WO2018120923A1 - 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法 - Google Patents

1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法 Download PDF

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WO2018120923A1
WO2018120923A1 PCT/CN2017/102056 CN2017102056W WO2018120923A1 WO 2018120923 A1 WO2018120923 A1 WO 2018120923A1 CN 2017102056 W CN2017102056 W CN 2017102056W WO 2018120923 A1 WO2018120923 A1 WO 2018120923A1
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water
acid
cyclen
added
mmol
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PCT/CN2017/102056
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English (en)
French (fr)
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孟周均
何一刚
魏彦君
邢艳平
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山东威智医药工业有限公司
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Priority to US16/473,242 priority Critical patent/US11214553B2/en
Priority to CA3048549A priority patent/CA3048549C/en
Priority to JP2019556400A priority patent/JP2020504175A/ja
Priority to KR1020197021751A priority patent/KR102265637B1/ko
Priority to EP17889406.9A priority patent/EP3564218B1/en
Priority to CN201780080570.8A priority patent/CN110198931B/zh
Priority to ES17889406T priority patent/ES2865297T3/es
Priority to MX2019007798A priority patent/MX2019007798A/es
Publication of WO2018120923A1 publication Critical patent/WO2018120923A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings

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  • the present invention relates to a process for the preparation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.
  • 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)
  • English name 1,4,7,10-tetraazacy-clododecane-1,4,7 , 10-tetraacetic acid its structure is shown in the following formula, is an important chemical intermediates and pharmaceutical intermediates.
  • Clarke and A. Martel Inorganica Chimica Acta, 190, pp 27-36 used cyclen and bromoacetic acid to react in the pH range of 11.2-11.3, then demineralized with ion exchange resin, concentrated the filtrate, and adjusted the pH with hydrochloric acid. After the value, it was purified by hot water recrystallization to obtain a product.
  • No. 5,922,862 discloses a crude purification of DOTA and cyclen derivatives by dissolving the crude product in water and purifying it with PVP ion exchange resin.
  • WO 2013076743 discloses that DOTA, diethyltriaminepentaacetic acid (DTPA), D03A-butrol, BOPTA are acid-adjusted to pH 0.75 to obtain the hydrochloride salt thereof, and the inorganic salt is purified by recrystallization, and the pH is adjusted by using A26OH ion exchange resin. The value is 1.5-3.0, and concentrated crystallization gives the corresponding product.
  • DTPA diethyltriaminepentaacetic acid
  • D03A-butrol D03A-butrol
  • BOPTA are acid-adjusted to pH 0.75 to obtain the hydrochloride salt thereof, and the inorganic salt is purified by recrystallization, and the pH is adjusted by using A26OH ion exchange resin.
  • the value is 1.5-3.0, and concentrated crystallization gives the corresponding product.
  • WO 2014114664 A1 discloses a process for the synthesis and purification of DOTA and its salts.
  • the synthesis of DOTA is carried out by using cyclen and an alkylating agent (bromoacetic acid, chloroacetic acid, iodoacetic acid) at a pH of >13.
  • an alkylating agent bromoacetic acid, chloroacetic acid, iodoacetic acid
  • the acid is adjusted to pH ⁇ 3, and the steps of heating and cooling are carried out.
  • the crude product was obtained, and the purification step was carried out by using different types of ion exchange resins to obtain high quality products, and the process monitoring and product analysis of DOTA were carried out by HPLC and IC methods.
  • WO 2015117911 A1 discloses a purification method for DOTA, which is synthesized by the techniques reported in the literature and then purified by nanofiltration to obtain the corresponding product.
  • the synthesis steps are basically similar, and the purification methods basically have three ways:
  • First, the purification step uses ion exchange resin, and the disadvantage is that the subsequent process The operation requires concentrated water removal, the required ionic resin needs pretreatment activation, and the energy consumption in the later concentration process is longer.
  • the technical problem to be solved by the present invention is to overcome the prior art preparation or presence of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • a preparation method suitable for large-scale industrial production of DOTA is provided, and the whole process does not need to be purified by ion exchange resin or cryogenic freezing, and the product yield and purity are high.
  • the present invention solves the above technical problems by the following technical solutions.
  • the invention provides a preparation method of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which comprises the following steps: in water, in binding acid The alkylation reaction of 1,4,7,10-tetraazacyclododecane (cyclen) with XCH 2 COOR; adjusting the pH to precipitate the crude DOTA; recrystallization;
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • the acid binding agent is an acid binding agent conventionally used in such an alkylation reaction in the art
  • the acid binding agent preferably used in the present invention is an alkali metal hydroxide, an alkaline earth metal hydroxide or a carbonate.
  • the alkali metal is preferably lithium, sodium, potassium, rubidium, cesium, or cesium
  • the alkaline earth metal is preferably strontium, magnesium, calcium, strontium, barium, or radium.
  • the acid binding agent is further preferably an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal phosphate, an alkali metal organic acid salt, an alkali metal alkoxide, and an organic amine.
  • an alkali metal hydroxide, an alkali metal carbonate, an alkali metal organic acid salt, and an organic amine are still more preferably one or more of an alkali metal hydroxide, an alkali metal carbonate, an alkali metal organic acid salt, and an organic amine.
  • the alkali metal hydroxide is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide and barium hydroxide;
  • the alkali metal carbonate is preferably lithium carbonate, One or more of sodium carbonate, potassium carbonate, cesium carbonate and cesium carbonate;
  • the alkali metal organic acid salt is preferably an alkali metal acetate, further preferably one of lithium acetate, sodium acetate and potassium acetate or A plurality of;
  • the organic amine is preferably triethylamine and/or diisopropylethylamine.
  • the acid binding agent is further preferably one or more selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium acetate; more preferably lithium hydroxide.
  • the hydrate of the acid binding agent when the hydrate of the acid binding agent is stably present, it may also participate in a reaction such as lithium hydroxide monohydrate in the form of its hydrate.
  • the amount of the acid binding agent is preferably such that the pH of the reaction system is 10-14 after the acid binding agent is added to the reaction system.
  • the molar ratio of the acid binding agent to the cyclen is 8.0:1 to 10.0:1; further preferably 8.4:1 to 9.2:1, such as 8.8:1.
  • the XCH 2 COOR is used as the alkylating agent for the alkylation reaction, wherein R is H, an alkali metal or a C 1 -C 6 alkyl group, and X is chlorine, bromine or iodine.
  • the alkali metal is preferably lithium, sodium or potassium
  • the C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkyl group, further preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group.
  • Base n-butyl, isobutyl or tert-butyl.
  • the XCH 2 COOR is further preferably one or more selected from the group consisting of chloroacetic acid, bromoacetic acid, iodoacetic acid, sodium chloroacetate, sodium bromoacetate and sodium iodoacetate, and more preferably bromoacetic acid.
  • the amount of the XCH 2 COOR used may be a conventional amount of such an alkylating agent in the art.
  • the molar ratio of the XCH 2 COOR to the cyclen is 4.0:1 to 5.0: 1, further preferably from 4.2:1 to 4.6:1, such as 4.4:1.
  • the XCH 2 COOR is preferably configured such that an aqueous solution thereof is further added to the above reaction system; further preferably, an aqueous solution having a molar concentration of 12.0-18.0 mol/L (for example, 14.7 mol/L) is added to the above reaction. system.
  • the water in the aqueous solution of XCH 2 COOR is preferably deionized water. That is, in a preferred embodiment of the invention, the XCH 2 COOR is preferably incorporated into the reaction in the form of an aqueous solution of XCH 2 COOR.
  • the alkylation reaction described in the present invention is carried out in water, and the present invention is preferably deionized water.
  • the amount of the water to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the molar concentration of the cyclen described in the present invention is preferably 0.5 to 1.5 mol/L, and more preferably 0.9 mol/L to 1.0 mol/L.
  • the molar concentration of the cyclen refers to the volume ratio of the amount of the cyclen substance in the cyclen aqueous solution.
  • the amount of water refers to the sum of the volume of water added separately and the volume of water in the XCH 2 COOR aqueous solution.
  • the reaction temperature of the alkylation reaction is conventionally employed in the art for carrying out such a reaction, and the present invention is preferably -10 ° C to 60 ° C, further preferably 5 to 50 ° C, still more preferably 20 to 30 ° C.
