Preparation method of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid

Abstract

The invention discloses a preparation method of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid, and relates to the technical field of compound synthesis. Comprising the following steps: salifying 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid ester and oxalic acid, purifying the obtained 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid ester oxalate in a crystallization mode, and then hydrolyzing to obtain the 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA). According to the purification method disclosed by the invention, the total yield in two steps is greater than 93%, the HPLC purity is greater than 99.9%, any single impurity is less than 0.05%, and the purification method has important significance on quality research and industrial production of various contrast agents.

Description

Technical Field

[0001] The present invention relates to the technical field of composite material preparation, and particularly relates to a preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Background Art

[0002] 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is a key intermediate and auxiliary material for a variety of contrast agents. Since contrast agents have the characteristic of a large daily dose, the requirement for impurity content is extremely high. Therefore, there are relatively high requirements for the impurities and purity of DOTA. At present, the literature CN108264491 reports that most of the synthesis of DOTA is the reaction of 1,4,7,10-tetraazacyclododecane with chloroacetic acid or sodium chloroacetate to obtain 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Although this route has short steps, the polarity of the compounds in each step is large, purification is difficult, impurity control is difficult, and it has a great impact on the quality of the finished contrast agent; the literature CN104955822 uses resin adsorption or nanofiltration to remove salts and impurities, and the purification yield is only 75-85%, resulting in large material losses and poor economic benefits.

[0003] At the same time, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate obtained by the reaction of 1,4,7,10-tetraazacyclododecane with bromoacetate (including esters with less than 5 carbons and benzyl esters) in the prior art is itself an oil or a solid with poor properties. It is difficult to directly purify with poor effects, and the quality of DOTA obtained by hydrolysis is also poor. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate is salified with oxalic acid, and the obtained 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate is purified by crystallization, and then hydrolyzed to obtain 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The total yield of the two steps is >93%, the HPLC purity is >99.9%, and any single impurity is <0.05%. It is of great significance for the quality research and industrial production of a variety of contrast agents.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is:

[0006] A preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, including the following:

[0007] (1) Reacting compound II with oxalic acid in a solvent to generate compound III;

[0008] (2) Hydrolyze compound Ⅲ in an alkaline solution, and after acidifying the reaction solution, compound DOTA is obtained.

[0009] The reaction general formula is as follows:

[0010]

[0011] Among them, R is selected from substituted or unsubstituted benzyl or C1-C 10 alkyl, and the value of n is 1-4.

[0012] Furthermore, the said R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or benzyl.

[0013] The inventor salts 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and purifies it by salting crystallization. During the R & D process, the inventor found that 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate itself has an ester structure and is unstable under strong acid and strong base conditions. The acidity of the acid radical is too strong, and the obtained solid is prone to residual beater hydrolysis by-products. Although the literature CN110835326 reports that the trisubstituted cyclen is relatively easy to form salts with multiple acid radicals to obtain a salt-type product with good properties and easy to purify, it is extremely difficult to obtain a salt-type with good properties and easy to separate and purify for the tetrasubstituted product. The inventor compared multiple organic acids or inorganic acids, such as: hydrochloric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, citric acid, fumaric acid, malic acid, salicylic acid, benzoic acid, etc., and none of them could obtain a solid with high purity or good properties. However, unexpectedly, oxalic acid was used to obtain 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, which can effectively control the impurities generated by the reaction of 1,4,7,10-tetraazacyclododecane with bromoacetate. The purity can reach more than 99%, and the purity of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid obtained by hydrolysis can also reach more than 99%; the total yield of the two steps > 93%.

[0014] After 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate forms a salt with oxalic acid, it can obtain crystals with good solid properties and can effectively remove the impurities in 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, especially polysubstituted impurities and incompletely substituted impurities (formulas IV, V, VI, VII, VIII are shown as follows) and excessive bromoacetate.

[0015]

[0016] Then, when preparing DOTA by hydrolysis, large polar impurities with similar structures such as polysubstitution and incomplete substitution in DOTA (Formula IX, Formula X, Formula XI, Formula XII, Formula XIII are shown as follows) can be successfully avoided, and DOTA with high yield and high purity can be obtained.

[0017]

[0018] Further, in step (1), the molar ratio of compound II to oxalic acid is 1:1.0 - 6.0.

[0019] Further, the molar ratio of compound II to oxalic acid is 1:3 - 5, preferably 1:4.4.

