacyclononane derivative involved in the above embodiment, because Boc 2The monobenzyl-substituted triazacyclononane is further substituted to obtain a triazacyclononane derivative, which is then purified and the Boc group is finally removed. Therefore, a free product with a purity of more than 96% can be obtained in a non-column chromatography manner without causing a significant loss in yield, thereby overcoming the disadvantages of the monobenzyl-substituted triazacyclononane being difficult to separate by column chromatography due to its high polarity and difficult to separate inorganic salt impurities.

[0071] The above-mentioned embodiments are preferred examples of the present invention and are not intended to limit the protection scope of the present invention.

Claims

1. A method for preparing a monobenzyl-substituted triazacyclononane, characterized in that: The reaction formula is as follows: In the above formula, BnX is a benzyl halide, The steps include: 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 post-treated to obtain compound 2.

2. The method for preparing a monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: in, The solvent is a mixed solvent composed of ethanol and water in a volume ratio of (2-5):

1.

3. The method for preparing a monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: in, The benzyl halide is benzyl bromide, and the molar ratio of the benzyl halide to the compound 1 is (0.8-1.2):

1.

4. The method for preparing a monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: in, The molar ratio of the lithium hydroxide or its hydrate to the compound 1 is (0.8-1.2):

1.

5. The method for preparing a monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: in, The post-processing steps include: The ethanol in the reaction solution was removed, and dichloromethane and water were added for extraction. The organic phase was taken, washed with a sodium chloride aqueous solution, dried, filtered, and concentrated to obtain compound 2.

6. The method for preparing a monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: The steps include: Dissolve compound 1 in ethanol, add an aqueous solution of lithium hydroxide or its hydrate, stir at 30-60°C for 0.2-1.0h, add an ethanol solution of benzyl bromide, react at 70-90°C for 2-5h to obtain a reaction solution, remove ethanol from the reaction solution, add dichloromethane and water for extraction, take the organic phase, wash with sodium chloride aqueous solution, dry, filter, and concentrate to obtain compound 2.

7. A method for purifying a monobenzyl-substituted triazacyclononane, characterized in that: The steps include: In the presence of a base and a solvent, the crude compound 2 is contacted with Boc2O for reaction, and purified to obtain compound 3; Compound 3 is contacted with an acid for reaction and purified to obtain pure compound 2. Wherein, the structural formula of the compound 3 is:

8. The method for purifying monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: The steps include: In the presence of triethylamine and dichloromethane, the crude compound 2 was contacted with Boc2O for reaction and purified to obtain compound 3; Compound 3 is contacted with hydrogen chloride solution for reaction and purified to obtain a pure product of compound 2 or its salt.

9. The method for purifying monobenzyl-substituted triazacyclononane according to claim 1, characterized in that: The steps include: 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, and dichloromethane and water were added for extraction, dried, and concentrated to obtain compound 3; Compound 3 was dissolved in ethyl acetate, and a solution of hydrogen chloride in ethyl acetate was added. The mixture was reacted at 20-30° C. for 1-5 h, and concentrated under reduced pressure. The alkaline ion exchange resin was freed to obtain pure compound 2.

10. A triazacyclononane derivative, characterized in that: The structural formula is as follows:

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