  • the progress of the alkylation reaction can be monitored by conventional detection methods in the art, such as thin layer chromatography (TLC), gas chromatography (GC), nuclear magnetic resonance spectroscopy (NMR) or high performance liquid chromatography (HPLC), etc.; the invention preferably employs TLC or HPLC.
  • TLC thin layer chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance spectroscopy
  • HPLC high performance liquid chromatography
  • the invention preferably employs TLC or HPLC.
  • TLC thin layer chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance spectroscopy
  • HPLC high performance liquid chromatography
  • the invention preferably employs TLC or HPLC.
  • TLC thin layer chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance spectroscopy
  • HPLC high performance liquid chromatography
  • the invention preferably employs TLC or HPLC.
  • TLC thin layer chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • reaction time of the alkylation reaction is preferably from 12 to 24 hours.
  • the order of addition of the reaction materials of the alkylation reaction can be conventionally used in such reactions in the art.
  • the cyclen, the acid binding agent, the water and the XCH 2 COOR are sequentially added to the reaction system, and it is further preferred to add the cyclen at 0-10 ° C, the An acid binding agent, said water; said XCH 2 COOR or an aqueous solution thereof is added at 5-15 ° C.
  • the operation of adjusting the pH value to precipitate the crude DOTA can be carried out by a conventional post-treatment method of the alkylation reaction in the art, without adjusting the type or amount of the pH adjuster used, and adjusting the pH.
  • the method or the pH monitoring method is specifically limited.
  • the pH adjustment method is to add a pH adjusting agent to the reaction system, and the pH monitoring method is preferably a pH meter.
  • the operation of adjusting the pH value to precipitate the crude DOTA is preferably the following method 1) or method 2):
  • the method 1) comprises the steps of: after the end of the alkylation reaction, adding an acidic pH adjuster, adjusting the pH of the reaction system to the crude DOTA acid salt, and then dissolving it in water, adding alkali
  • the pH adjuster adjusts the pH of the reaction system to the complete precipitation of DOTA.
  • the acidic pH adjusting agent may be an acidic pH adjusting agent conventional in the art, and the present invention is preferably one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid and sulfuric acid, further preferably hydrochloric acid. Further, an aqueous hydrochloric acid solution having a mass fraction of 36% is further preferred.
  • the acidic pH adjuster is used in an amount sufficient to reduce the pH of the reaction system to 1 or less, thereby converting the product of the alkylation reaction (completely deprotonated DOTA) to complete The protonated DOTA acid salt is completely precipitated from the reaction system.
  • the alkaline pH adjusting agent is a basic pH adjusting agent conventional in the art, and the present invention is preferably one or more of ammonia water, triethylamine and triisopropylamine, and further preferably triethylamine.
  • the alkaline pH adjusting agent is used in an amount sufficient to bring the pH of the reaction system to be near the isoelectric point of DOTA (preferably 2.0-4.0, more preferably 3.0-4.0 in the present invention), thereby The DOTA acid salt is again completely converted to free DOTA and completely precipitated from its aqueous solution.
  • Process 2 comprises the steps of: after the end of the alkylation reaction, adding an acidic pH adjuster, adjusting the pH of the reaction system to complete precipitation of the crude DOTA.
  • the acidic pH adjusting agent can be an acidic pH adjusting agent conventionally used in the field for adjusting the pH of the aqueous phase, and the present invention preferably is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid.
  • One or more of sulfuric acid and sulfuric acid are further preferably hydrochloric acid, and still more preferably an aqueous hydrochloric acid solution having a mass fraction of 36%.
  • the acidic pH adjusting agent is used in an amount sufficient to bring the pH of the reaction system to be near the isoelectric point of DOTA (preferably 2.0 to 4.0 in the present invention, further preferably 3.0 to 4.0), thereby allowing the alkylation.
  • the product of the reaction (completely deprotonated DOTA) is all converted to free DOTA and completely precipitated therefrom. It is further preferred in the present invention that the molar ratio of hydrogen proton to cyclen in the acidic pH adjuster is 4.4:1, or the molar concentration of hydrogen protons and the acid binding agent in the acidic pH adjuster The ratio is 1:2.
  • the crude DOTA obtained by the above-mentioned post-treatment can be collected by a conventional treatment method of such a reaction in the art.
  • an organic solvent to precipitate the crude DOTA, and it is further preferred that the organic solvent is methanol or ethanol.
  • the organic solvent is methanol or ethanol.
  • the amount of the organic solvent used may be a conventional amount of such a reaction in the art, and the ratio of the amount of the cyclicn substance to the volume of the organic solvent is preferably 1:6 mol/L.
  • the method 2) preferably comprises the steps of: adding an acidic pH adjuster and an organic solvent after the end of the alkylation reaction, adjusting the pH of the reaction system to a crude DOTA product. Completely precipitated.
  • the solvent for recrystallization is water or a mixed solvent of water and an organic solvent.
  • the organic solvent is a common organic solvent which is miscible with water in the art, and one or more of acetone, acetonitrile, methanol, ethanol, isopropanol, and tetrahydrofuran are preferred in the present invention, and further preferably Methanol and / or ethanol.
  • the recrystallized solvent is a mixed solvent of water and an organic solvent
  • the volume ratio of the water to the organic solvent may be a conventional ratio in the art, preferably 1:1 to 1:20, further preferably 1:2-1:15, still more preferably 1:3-1:10, most preferably 1:3-1:5.
  • the mass to volume ratio of the crude DOTA to the recrystallized solvent may be a conventional ratio of DOTA recrystallization in the art.
  • the amount is usually such that the solvent is heated under conditions (e.g., solvent reflux temperature), the crude DOTA is substantially completely dissolved or completely dissolved, and the resulting mixture is capable of precipitating DOTA after standing or stirring.
  • the operation of the recrystallization may be carried out by a conventional operation of recrystallization in the art, and the operating parameters including temperature, stirring speed and the like are not particularly limited.
  • the recrystallization temperature may be room temperature or a solvent reflux temperature.
  • the temperature, stirring speed, and the like in the recrystallization operation are such that the crude DOTA is substantially completely dissolved or completely dissolved in the solvent.
  • those skilled in the art are aware that it is possible to achieve a technical means equivalent to the effect of the recrystallization technique by using a beating or heating/cooling step.
  • the product obtained by recrystallization after the completion of the recrystallization, it is preferred to further dry the product obtained by recrystallization to remove the solvent having a low boiling point therein, and it is further preferred to carry out the drying at 60 °C.
  • the preparation method of the present invention can be further applied to a salt of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), or a hydrate thereof, or an industrial thereof
  • Downstream products such as citric acid, meglumine citrate, gadobutrol, etc. are prepared in series.
  • the reagents and starting materials used in the present invention are commercially available.
  • the invention can effectively reach the isoelectric point of DOTA by controlling the pH value, and compared with the prior art, the requirement of strong acid resistance of the reaction kettle can be avoided, and the service life of the equipment is prolonged;
  • the invention can remove the inorganic salt impurities in the product by designing the reaction parameters and the purification process parameters, and only requires simple crystallization purification, thereby obtaining a high quality DOTA product; compared with the prior art, No need to use the corresponding ion exchange resin and reduce the post-concentration water process while avoiding low temperature freezing, on the equipment Simplification of requirements and processes, facilitating the production of industrial scale-up, and effectively reducing production costs;
  • the present invention deeply studies the difference in solubility data of lithium salt, sodium salt and potassium salt in water and organic solvent, and selects lithium salt as an acid binding agent in a preferred scheme, thereby avoiding the tedious stage in the later purification process of the present invention. And can effectively control the limits of lithium ions;
  • the DOTA product obtained by some embodiments of the present invention has a high yield, a purity of more than 99.0%, a single impurity content of ⁇ 0.05%, a burning residue of ⁇ 0.10%, and conforms to the quality standard of the raw material drug of the product. .
  • Figure 1 is a HPLC purity spectrum of the product obtained in Example 2.
  • Figure 2 is a HPLC purity spectrum of the product obtained in Example 38.