[0020] Further, in step (1), the solvent is selected from ethyl acetate, dichloromethane, methanol, isopropanol, ethanol, acetone or a mixed solution of two or more thereof;

[0021] Further, the solvent is acetone.

[0022] Further, in step (1), the reaction temperature is 0 - 60 °C; further, the reaction temperature is 20 - 30 °C.

[0023] Further, in step (2), the alkali solution is a mixed solution of ethanol, water and an alkali;

[0024] Further, the ethanol is absolute ethanol and the alkali is sodium hydroxide.

[0025] Further, in step (2), the mass ratio of compound III, absolute ethanol and water is 1:1 - 10:1 - 5;

[0026] Further, the mass ratio of compound III, absolute ethanol and water is 1:7.9:1.

[0027] Further, in step (2), the molar ratio of compound III to sodium hydroxide is 1:10 - 18;

[0028] Further, the molar ratio of compound III to sodium hydroxide is 1:14.

[0029] Further, in step (2), the acid is hydrochloric acid, and the pH value of the reaction solution after acidification is 2 - 4.

[0030] The present invention also provides a compound shown in Formula III

[0031]

[0032] Among them, R is selected from substituted or unsubstituted benzyl or C1 - C 10 alkyl, and the value of n is 1 - 4.

[0033] Further, R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or benzyl.

[0034] n can be selected from integers of 1-4, such as 1, 2, 3 or 4, or can be decimals of 1-4, such as 1.5, 2.5, 3.5, 2.8, etc. Preferably, n is 3-4.

[0035] The present invention uses 1,4,7,10-tetraazacyclododecane (cyclen) as a raw material, and prepares compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (compound II) with reference to the document "Gd3+cFLFLFK conjugate for MRI: a targeted contrast agent for FPR1 in inflammation. Chem. Commun, 2013, 49, 564-566.".

[0036] The beneficial effects of the present invention are as follows:

[0037] 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate is salted with oxalic acid, purified by crystallization, and then hydrolyzed to obtain 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The total yield of the two steps is >93%, the HPLC purity is >99.9%, and any single impurity is <0.05%. It is of great significance for the quality research and industrial production of various contrast agents. Specific embodiments

[0038] The technical solutions of the present invention are described clearly and completely below. Obviously, the embodiments described herein are only a part of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0039] Example 1

[0040] Preparation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (compound II):

[0041] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate to a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 78.1 g (510.83 mmol) of methyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain an oily substance, methyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 461.2610 (M+H) + 。

[0042] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate to a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 85.3 g (510.83 mmol) of ethyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain an oily substance, ethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 517.3236 (M+H) + 。

[0043] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate to a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 93.8 g (510.83 mmol) of propyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain an oily substance, propyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 573.3860 (M+H) + 。

[0044] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate to a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 93.8 g (510.83 mmol) of isopropyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain the oily substance isopropyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 573.3861 (M+H) + 。

[0045] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate to a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 99.6 g (510.83 mmol) of n-butyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain the oily substance n-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 629.4480 (M+H) + 。

[0046] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate to a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 99.6 g (510.83 mmol) of tert-butyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain the poorly shaped solid tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 629.4485 (M+H) + 。

[0047] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate into a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 99.6 g (510.83 mmol) of isobutyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain the oily product isobutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 629.4483 (M + H) + 。

[0048] Add 20 g (116.10 mmol) of 1,4,7,10-tetraazacyclododecane, 200 ml of chloroform, and 80.2 g (580.48 mmol) of potassium carbonate into a 500-ml reaction flask. Stir at 0 - 10 °C. Separately, slowly add 117.0 g (510.83 mmol) of benzyl bromoacetate dropwise to the reaction system. After completion, react at room temperature for 24 hours. Add 200 ml of water, separate the layers, take the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain the oily product benzyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate. ESI-MS: 765.3854 (M + H) + 。

[0049] (1) Preparation of 1,4,7,10-tetraazacyclododecane and -1,4,7,10-tetraacetate oxalate (Compound III):

[0050] Add 50 g (108.57 mmol) of methyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and 500 ml of acetone into a reaction flask. Stir and dissolve at 20 - 30 °C. Add 43.0 g (477.71 mmol) of oxalic acid, and continue to stir at room temperature for 2 hours. Filter and dry to obtain methyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 97.4%, HPLC purity: 99.97%, and individual impurities < 0.05%.