  • Determination method of ignition residue Take porcelain crucible which is blazed for 30 minutes at 600 °C ⁇ 50 °C and cooled in a desiccator, accurately weigh (m 1 ); add 1.0 g for the test sample, accurately weigh (m 2 The sample was wetted with 1 mL of sulfuric acid and then slowly heated at the lowest possible temperature until the test article was completely charred and cooled. The residue was wetted with 1 mL of sulfuric acid and slowly heated until no white smoke formed. It is burned to a complete ash at 600 °C ⁇ 50 °C. Cool in a desiccator, accurately weigh (m 3 ), and calculate the percentage of residue. If the residue content exceeds the limit, continue to wet with sulfuric acid, heat, blaze, ignite time for 30 min, accurately weigh (m n ), until the difference between the two consecutive ignition residue is less than 0.5 mg.
  • m 1 represents the mass of porcelain crucible, the unit is g;
  • m 2 represents the mass of porcelain crucible containing the sample before ignition, and the unit is g;
  • m 3 represents the quality of porcelain crucible containing residue after burning constant weight , the unit is g.
  • hydrochloric acid means an aqueous solution of hydrochloric acid having a mass fraction of 36%, and the percentage refers to the percentage of the mass of hydrochloric acid to the total mass of the aqueous hydrochloric acid solution.
  • the operation of adjusting the pH to precipitate the crude DOTA may be as follows: 1) or 2):
  • the method 1) comprises the steps of: after the end of the alkylation reaction, adding an acidic pH adjuster, adjusting the pH of the reaction system to the crude DOTA acid salt, and then dissolving it in water, adding alkali a pH adjusting agent, wherein the pH of the reaction system is adjusted to completely precipitate the crude DOTA; the acidic pH adjusting agent is used in an amount sufficient to lower the pH of the reaction system to 1 or less, thereby allowing the alkyl group to be Product of the reaction (completely The protonated DOTA) is completely converted to a fully protonated DOTA acid salt and completely precipitated from the reaction system.
  • the alkaline pH adjusting agent is used in an amount sufficient to bring the pH of the reaction system to be near the isoelectric point of DOTA (preferably 2.0-4.0 in the present invention, further preferably 3.0-4.0), thereby allowing the DOTA acid salt Again, it is completely converted to free DOTA and completely precipitated from its aqueous solution.
  • Process 2 comprises the steps of: after the end of the alkylation reaction, adding an acidic pH adjuster and an organic solvent, and adjusting the pH of the reaction system to a complete precipitation of DOTA.
  • the acidic pH adjusting agent is used in an amount sufficient to bring the pH of the reaction system near the isoelectric point of DOTA (preferably 2.0-4.0, more preferably 3.0-4.0 in the present invention), thereby producing the product of the alkylation reaction. (completely deprotonated DOTA) is all converted to free DOTA.
  • the mass-to-volume ratio of the crude DOTA to the recrystallized solvent may be a conventional ratio of DOTA recrystallization in the art upon recrystallization.
  • the amount is usually such that the solvent is heated under conditions (e.g., solvent reflux temperature), the crude DOTA is substantially completely dissolved or completely dissolved, and the resulting mixture is capable of precipitating DOTA after standing or stirring.
  • the recrystallization temperature may be room temperature or a solvent reflux temperature. And if necessary, it can be stirred during the recrystallization process.
  • the temperature, stirring speed, and the like in the recrystallization operation are such that the crude DOTA is substantially completely dissolved or completely dissolved in the solvent.
  • the HPLC spectrum of the product is shown in Fig. 1.
  • the HPLC purity data in Fig. 1 is shown in Table 1, and the retention time is 9.447 min.
  • a cyclen (6.90 kg, 40.0 mol), lithium hydroxide monohydrate (14.78 kg, 352.0 mol), and water (23.0 kg) were added to a glass-lined reactor (200 L).
  • the reaction was heated to 20-30 ° C for 24 h, and TLC detected that the raw material cyclen had no residue.
  • a cyclen (69.0 kg, 400.0 mol), lithium hydroxide monohydrate (147.8 kg, 3523.8 mol), and water (230.0 kg) were added to a glass-lined reactor (2000 L).
  • a solution of bromoacetic acid (244.6 kg, 1760.0 mol) in water (100 kg) was added at 5-15 °C.
  • the reaction was heated to 20-30 ° C for 24 h, and TLC detected that the raw material cyclen had no residue.
  • the obtained solid is further purified by concentrated hydrochloric acid (using about 30 mL) to obtain 40.05 g of crude DOTA hydrochloride.
  • HPLC The purity was 75%, the obtained crude product was dissolved in water (150 mL) in another 1 L four-necked flask, and the pH of the system was adjusted to 3.5-4.0 with triethylamine, stirred, acetone (300 mL) was added, filtered, and dried at 60 ° C to obtain DOTA.
  • a three-necked flask 1000 mL was charged with cyclen (17.27 g, 100 mmol), sodium hydroxide (35.20 g, 880 mmol), water (80 mL).
  • the reaction was heated to 20-30 ° C for 24 h, and TLC detected that the raw material cyclen had no residue.
  • the system was added with 36% hydrochloric acid to adjust the pH value of ⁇ 0.5, and the temperature was lowered to about 0 ° C to obtain a solid.
  • the obtained solid was further purified by concentrated hydrochloric acid (30 mL) to obtain 42.00 g of crude DOTA hydrochloride.
  • the HPLC purity was 75%.
  • the obtained crude product was dissolved in water (150 mL) in another 1 L four-necked flask, and the pH of the system was adjusted to 3.5-4.0 with ammonia water, stirred, acetone (300 mL) was added, filtered, and dried at 60 ° C to obtain DOTA.
  • a three-necked flask 1000 mL was charged with cyclen (17.27 g, 100 mmol), sodium hydroxide (35.20 g, 880 mmol), water (80 mL).
  • the reaction was heated to 20-30 ° C for 24 h, and TLC detected that the raw material cyclen had no residue.
  • the system was added with 36% hydrochloric acid to adjust the pH value of ⁇ 0.5, and the temperature was lowered to about 0 ° C to obtain a solid.
  • the obtained solid was further purified by concentrated hydrochloric acid (30 mL) to obtain 40.05 g of crude DOTA hydrochloride.
  • the HPLC purity was 75%.
  • the obtained crude product was dissolved in water (150 mL) in another 1 L four-necked flask, and the pH of the system was adjusted to 3.5-4.0 with triethylamine, stirred, added with ethanol (300 m L), filtered, and dried at 60 ° C to obtain DOTA.
  • the HPLC spectrum of the product is shown in Fig. 2, and the purity data is shown in Table 2 below, and the retention time is 9.580 min.
  • the obtained solid was purified by recrystallization from concentrated hydrochloric acid (120 mL) to obtain 119.6 g of crude crude DOTA hydrochloride.
  • the resulting crude product continues to be used in another four-neck bottle (1L). After the mL water was dissolved, the pH of the system was adjusted to 3 to 4 with triethylamine (about 50 mL), stirred, and 1 L of acetone was added, and dried by filtration to obtain DOTA.
  • the system was added with 36% hydrochloric acid to adjust the pH value of ⁇ 0.75, and the temperature was lowered to about 0 ° C to obtain a solid. After filtration, the obtained solid was continuously re-crystallized with water to the residue of ⁇ 0.10% in DOTA hydrochloride.
  • the obtained crude product was dissolved in water (80 mL) in another 500 L four-necked flask, and the pH of the system was adjusted to 2.5-3.0 with A26OH ion exchange resin, filtered, and the filtrate was concentrated to a volume of 20-30 mL, and acetone (180 mL) was added to precipitate a solid, and filtered. Dry at 60 ° C to obtain DOTA.
  • the system was added with 36% hydrochloric acid to adjust the pH value of ⁇ 0.75, and the temperature was lowered to about 0 ° C to obtain a solid. After filtration, the obtained solid was continuously re-crystallized with water to the residue of ⁇ 0.10% in DOTA hydrochloride.
  • the obtained crude product was dissolved in water (80 mL) in another 500 L four-necked flask, and the pH of the system was adjusted to 2.5-3.0 with ammonia water, filtered, and the filtrate was concentrated to a volume of 20-30 mL, and acetone (180 mL) was added to precipitate a solid, and filtered, 60 ° C Dry to obtain DOTA.

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Abstract

本发明公开了一种1,4,7,10-四氮杂环十二垸-1,4,7,10-四乙酸(DOTA)式(II)的制备方法。本发明的制备方法包括以下步骤：在水中，在缚酸剂的作用下，将(cyclen)式(I)与XCH2COOR进行垸基化反应；调节pH值以析出DOTA粗品；重结晶。本发明的制备方法适合于大规模工业化生产DOTA,整个过程无需采用离子交换树脂或低温冷冻方式进行纯化，产品的纯度和收率均较高。

Description

1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法
本申请要求申请日为2016年12月30日的中国专利申请CN201611262335.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法。
背景技术
1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)，英文名为1,4,7,10-tetraazacy-clododecane-1,4,7,10-tetraacetic acid，其结构如下式所示，是一种重要的化工中间体和医药中间体。
Figure PCTCN2017102056-appb-000001
1976年Stetter Hermann和Wolfram Frank第一次报道了关于DOTA的合成(Angewandte Chemie International Edition in English 15(11):686)，采用1,4,7,10-四氮杂环十二烷(cyclen)和氯乙酸在碱性介质中反应，然后通过Dowex-2×8的离子交换树脂进行纯化除去无机盐而获得合格产品。
1980年J.F.Desreux采用氢氧化钠作碱，反应温度为80℃，然后酸化调节pH值至2.5得到产品，并采用Dowex 50W-X4离子交换树脂纯化DOTA(Inorg.Chem.1980,19,pp.1319-1324.)。
1982年R.Delgado采用控制碱性介质pH值为10的条件来合成DOTA(Talanta,Vol.29,pp.815-822,Issue 10,1982)，后采用盐酸调节至pH值为2，冷冻得到产品，其中未涉及纯化步骤。
1991年Clarke和A.Martel(Inorganica Chimica Acta,190,pp 27-36)采用cyclen和溴乙酸在pH值为11.2-11.3范围内反应，然后采用离子交换树脂除盐后浓缩滤液，用盐酸调节pH值后采用热水重结晶纯化得到产品。
WO 9905128 A1中采用溴乙酸或者氯乙酸及其相应的酯在碱性条件下进行烷基化和 水解，所得产物经离子交换树脂进行纯化后可获得高质量的DOTA。
US 5922862公开了DOTA及cyclen衍生物的粗品纯化方式，即将粗品溶解于水中后用PVP离子交换树脂进行纯化。
WO 2013076743公开了DOTA、二乙基三胺五乙酸(DTPA)、D03A-butrol、BOPTA采用酸调节pH值至0.75得其盐酸盐，重结晶纯化除去无机盐，再采用A26OH离子交换树脂调节pH值至1.5-3.0，浓缩结晶得到相应产品。
WO 2014114664A1公开了DOTA及其盐的合成和纯化方法。其中，DOTA的合成采用cyclen和烷基化试剂(溴乙酸，氯乙酸，碘乙酸)在pH值>13的条件下进行反应，反应完全后以酸调节至pH值≤3，通过加热和降温步骤得到粗品，纯化步骤采用不同类型的离子交换树脂进行纯化得到高质量的产品，并对DOTA的过程监控和产品分析采用HPLC和IC方式进行检测。
WO 2015117911 A1公开了一种关于DOTA的纯化方式，采用文献报道的技术合成得到的粗品，然后经过纳米过滤技术(nanofiltration)纯化得到相应的产品。
通过对上述文献和专利进行分析总结，现有的关于DOTA合成和精制方法的技术中，合成步骤基本类似，而精制方法基本有三种方式：一是纯化步骤采用离子交换树脂，其缺点是后续过程中均需要浓缩除水的操作、所需离子树脂需要预处理活化、以及后期浓缩过程中耗能耗时均较长；二是以低温冷冻方式得到高质量的DOTA产品，对温度的要求比较高，不易操作；三是非通用技术纯化，如纳米过滤技术，一般企业较难实现该技术。
发明内容
本发明所要解决的技术问题是为了克服现有技术中的1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)制备过程中或存在预处理活化离子树脂、后期需要浓缩除水以及浓缩过程中耗能耗时较长的问题，或存在对温度的要求较高、不易操作的问题，或存在需要采用纳米过滤技术等非通用技术的问题等，而提供了一种适合大规模工业化生产DOTA的制备方法，整个过程无需采用离子交换树脂或低温冷冻方式进行纯化，且产品收率和纯度均较高。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)的制备方法，其包括以下步骤：在水中，在缚酸剂的作用下，将1,4,7,10-四氮杂环十二烷(cyclen)与XCH2COOR进行烷基化反应；调节pH值以析出DOTA粗品；重结晶；即可；
Figure PCTCN2017102056-appb-000002
其中，所述的缚酸剂为本领域进行此类烷基化反应常规所用的缚酸剂，本发明优选所述的缚酸剂为碱金属氢氧化物、碱土金属氢氧化物、碳酸盐、碳酸氢盐、磷酸盐、有机酸盐、醇盐和有机胺中的一种或多种。其中，所述的碱金属优选为锂、钠、钾、铷、铯、或钫；所述的碱土金属优选铍、镁、钙、锶、钡、或镭。
本发明中，所述的缚酸剂进一步优选为碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸盐、碱金属有机酸盐、碱金属醇盐和有机胺中的一种或多种，更进一步优选为碱金属氢氧化物、碱金属碳酸盐、碱金属有机酸盐和有机胺中的一种或多种。其中，所述的碱金属氢氧化物优选氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷和氢氧化铯中的一种或多种；所述的碱金属碳酸盐优选碳酸锂、碳酸钠、碳酸钾、碳酸铷和碳酸铯中的一种或多种；所述的碱金属有机酸盐优选碱金属醋酸盐，进一步优选为醋酸锂、醋酸钠和醋酸钾中的一种或多种；所述的有机胺优选三乙胺和/或二异丙基乙基胺。
本发明中，所述的缚酸剂进一步优选为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾和醋酸钠中的一种或多种；更进一步优选为氢氧化锂。
本发明中，当所述的缚酸剂的水合物可稳定存在，其还可以其水合物形式参与反应，如氢氧化锂一水合物。
本发明中，所述的缚酸剂的用量以当在反应体系中加入所述的缚酸剂后，反应体系pH值为10-14为宜。本发明优选所述的缚酸剂与所述的cyclen的摩尔比为8.0:1-10.0:1；进一步优选为8.4:1-9.2:1，如8.8:1。
本发明中，所述的XCH2COOR作为所述的烷基化反应的烷基化试剂，其中，R为H、碱金属或C1-C6烷基，X为氯、溴或碘。其中，所述的碱金属优选为锂、钠或钾；所述的C1-C6烷基优选为C1-C4烷基，进一步优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
本发明中，所述的XCH2COOR进一步优选为氯乙酸、溴乙酸、碘乙酸、氯乙酸钠、溴乙酸钠和碘乙酸钠中的一种或多种，更进一步优选为溴乙酸。
本发明中，所述的XCH2COOR的用量可采用本领域此类烷基化试剂的常规用量，本 发明优选所述的XCH2COOR与所述的cyclen的摩尔比为4.0:1-5.0:1，进一步优选为4.2:1-4.6:1，如4.4:1。
本发明中，所述的XCH2COOR优选配置成其水溶液再加入上述反应体系中；进一步优选配制成其摩尔浓度为12.0-18.0mol/L(如14.7mol/L)的水溶液加入上述反应体系。所述的XCH2COOR水溶液中的水优选使用去离子水。即在本发明一优选实施方案中，所述的XCH2COOR优选以XCH2COOR水溶液的形式参与到反应中。
本发明中所述的烷基化反应在水中进行，本发明优选为去离子水。
本发明中，所述的水的用量可不作具体限定，只要不影响反应进行即可。本发明优选所述的cyclen的摩尔浓度为0.5-1.5mol/L，进一步优选为0.9mol/L-1.0mol/L。所述的cyclen的摩尔浓度是指cyclen的物质的量在cyclen水溶液的体积比。
本发明中，如未作特别说明，当XCH2COOR以水溶液的形式参与到反应中时，水的用量是指单独加入的水的体积与XCH2COOR水溶液中水的体积之和。
本发明中，所述的烷基化反应的反应温度为本领域进行此类反应常规所用，本发明优选-10℃-60℃，进一步优选5-50℃，更进一步优选20-30℃。
本发明中，所述的烷基化反应的反应进程可采用本领域常规检测方式进行监测，如薄层色谱(TLC)、气相色谱(GC)、核磁共振波谱(NMR)或高效液相色谱(HPLC)等；本发明优选采用TLC或HPLC。当采用TLC作为检测手段时，优选以所述的cyclen消失时作为反应终点。当采用HPLC作为监测手段时，优选以反应体系中所述的cyclen不再参与反应或其浓度低于0.5％作为反应终点。此处的百分比是指cyclen的质量占反应结束后的反应混合液总质量的质量百分比。
本发明中，所述的烷基化反应的反应时间优选为12-24h。
本发明中，所述的烷基化反应的反应物料的加料顺序可为本领域中此类反应常规所用。本发明优选将所述的cyclen、所述的缚酸剂、所述的水和所述的XCH2COOR依次加入反应体系中，进一步优选在0-10℃下加入所述的cyclen、所述的缚酸剂、所述的水；在5-15℃下加入所述的XCH2COOR或其水溶液。
本发明中，所述的调节pH值以析出DOTA粗品的操作可采用本领域此类烷基化反应的常规后处理方式进行，并不对其所用的pH值调节剂的种类或用量、pH值调节方式、或pH值监测方式做特别限定。
其中，本发明优选所述的pH值调节方式为将pH值调节剂滴加至反应体系中，优选所述的pH值监测方式为采用pH计进行监测。
本发明中，所述的调节pH值以析出DOTA粗品的操作优选下列方法1)或方法2)：
方法1)包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂，将反应体系pH值调至DOTA酸式盐粗品完全析出；再将其溶于水中，加入碱性pH值调节剂，将所述的反应体系pH值调至DOTA粗品完全析出。