[0051] 1 H NMR (5400 MHz, DMSO-d6) δ 3.66 (s, 12H), 3.54 (s, 12H), 3.16 (s, 8H), 2.75 (s, 8H), 2.66 (s, 8H).

[0052] Add 50 g (96.78 mmol) of ethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and 500 ml of acetone to a reaction flask. Stir and dissolve at 20 - 30 °C. Add 38.3 g (425.41 mmol) of oxalic acid, and continue to stir at room temperature for 2 hours. Filter and dry to obtain ethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 98.4%, HPLC purity: 99.98%, and individual impurities < 0.05%.

[0053] 1 H NMR (400 MHz, DMSO-d6) δ 4.16 (q, J = 11.8 Hz, 8H), 3.66 (s, 8H), 3.16 (s, 8H), 2.78–2.71 (m, 8H), 2.68–2.61 (m, 8H), 1.21 (t, J = 11.8 Hz, 12H).

[0054] Add 50 g (87.30 mmol) of propyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and 500 ml of acetone to a reaction flask. Stir and dissolve at 20 - 30 °C. Add 35.6 g (395.42 mmol) of oxalic acid, and continue to stir at room temperature for 2 hours. Filter and dry to obtain propyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 97.9%, HPLC purity: 99.96%, and individual impurities < 0.05%.

[0055] 1 H NMR (400 MHz, DMSO-d6) δ 4.13 (t, J = 9.2 Hz, 8H), 3.60 (s, 8H), 3.17 (s, 8H), 2.76 (s, 8H), 2.67 (dd, J = 6.4, 4.1 Hz, 8H), 1.73 (s, 8H), 1.01 (t, J = 13.4 Hz, 12H). Add 50 g (87.30 mmol) of isopropyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and 500 ml of acetone to a reaction flask. Stir and dissolve at 20 - 30 °C. Add 35.6 g (395.42 mmol) of oxalic acid, and continue to stir at room temperature for 2 hours. Filter and dry to obtain isopropyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 97.5%, HPLC purity: 99.97%, and individual impurities < 0.05%.

[0056] 11H NMR (400 MHz, DMSO-d6) δ 4.95 (hept, J = 11.2 Hz, 4H), 3.57 (s, 8H), 3.15 (s, 8H), 2.80–2.70 (m, 8H), 2.69–2.58 (m, 8H), 1.20 (s, 12H), 1.18 (s, 12H).

[0057] 50 g (79.51 mmol) of tetrabutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate was added to a reaction flask, and 500 ml of acetone was added. The mixture was stirred and dissolved at 20–30 °C. 31.5 g (349.88 mmol) of oxalic acid was added, and the mixture was continuously stirred at room temperature for 2 hours. Then it was filtered and dried to obtain tetrabutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 96.9%, HPLC purity: 99.96%, and individual impurities < 0.05%. 1 1H NMR (400 MHz, DMSO-d6) δ 4.19 - 4.07 (m, 8H), 3.55 (s, 8H), 3.16 (s, 8H), 2.80 - 2.70 (m, 8H), 2.70 - 2.58 (m, 8H), 1.63 - 1.32 (m, 16H), 0.90 (t, J = 13.0 Hz, 12H).

[0058] 50 g (79.51 mmol) of tetraisobutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate was added to a reaction flask, and 500 ml of acetone was added. The mixture was stirred and dissolved at 20–30 °C. 31.5 g (349.88 mmol) of oxalic acid was added, and the mixture was continuously stirred at room temperature for 2 hours. Then it was filtered and dried to obtain tetraisobutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 97.1%, HPLC purity: 99.95%, and individual impurities < 0.05%.

[0059] 1 1H NMR (400 MHz, DMSO-d6) δ 3.86 (d, J = 13.7 Hz, 8H), 3.61 (s, 8H), 3.16 (s, 8H), 2.98–2.42 (m, 16H), 2.10–1.84 (m, 4H), 0.95 (d, J = 12.7 Hz, 24H).

[0060] Add 50 g (79.51 mmol) of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and 500 ml of acetone to a reaction flask, stir and dissolve at 20 - 30 °C, add 31.5 g (349.88 mmol) of oxalic acid, continue to stir at room temperature for 2 hours, filter, and dry to obtain tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 97.8%, HPLC purity: 99.97%, and individual impurities < 0.05%.