其中，所述的酸性pH值调节剂可为本领域常规的酸性pH调节剂，本发明优选为盐酸、氢溴酸、氢碘酸、硝酸和硫酸中的一种或多种，进一步优选为盐酸，更进一步优选为质量分数为36％的盐酸水溶液。本发明优选所述的酸性pH调节剂的用量为足以使所述的反应体系pH降低至1甚至0.5以下，从而使所述烷基化反应的产物(完全去质子化的DOTA)全部转化为完全质子化的DOTA酸式盐并从所述的反应体系中完全析出。
其中，所述的碱性pH调节剂可为本领域常规的碱性pH调节剂，本发明优选为氨水、三乙胺和三异丙胺中的一种或多种，进一步优选为三乙胺。本发明优选所述的碱性pH调节剂的用量为足以使所述的反应体系pH处于DOTA等电点附近(本发明优选为2.0-4.0，进一步优选为3.0-4.0)，从而使所述的DOTA酸式盐再次全部转化为游离态的DOTA并从其水溶液中完全析出。
方法2)包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂，将所述的反应体系pH值调至DOTA粗品完全析出。
方法2)中，所述的酸性pH值调节剂可为本领域中在进行水相pH值调节时常规所用的酸性pH值调节剂，本发明优选为盐酸、氢溴酸、氢碘酸、硝酸和硫酸中的一种或多种，进一步优选为盐酸，更进一步优选为质量分数为36％的盐酸水溶液。本发明优选所述的酸性pH值调节剂的用量为足以使反应体系pH值处于DOTA等电点附近(本发明优选为2.0-4.0，进一步优选为3.0-4.0)，从而使所述烷基化反应的产物(完全去质子化的DOTA)全部转化为游离态的DOTA并从中完全析出。本发明进一步优选所述的酸性pH值调节剂中的氢质子与cyclen的摩尔浓度比为4.4:1，或所述的酸性pH值调节剂中的氢质子与所述的缚酸剂的摩尔浓度比为1:2。
方法2)中，由上述后处理得到的DOTA粗品可采用本领域此类反应的常规处理方式进行收集，本发明优选加入有机溶剂以使DOTA粗品析出，进一步优选所述的有机溶剂为甲醇、乙醇、异丙醇、四氢呋喃、丙酮和乙腈中的一种或多种，更进一步优选为甲醇和/或乙醇。所述的有机溶剂的用量可为本领域此类反应的常规用量，本发明优选所述的cyclen的物质的量与所述的有机溶剂的体积之比为1:6mol/L。
在本发明一优选实施方案中，方法2)优选包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂和有机溶剂，将所述的反应体系pH值调至DOTA粗品完全析出。
本发明中，所述的重结晶的溶剂为水、或水与有机溶剂的混合溶剂。其中，所述的有机溶剂可为本领域中能与水互溶的常见的有机溶剂，本发明优选丙酮、乙腈、甲醇、乙醇、异丙醇、和四氢呋喃中的一种或多种，进一步优选为甲醇和/或乙醇。当所述的重结晶的溶剂为水与有机溶剂的混合溶剂时，所述的水和所述的有机溶剂的体积比可为本领域常规比例，优选1:1-1:20，进一步优选为1:2-1:15，更进一步优选为1:3-1:10，最优选为1:3-1:5。
本发明中，所述的DOTA粗品与所述的重结晶的溶剂的质量体积比可为本领域DOTA重结晶的常规比例。其用量通常为能够使溶剂在加热条件下(例如溶剂回流温度)，所述的DOTA粗品基本上完全溶解或完全溶解，且所得混合液在静置或搅拌后，能够析出DOTA。
本发明中，所述的重结晶的操作可采用本领域中重结晶的常规操作进行，包括温度、搅拌速度等操作参数都不做特别限定。例如重结晶温度可以为室温，也可以为溶剂回流温度。重结晶操作中的温度、搅拌速度等是为了使DOTA粗品在溶剂中基本上完全溶解或完全溶解。本发明中，所述的重结晶在进行工业化生产时，本领域技术人员均知晓其可采用打浆或加热/冷却步骤等能够实现等同于重结晶技术效果的技术手段。
本发明中，所述的重结晶在进行工业化生产时，本领域技术人员均知晓其还可进行多次操作以使产品纯度更高。
本发明中，在所述的重结晶结束后，优选还包括将重结晶所得产品进行干燥以去除其中低沸点溶剂，进一步优选在60℃进行干燥。
本发明的制备方法还可进一步应用于1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)的盐、或其水合物、或其工业下游产品如钆特酸、钆特酸葡甲胺、钆布醇等钆系列产品的制备中。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
1)本发明通过对pH值的控制可以有效的达到DOTA的等电点，与现有技术比较，可以避免需要反应釜耐强酸的要求，延长设备使用期限；
2)本发明通过对反应参数和纯化工艺参数的设计，并在其协同配合仅需简单的结晶纯化，即可除去产品中的无机盐杂质，得到高质量的DOTA产品；与现有技术比较，无需相应的离子交换树脂的使用和减少后期浓缩水工艺过程，同时避免低温冷冻，对设备 要求和工艺过程进行简化，便于实现工业放大的生产化，有效降低了生产成本；
3)本发明对锂盐、钠盐和钾盐在水中和有机溶剂中的溶解度数据的差异进行深入研究，优选方案中选择锂盐作为缚酸剂，避免了本发明后期纯化过程中的繁琐阶段，并能有效控制锂离子的限度；
4)根据本发明的制备方法，本发明一些实施例制得的DOTA产品收率较高、纯度在99.0％以上、单个杂质含量≤0.05％、炽灼残渣＜0.10％、符合产品原料药质量标准。
附图说明
图1为实施例2所制得产品的HPLC纯度谱图。
图2为实施例38所制得产品的HPLC纯度谱图。
具体实施方式
如无特别说明，以下实施例中：
炽灼残渣的测定方法：取600℃±50℃下炽灼30分钟并在干燥器中冷却后的瓷坩埚，精确称重(m1)；加入1.0g供试品，精确称重(m2)，用1mL硫酸润湿样品，然后在尽可能低的温度下缓慢加热，直至供试品完全炭化，冷却。用1mL硫酸润湿残渣，缓慢加热直至无白色烟雾形成。在600℃±50℃炽灼至彻底灰化。在干燥器中冷却，精确称重(m3)，计算残渣百分数。如果残渣含量超过限度，那么继续用硫酸湿润，加热，炽灼，炽灼时间为30min，精确称重(mn)，直到连续两次炽灼残渣称重的差值不超过0.5mg。
ω炽灼残渣＝(m2-m3)/(m2-m1)×100％
式中：m1表示瓷坩埚的质量，单位为g；m2表示炽灼前盛有试料的瓷坩埚的质量，单位为g；m3表示炽灼恒重后盛有残渣的瓷坩埚质量，单位为g。
下述实施例中，如未作特别说明，未限定温度的操作，均是在室温条件下进行。36％盐酸是指质量分数为36％的盐酸水溶液，所述的百分比是指盐酸的质量占盐酸水溶液总质量的百分比。
下述实施例中，所述的调节pH值以析出DOTA粗品的操作任选下列方法1)或方法2)：
方法1)包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂，将反应体系pH值调至DOTA酸式盐粗品完全析出；再将其溶于水中，加入碱性pH值调节剂，将所述的反应体系pH值调至DOTA粗品完全析出；所述的酸性pH值调节剂的用量为足以使反应体系pH值降低至1甚至0.5以下，从而使所述烷基化反应的产物(完全去 质子化的DOTA)全部转化为完全质子化的DOTA酸式盐并从反应体系中完全析出。所述的碱性pH值调节剂的用量为足以使反应体系pH值处于DOTA等电点附近(本发明优选为2.0-4.0，进一步优选为3.0-4.0)，从而使所述的DOTA酸式盐再次全部转化为游离态的DOTA并从其水溶液中完全析出。
方法2)包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂和有机溶剂，将所述的反应体系pH值调至DOTA粗品完全析出。所述的酸性pH值调节剂的用量为足以使反应体系pH值处于DOTA等电点附近(本发明优选为2.0-4.0，进一步优选为3.0-4.0)，从而使所述烷基化反应的产物(完全去质子化的DOTA)全部转化为游离态的DOTA。
下述实施例中，重结晶时，所述的DOTA粗品与所述的重结晶的溶剂的质量体积比可为本领域DOTA重结晶的常规比例。其用量通常为能够使溶剂在加热条件下(例如溶剂回流温度)，所述的DOTA粗品基本上完全溶解或完全溶解，且所得混合液在静置或搅拌后，能够析出DOTA。重结晶温度可以为室温，也可以为溶剂回流温度。并根据需要，在重结晶过程中可以搅拌。重结晶操作中的温度、搅拌速度等是为了使DOTA粗品在溶剂中基本上完全溶解或完全溶解。
实施例1
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:85.5％，HPLC:99.7％，炽灼残渣:0.05％，水分:7.80％。
实施例2
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。保温至5-15℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:78.0％，HPLC:99.9％，炽灼残渣:0.05％，水分:6.25％。
其中，产品的HPLC谱图见图1，图1中HPLC纯度数据见表1，其保留时间为9.447min。
表1
Figure PCTCN2017102056-appb-000003
实施例3
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至35-45℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:82.3％，HPLC:99.6％，炽灼残渣:0.06％，水分:5.60％。
实施例4
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至50-60℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:75.9％，HPLC:99.7％，炽灼残渣:0.07％，水分:6.37％。
实施例5
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入碘乙酸(81.82g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:72.0％，HPLC:99.7％，炽灼残渣:0.02％，水分:6.20％。
实施例6
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入氯乙酸(41.58g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:75.8％，HPLC:99.8％，炽灼残渣:0.08％，水分:7.50％。
实施例7
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入40％氢溴酸(89.00g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:67.8％，HPLC:99.7％，炽灼残渣:0.02％，水分:6.50％。
实施例8
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入45％氢碘酸(125.07g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:77.8％，HPLC:99.8％，炽灼残渣:0.66％，水分:7.40％。
实施例9
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶 液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入甲醇(600mL)，析出固体，过滤，所得固体用甲醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:18.5％，HPLC:99.7％，炽灼残渣:0.02％，水分:6.20％。
实施例10
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙腈(600mL)，析出固体，过滤，所得固体用乙腈/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:67.0％，HPLC:99.6％，炽灼残渣:0.08％，水分:8.50％。
实施例11
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入异丙醇(600mL)，析出固体，过滤，所得固体用异丙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:80.0％，HPLC:99.4％，炽灼残渣:0.12％，水分:5.78％。
实施例12
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入丙酮(600mL)，析出固体，过滤，所得固体用丙酮/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:78.9％，HPLC:99.2％，炽灼残渣:0.09％，水分:6.88％。
实施例13
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入四氢呋喃(600mL)，析出固体，过滤，所得固体用四氢呋喃/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:23.0％，HPLC:99.0％，炽灼残渣:0.02％，水分:8.80％。
实施例14
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为1:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:65.7％，HPLC:99.7％，炽灼残渣:0.02％，水分:6.45％。
实施例15
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用水(粗品DOTA与水的质量体积比为1:2)体系重结晶纯化，60℃干燥得到DOTA。
收率:40.0％，HPLC:99.7％，炽灼残渣:0.03％，水分:8.80％。
实施例16
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用水(粗品DOTA与水的质量体积比为1:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:25.0％，HPLC:99.7％，炽灼残渣:0.01％，水分:7.50％。
实施例17
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为5:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:83.4％，HPLC:99.4％，炽灼残渣:0.09％，水分:8.22％。
实施例18
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂 (36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为10:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:85.5％，HPLC:99.0％，炽灼残渣:0.09％，水分:7.81％。
实施例19
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为15:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:87.8％，HPLC:99.0％，炽灼残渣:0.11％，水分:7.90％。
实施例20
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为20:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:87.0％，HPLC:99.1％，炽灼残渣:0.09％，水分:6.78％。
实施例21
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(35.25g,840mmol)，水(80mL)。5-15℃下加入溴乙酸(58.37g,420mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(42.6g,420mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:81.3％，HPLC:99.7％，炽灼残渣:0.02％，水分:6.92％。
实施例22
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(38.60g,920mmol)，水(80mL)。5-15℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(46.64g,460mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为 3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:78.9％，HPLC:99.7％，炽灼残渣:0.05％，水分:7.20％。
实施例23
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(40.28g,960mmol)，水(80mL)。5-15℃下加入溴乙酸(66.70g,480mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(48.67g,480mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:82.3％，HPLC:99.7％，炽灼残渣:0.06％，水分:7.58％。
实施例24
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(38.60g,920mmol)，水(80mL)。5-15℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值为3.4-3.6，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:83.0％，HPLC:99.6％，炽灼残渣:0.05％，水分:7.80％。
实施例25
0-10℃时，向四口烧瓶(20L)中加入cyclen(690.0g，4.0mol)，一水合氢氧化锂(1477.2g,35.2mol)，水(1400mL)。5-15℃下加入溴乙酸(2445.6g,17.6mol)的水(1200mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(1785.0g,17.6mol)，加入乙醇(12L)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到1343.0g DOTA。
收率:83.0％，HPLC:99.6％，炽灼残渣:0.07％，含水量:4.92％。
实施例26
0-10℃时，向搪玻璃反应釜(200L)中加入cyclen(6.90kg，40.0mol)，一水合氢氧化锂(14.78kg,352.0mol)，水(23.0kg)。5-15℃下加入溴乙酸(24.46kg,176.0mol)的水(10kg)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(17.36kg,176.0mol)，加入乙醇(120kg)，析出固体，离心，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥36h得到12.95kg DOTA。
收率:80.1％，HPLC:99.7％，炽灼残渣:0.05％，含水量:4.73％。
实施例27
0-10℃时，向搪玻璃反应釜(2000L)中加入cyclen(69.0kg，400.0mol)，一水合氢氧化锂(147.8kg,3523.8mol)，水(230.0kg)。5-15℃下加入溴乙酸(244.6kg,1760.0mol)的水(100kg)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(173.6kg,1760.0mol)，加入乙醇(1200kg)，析出固体，离心，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥48h得到138.5kg DOTA。
收率:85.6％，HPLC:99.8％，炽灼残渣:0.04％，含水量:5.50％。
实施例28
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:90.5％，HPLC:57.5％，炽灼残渣:20.8％，水分:8.55％。
实施例29