[0061] 1 HNMR (deuterated DMSO): 1.44 (s, 36H), 3.00 (s, 16H), 3.69 (s, 8H).

[0062] Add 50 g (65.37 mmol) of benzyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate and 500 ml of acetone to a reaction flask, stir and dissolve at 20 - 30 °C, add 25.9 g (287.68 mmol) of oxalic acid, continue to stir at room temperature for 2 hours, filter, and dry to obtain benzyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, with a yield of 95.9%, HPLC purity: 99.96%, and individual impurities < 0.05%.

[0063] 1 H NMR (500 MHz, Chloroform) δ 7.32 (s, 20H), 5.20 (s, 8H), 3.15 (s, 8H), 2.76 (s, 8H), 2.65 (s, 8H).

[0064] (2) Preparation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) using 1,4,7,10-tetraazacyclododecane and -1,4,7,10-tetraacetate oxalate:

[0065] Add 20 g (24.37 mmol) of methyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 13.6 g (340.0 mmol) of sodium hydroxide to a reaction flask, heat under reflux for 14 h, filter while hot to obtain a filter cake, transfer it to a reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until pH = 2 - 4, heat to 60 - 70 °C until all the solid dissolves, cool to 0 - 10 °C and stir for 2 hours, filter, and dry to obtain DOTA, with a yield of 96.4%, HPLC purity: 99.98%, and individual impurities < 0.05%.

[0066] 1HNMR (400 MHz, D2O): δ: 3.61 (s, 8H), 3.12 (s, 16H), ESI-MS: 405.1981 (M+H -) + .

[0067] Add 20 g (22.81 mmol) of ethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 12.8 g (320.0 mmol) of sodium hydroxide to a reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solid dissolves, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 96.7%, HPLC purity: 99.97%, individual impurity < 0.05%.

[0068] Add 20 g (21.44 mmol) of propyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 12.0 g (300.0 mmol) of sodium hydroxide to a reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solid dissolves, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 96.3%, HPLC purity: 99.95%, individual impurity < 0.05%.

[0069] Add 20 g (21.44 mmol) of propyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 12.0 g (300.0 mmol) of sodium hydroxide to a reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solid dissolves, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 96.3%, HPLC purity: 99.96%, individual impurity < 0.05%.

[0070] Add 20 g (21.44 mmol) of isopropyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 12.0 g (300.0 mmol) of sodium hydroxide to the reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solids dissolve, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 96.3%, HPLC purity: 99.95%, individual impurity < 0.05%.

[0071] Add 20 g (20.22 mmol) of n-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 11.3 g (282.5 mmol) of sodium hydroxide to the reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solids dissolve, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 97.1%, HPLC purity: 99.93%, individual impurity < 0.05%.

[0072] Add 20 g (20.22 mmol) of isobutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 11.3 g (282.5 mmol) of sodium hydroxide to the reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solids dissolve, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 96.9%, HPLC purity: 99.95%, individual impurity < 0.05%.

[0073] Add 20 g (20.22 mmol) of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 11.3 g (282.5 mmol) of sodium hydroxide to the reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer it to the reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solids dissolve, cool to 0 - 10 °C and stir for 2 h, filter, and dry to obtain DOTA. Yield: 97.0%, HPLC purity: 99.96%, individual impurity < 0.05%.

[0074] Add 20 g (17.78 mmol) of benzyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate, 200 ml of absolute ethanol, 20 ml of water, and 10.0 g (250.0 mmol) of sodium hydroxide to a reaction flask. Heat under reflux for 14 h, filter while hot to obtain a filter cake. Transfer the filter cake to a reaction flask, add 100 ml of water, slowly add 6 mol / L hydrochloric acid until the pH is 2 - 4, heat to 60 - 70 °C until all the solids dissolve, cool to 0 - 10 °C and stir for 2 hours, filter, and dry to obtain DOTA. Yield: 97.0%, HPLC purity: 99.96%, individual impurity < 0.05%.

[0075] Comparative Example 1

[0076] Directly prepare 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) using the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate prepared in Example 1:

[0077] Add 50 g (108.57 mmol) of methyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, 500 ml of absolute ethanol, 50 ml of water, and 26.1 g (652.5 mmol) of sodium hydroxide to a 500 ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250 ml reaction flask, add 110 ml of water, stir until all the solids dissolve, slowly add hydrochloric acid until the pH is 2 - 4, filter, collect the solid, and dry to obtain 38.9 g of DOTA. Yield: 88.6%, HPLC purity: 97.91%, individual impurity > 0.20%, total impurity = 2.09%.