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钾(49.28g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:88.0％，HPLC:47.5％，炽灼残渣:21.3％，水分:7.23％。
实施例30
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，醋酸钠(72.16g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:86.7％，HPLC:78.5％，炽灼残渣:24.8％，水分:8.80％。
实施例31
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入氯乙酸钠(51.25g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸 (44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:85.0％，HPLC:89％，炽灼残渣:12.5％，水分:7.23％。
实施例32
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入40％氢溴酸(89.00g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:62.3％，HPLC:96.8％，炽灼残渣:7.00％，水分:8.58％。
实施例33
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(61.14g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入45％氢碘酸(125.07g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:75.3％，HPLC:97.8％，炽灼残渣:4.61％，水分:8.20％。
实施例34
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值＜0.5，降温至0℃左右得到固体，过滤，所得固体继续采用浓盐酸(使用量约为30mL)进行打浆纯化得到40.05g DOTA盐酸盐粗品，HPLC纯度75％，所得粗品在另一1L四口瓶中继续用水(150mL)溶解后用三乙胺调节体系pH至3.5-4.0，搅拌，加入丙酮(300mL)，过滤，60℃干燥得到DOTA。
收率:90.0％，HPLC:93.74％，炽灼残渣7.63％，含水量:8.80％。
实施例35
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值＜0.5，降温至0℃左右得到固体，过滤，所得固体继续采用浓盐酸(30mL)进行打浆纯 化得到42.00g DOTA盐酸盐粗品，HPLC纯度75％，所得粗品在另一1L四口瓶中继续用水(150mL)溶解后用氨水调节体系pH值至3.5-4.0，搅拌，加入乙醇(300m L)，过滤，60℃干燥得到DOTA。
收率:91.3％，HPLC:89.56％，炽灼残渣:6.60％，含水量:7.80％。
实施例36
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值＜0.5，降温至0℃左右得到固体，过滤，所得固体继续采用浓盐酸(30mL)进行打浆纯化得到42.00g DOTA盐酸盐粗品，HPLC纯度75％，所得粗品在另一1L四口瓶中继续用水(150mL)溶解后用氨水调节体系pH值至3.5-4.0，搅拌，加入丙酮(300mL)，过滤，60℃干燥得到DOTA。
收率:88.6％，HPLC:92.6％，炽灼残渣:7.58％，含水量:6.08％
实施例37
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(80mL)。5-15℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值＜0.5，降温至0℃左右得到固体，过滤，所得固体继续采用浓盐酸(30mL)进行打浆纯化得到40.05g DOTA盐酸盐粗品，HPLC纯度75％，所得粗品在另一1L四口瓶中继续用水(150mL)溶解后用三乙胺调节体系pH值至3.5-4.0，搅拌，加入乙醇(300m L)，过滤，60℃干燥得到DOTA。
收率:88.8％，HPLC:93.3％，炽灼残渣:5.68％，含水量:8.50％。
实施例38
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(18.46g,440mmol)，水(80mL)。5-15℃下加入溴乙酸钠(51.25g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,880mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:67.8％，HPLC:75.5％，炽灼残渣:1.23％，水分:7.23％。
其中，产品的HPLC谱图参见图2，纯度数据见下表2，其保留时间为9.580min。
表2
Figure PCTCN2017102056-appb-000004
实施例39
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(18.46g,440mmol)，水(80mL)。5-15℃下加入氯乙酸锂(44.19g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,880mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:43.8％，HPLC:99.6％，炽灼残渣:0.07％，水分:6.50％。
实施例40
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(18.46g,440mmol)，水(80mL)。5-15℃下加入碘乙酸钾(98.58g,440mmol)的水(30mL) 溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,880mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:62.5％，HPLC:86.0％，炽灼残渣:12.30％，水分:6.50％。
实施例41
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(18.46g,440mmol)，水(80mL)。5-15℃下加入碘乙酸钠(91.49g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,880mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:51.8％，HPLC:87.0％，炽灼残渣:11.80％，水分:7.90％。
实施例42
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入溴乙酸乙酯(73.48g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,880mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:24.8％，HPLC:98.5％，炽灼残渣:0.25％，水分:8.80％。
实施例43
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，一水合氢氧化锂(36.92g,880mmol)，水(80mL)。5-15℃下加入氯乙酸甲酯(47.75g,440mmol)的水(30mL)溶液。加热至20-30℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,880mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)体系重结晶纯化，60℃干燥得到DOTA。
收率:32.5％，HPLC:98.7％，炽灼残渣:0.18％，水分:5.28％。
实施例44
15～25℃下，向四口烧瓶(500mL)中加入cyclen(40.00g)，氢氧化钠(81.80g)，水(162mL)。15～25℃下加入溴乙酸(142g)的水(50mL)溶液。加热升温至60℃搅拌反应直至TLC检测原料cyclen无剩余。加入浓盐酸(210mL)，调节pH值＜0.5，降温至0℃左右得到固体，过滤，所得固体继续采用浓盐酸(120mL)进行重结晶纯化得到119.6g DOTA盐酸盐粗品，HPLC纯度75％，所得粗品在另一四口瓶(1L)中继续用500 mL水溶解后，用三乙胺(约50mL)调节体系pH值至3～4，搅拌，加入丙酮1L，过滤干燥得到DOTA。
收率：90％，HPLC：93.74％，炽灼残渣7.63％，含水量≤6.0％。
对比例1(参考专利WO2013076743)
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(170mL)。0-10℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液，补加氢氧化钠维持体系pH值为10-10.5。加热至70-75℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值＜0.75，降温至0℃左右得到固体，过滤，所得固体继续采用水进行打浆重结晶至DOTA盐酸盐中炽灼残渣＜0.10％。所得粗品在另一500L四口瓶中继续用水(80mL)溶解后用A26OH离子交换树脂调节体系pH值至2.5-3.0，过滤，滤液浓缩至20-30mL体积，加入丙酮(180mL)析出固体，过滤，60℃干燥得到DOTA。
收率:72.3％，HPLC:99.3％，炽灼残渣:0.04％，含水量:4.60％。
对比例2
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(170mL)。0-10℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液，补加氢氧化钠维持体系pH值为10-10.5。加热至70-75℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸调节体系pH值＜0.75，降温至0℃左右得到固体，过滤，所得固体继续采用水进行打浆重结晶至DOTA盐酸盐中炽灼残渣＜0.10％。所得粗品在另一500L四口瓶中继续用水(80mL)溶解后用氨水调节体系pH值至2.5-3.0，过滤，滤液浓缩至20-30mL体积，加入丙酮(180mL)析出固体，过滤，60℃干燥得到DOTA。