[0078] Add 50 g (96.78 mmol) of ethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate to a 500 ml reaction flask, add 500 ml of absolute ethanol, 50 ml of water, and 23.2 g (580.0 mmol) of sodium hydroxide. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250 ml reaction flask, add 110 ml of purified water, stir until all the solids dissolve, slowly add hydrochloric acid until the pH is 2 - 4, filter, collect the solid, and dry to obtain 30.2 g of DOTA. Yield: 89.7%, HPLC purity: 98.11%, individual impurity > 0.30%, total impurity = 1.89%.

[0079] Add 50 g (87.30 mmol) of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid propyl ester, 500 ml of absolute ethanol, 50 ml of water, and 21.0 g (525.0 mmol) of sodium hydroxide to a 500 ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250 ml reaction flask, add 110 ml of purified water, stir until all the solids are dissolved, slowly add hydrochloric acid until the pH is 2 - 4, filter, collect the solid, and dry to obtain 31.3 g of DOTA. Yield: 88.7%, HPLC purity: 98.21%, individual impurity > 0.20%, total impurities = 1.79%.

[0080] Add 50 g (87.30 mmol) of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid isopropyl ester, 500 ml of absolute ethanol, 50 ml of water, and 21.0 g (525.0 mmol) of sodium hydroxide to a 500 ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250 ml reaction flask, add 110 ml of water, stir until all the solids are dissolved, slowly add hydrochloric acid until the pH is 2 - 4, filter, collect the solid, and dry to obtain 31.0 g of DOTA. Yield: 87.8%, HPLC purity: 98.51%, individual impurity > 0.20%, total impurities = 1.49%.

[0081] Add 50 g (79.51 mmol) of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid butyl ester, 500 ml of absolute ethanol, 50 ml of water, and 19.1 g (477.5 mmol) of sodium hydroxide to a 500 ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250 ml reaction flask, add 110 ml of purified water, stir until all the solids are dissolved, slowly add hydrochloric acid until the pH is 2 - 4, filter, collect the solid, and dry to obtain 28.6 g of DOTA. Yield: 88.8%, HPLC purity: 98.31%, individual impurity > 0.20%, total impurities = 1.69%.

[0082] Add 50 g (79.51 mmol) of isobutyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, 500 ml of absolute ethanol, 50 ml of water, and 19.1 g (477.5 mmol) of sodium hydroxide to a 500-ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250-ml reaction flask, add 110 ml of water, stir until all the solids are dissolved, slowly add hydrochloric acid dropwise until the pH is 2 - 4, filter, collect the solid, and dry to obtain 28.7 g of DOTA. Yield: 89.1%, HPLC purity: 98.25%, individual impurity > 0.20%, total impurity = 1.75%.

[0083] Add 50 g (79.51 mmol) of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, 500 ml of absolute ethanol, 50 ml of water, and 19.1 g (477.5 mmol) of sodium hydroxide to a 500-ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250-ml reaction flask, add 110 ml of purified water, stir until all the solids are dissolved, slowly add hydrochloric acid dropwise until the pH is 2 - 4, filter, collect the solid, and dry to obtain 28.5 g of DOTA. Yield: 88.5%, HPLC purity: 98.55%, individual impurity > 0.20%, total impurity = 1.45%.

[0084] Add 50 g (65.37 mmol) of benzyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, 500 ml of absolute ethanol, 50 ml of water, and 15.7 g (392.5 mmol) of sodium hydroxide to a 500-ml reaction flask. Heat under reflux for 14 hours, cool to room temperature, and filter to obtain a filter cake. Transfer the filter cake to a 250-ml reaction flask, add 110 ml of purified water, stir until all the solids are dissolved, slowly add hydrochloric acid dropwise until the pH is 2 - 4, filter, collect the solid, and dry to obtain 22.9 g of DOTA. Yield: 86.7%, HPLC purity: 98.55%, individual impurity > 0.30%, total impurity = 1.45%.

[0085] Comparative Example 2

[0086] Refer to Patent CN108264491 to directly prepare 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) using 1,4,7,10-tetraazacyclododecane:

[0087] At 0-10 °C, add 1,4,7,10-tetraazacyclododecane (17.27 g, 100 mmol), lithium hydroxide monohydrate (36.92 g, 880 mmol), and water (80 ml) to a three-necked flask (1000 ml). Add a solution of bromoacetic acid (61.14 g, 440 mmol) in water (30 ml) at 5-15 °C. Heat to 20-30 °C and react for 24 h. TLC detection shows that there is no remaining raw material 1,4,7,10-tetraazacyclododecane. Add 36% hydrochloric acid (44.6 g, 440 mmol) to the system, add ethanol (600 ml), precipitate a solid, filter, and recrystallize and purify the obtained solid with an ethanol / water (volume ratio 3:1) system. Dry at 60 °C to obtain DOTA, with a yield of 84.5%, an HPLC purity of 98.79%, a single impurity > 0.4%, and a total impurity = 1.21%.

[0088] From the data analysis of Comparative Examples 1-2 and Example 1, it can be seen that directly hydrolyzing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate to obtain DOTA has a yield < 90%, an HPLC purity < 99%, and a single impurity > 1.45%; directly preparing DOTA from 1,4,7,10-tetraazacyclododecane has a yield < 85%, an HPLC purity < 99%, and a single impurity > 1.21%; while first obtaining 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate through the present invention and then hydrolyzing to obtain DOTA, the total yield of the two steps > 93%, the HPLC purity > 99.9%, and any single impurity < 0.05%.

[0089] In summary, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate of the present invention has the characteristics of good process impurity removal effect, high yield, high purity, and simple operation for the synthesis of DOTA.

[0090] Example 2

[0091] Salt formation of other organic acids or inorganic acids with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate:

[0092] Add 10 g (15.9 mmol) of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate to a reaction flask, add 100 ml of acetone, stir and dissolve at 20-30 °C, add 4.3-4.4 equivalents of acid, and continue to stir at room temperature for 2 h to observe the salt formation situation.

[0093] The salt formation situation of the system after adding different kinds of acids is shown in Table 1.

[0094] Table 1 Salt formation situation of the system after adding different kinds of acids

[0095]

[0096] Note: Post-treatment method for the precipitated solid: Filter the reaction solution to obtain the solid, and dry the solid;

[0097] Add 36% concentrated hydrochloric acid to obtain tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate hydrochloride, ESI-MS: 629.4483 (M+H) + , and the solid has poor properties;

[0098] Add 48% hydrobromic acid to obtain tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate hydrobromide, ESI-MS: 629.4480 (M+H) + , and the solid has poor properties.

[0099] As shown in Table 1, the inventors compared that hydrochloric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, citric acid, fumaric acid, malic acid, salicylic acid, benzoic acid, etc. could not obtain solids with high purity or good properties, while unexpectedly obtaining tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate oxalate by using oxalic acid, which can effectively control the impurities generated from the reaction of 1,4,7,10-tetraazacyclododecane and bromoacetate, and the purity can reach over 99.9%.

Claims

1. A method for preparing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, characterized in that, It includes the following: (1) Reacting compound II with oxalic acid in a solvent to form compound III; (2) Hydrolyzing compound III in an alkaline solution, and acidifying the reaction solution to obtain compound DOTA; The reaction general formula is as follows: Among them, R is selected from substituted or unsubstituted benzyl or C1-C 10 alkyl group, and the value of n is 1-4.

2. The purification method according to claim 1, characterized in that, The R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or benzyl.

3. The purification method according to claim 1, wherein In step (1), the molar ratio of compound II to oxalic acid is 1:1.0 - 6.0; Further, the molar ratio of compound II to oxalic acid is 1:3 - 5.

4. The purification method according to claim 1, wherein In step (1), the solvent is selected from ethyl acetate, dichloromethane, methanol, isopropanol, ethanol, acetone or a mixed solution of two or more of them; Further, the solvent is acetone.

5. The purification method according to claim 1, wherein In step (1), the reaction temperature is 0 - 60 °C; further, the reaction temperature is 20 - 30 °C.

6. The purification method according to claim 1, wherein, In step (2), the alkaline solution is a mixed solution of ethanol, water and an alkali; Further, the ethanol is absolute ethanol and the alkali is sodium hydroxide.

7. A compound represented by formula III Among them, R is selected from substituted or unsubstituted benzyl or C1-C 10 alkyl, and n ranges from 1 to 4.

8. The compound according to claim 7, wherein R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or benzyl.

9. The compound according to claim 7, wherein n can be selected from 1, 1.5, 2, 2.5, 3, 3.5 or 4.

Images