收率:60.3％，HPLC:99.2％，炽灼残渣:0.04％，含水量:5.80％。
对比例3
0-10℃时，向三口烧瓶(1000mL)中加入cyclen(17.27g，100mmol)，氢氧化钠(35.20g,880mmol)，水(170mL)。0-10℃下加入溴乙酸(63.93g,460mmol)的水(30mL)溶液，补加氢氧化钠维持体系pH值为10-10.5。加热至70-75℃反应24h，TLC检测原料cyclen无剩余。向体系中加入36％盐酸(44.6g,440mmol)，加入乙醇(600mL)，析出固体，过滤，所得固体用乙醇/水(体积比为3:1)。
收率:78.0％，HPLC:88.0％，炽灼残渣:13.50％，水分:7.80％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变 更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (19)

  1. 一种DOTA的制备方法，其包括以下步骤：在水中，在缚酸剂的作用下，将cyclen与XCH2COOR进行烷基化反应；调节pH值以析出DOTA粗品；重结晶；即可；其中，R为H、碱金属或C1-C6烷基，X为氯、溴或碘；所述的重结晶的溶剂为水或水与有机溶剂的混合溶剂；
    Figure PCTCN2017102056-appb-100001
  2. 如权利要求1所述的制备方法，其中，
    所述的缚酸剂为碱金属氢氧化物、碱土金属氢氧化物、碳酸盐、碳酸氢盐、磷酸盐、有机酸盐、醇盐和有机胺中的一种或多种；其中，所述的碱金属为锂、钠、钾、铷、铯、或钫；所述的碱土金属为铍、镁、钙、锶、钡、或镭；
    和/或，所述的缚酸剂与所述的cyclen的摩尔比为8.0:1-10.0:1；
    和/或，当R为碱金属时，所述的碱金属为锂、钠或钾；
    和/或，当R为C1-C6烷基时，所述的C1-C6烷基为C1-C4烷基；
    和/或，所述的XCH2COOR与所述的cyclen的摩尔比为4.0:1-5.0:1；
    和/或，将所述的XCH2COOR配置成其水溶液再加入上述反应体系中
    和/或，所述的cyclen在反应体系中的摩尔浓度为0.5-1.5mol/L。
  3. 如权利要求1或2所述的制备方法，其中，
    所述的缚酸剂与所述的cyclen的摩尔比为8.4:1-9.2:1；
    和/或，当R为C1-C6烷基时，所述的C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，所述的XCH2COOR与所述的cyclen的摩尔比为4.2:1-4.6:1；
    和/或，所述的XCH2COOR配置成其水溶液再加入上述反应体系中；摩尔浓度优选为12.0-18.0mol/L的水溶液；
    和/或，所述的cyclen在反应体系中的摩尔浓度为0.9-1.0mol/L。
  4. 如权利要求1-3中至少一项所述的制备方法，其中，
    所述的缚酸剂为碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐、碱金属磷酸盐、 碱金属有机酸盐、碱金属醇盐和有机胺中的一种或多种；
    和/或，所述的XCH2COOR为氯乙酸、溴乙酸、碘乙酸、氯乙酸钠、溴乙酸钠和碘乙酸钠中的一种或多种，优选为溴乙酸；
    和/或，当所述的缚酸剂的水合物稳定存在时，所述的XCH2COOR以其水合物的形式参与反应。
  5. 如权利要求1-4中至少一项所述的制备方法，其中，
    所述的缚酸剂为为碱金属氢氧化物、碱金属碳酸盐、碱金属有机酸盐和有机胺中的一种或多种；
    和/或，所述的XCH2COOR为溴乙酸。
  6. 如权利要求5中所述的制备方法，其中，
    所述的碱金属氢氧化物为氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铷和氢氧化铯中的一种或多种；
    和/或，所述的碱金属碳酸盐为碳酸锂、碳酸钠、碳酸钾、碳酸铷和碳酸铯中的一种或多种；
    和/或，所述的碱金属有机酸盐为碱金属醋酸盐，进一步优选为醋酸锂、醋酸钠和醋酸钾中的一种或多种；
    和/或，所述的有机胺为三乙胺和/或二异丙基乙基胺。
  7. 如权利要求1-6中至少一项所述的制备方法，其中，所述的缚酸剂为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾和醋酸钠中的一种或多种。
  8. 如权利要求1-7中至少一项所述的制备方法，其中，所述的缚酸剂为氢氧化锂和/或氢氧化锂一水合物。
  9. 如权利要求1-8中至少一项所述的制备方法，其中，
    所述的烷基化反应的反应温度为-10℃-60℃；
    和/或，所述的烷基化反应的反应物料的加料方式为：将所述的cyclen、所述的缚酸剂、所述的水、和所述的XCH2COOR依次加入反应体系中。
  10. 如权利要求1-9中至少一项所述的制备方法，其中，
    所述的烷基化反应的反应温度为5-50℃或20-30℃；
    和/或，所述的烷基化反应的反应物料的加料方式为：在0-10℃下加入所述的cyclen、所述的缚酸剂、所述的水，在5-15℃下加入所述的XCH2COOR或其水溶液。
  11. 如权利要求1-10中至少一项所述的制备方法，其中，
    所述的调节pH值以析出DOTA粗品的的操作为下列方法1)或方法2)：
    方法1)包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂，将所述的反应体系pH值调至DOTA酸式盐粗品完全析出；再将其溶于水中，加入碱性pH值调节剂，将所述的反应体系pH值调至DOTA粗品完全析出；
    方法2)包括下列步骤：在所述的烷基化反应结束后，加入酸性pH值调节剂，将所述的反应体系pH值调至DOTA粗品完全析出。
  12. 如权利要求11所述的制备方法，其中，
    方法1)中，所述的酸性pH值调节剂为盐酸、氢溴酸、氢碘酸、硝酸和硫酸中的一种或多种；
    和/或，方法1)中，所述的酸性pH值调节剂的用量为使所述的反应体系pH值降低至1以下；
    和/或，方法1)中，所述的碱性pH值调节剂为氨水、三乙胺和三异丙胺中的一种或多种；
    和/或，方法1)中，所述的碱性pH值调节剂的用量为使所述的反应体系pH值为2.0-4.0；
    和/或，方法2)中，所述的酸性pH值调节剂为盐酸、氢溴酸、氢碘酸、硝酸和硫酸中的一种或多种；
    和/或，方法2)中，所述的酸性pH值调节剂的用量为使所述的反应体系pH值为2.0-4.0；
    和/或，方法2)中，所述的酸性pH值调节剂中的氢质子与cyclen的摩尔浓度比为4.4:1，或所述的酸性pH值调节剂中的氢质子与所述的缚酸剂的摩尔浓度比为1:2；
    和/或，方法2)中，所述的有机溶剂为甲醇、乙醇、异丙醇、四氢呋喃、丙酮和乙腈中的一种或多种，优选为甲醇和/或乙醇；
    和/或，方法2)中，所述的cyclen的物质的量与所述的有机溶剂的体积之比为1:6mol/L。
  13. 如权利要求12或13中所述的方法，其中，
    方法1)中，所述的酸性pH值调节剂为质量分数为36％的盐酸水溶液；
    和/或，方法1)中，所述的酸性pH值调节剂的用量为使所述的反应体系pH值降低至0.5以下；
    和/或，方法1)中，所述的碱性pH值调节剂为三乙胺；
    和/或，方法1)中，所述的碱性pH值调节剂的用量为使所述的反应体系pH值为3.0-4.0；
    和/或，方法2)中，所述的酸性pH值调节剂为质量分数为36％的盐酸水溶液；
    和/或，方法2)中，所述的酸性pH值调节剂的用量为使所述的反应体系pH值为3.0-4.0；
    和/或，方法2)中，所述的有机溶剂为甲醇和/或乙醇。
  14. 如权利要求1-13中至少一项所述的制备方法，其中，
    当所述的重结晶的溶剂为水与有机溶剂的混合溶剂时，所述的有机溶剂为丙酮、乙腈、甲醇、乙醇、异丙醇和四氢呋喃中的一种或多种；
    和/或，所述的重结晶中，所述的水和所述的有机溶剂的体积比为1:1-1:20。
  15. 如权利要求1-14中至少一项所述的制备方法，其中，
    当所述的重结晶的溶剂为水与有机溶剂的混合溶剂时，所述的有机溶剂为甲醇和/或乙醇；
    和/或，所述的重结晶中，所述的水和所述的有机溶剂的体积比为1:2-1:15。
  16. 如权利要求1-15中至少一项所述的制备方法，其中，所述的重结晶中，所述的水和所述的有机溶剂的体积比为1:3-1:10。
  17. 如权利要求1-16中至少一项所述的制备方法，其中，所述的重结晶中，所述的水和所述的有机溶剂的体积比为1:3-1:5。
  18. 如权利要求1-17中至少一项所述的制备方法，其中，在所述的重结晶结束后，还包括将重结晶所得产品进行干燥以去除其中低沸点溶剂的操作。
  19. 如权利要求18中所述的制备方法，其中，所述的干燥的温度为60℃。
PCT/CN2017/102056 2016-12-30 2017-09-18 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法 WO2018120923A1 (zh)

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US16/473,242 US11214553B2 (en) 2016-12-30 2017-09-18 Method for preparing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
CA3048549A CA3048549C (en) 2016-12-30 2017-09-18 Method for preparing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
JP2019556400A JP2020504175A (ja) 2016-12-30 2017-09-18 １，４，７，１０−テトラアザシクロドデカン−１，４，７，１０−四酢酸の製造方法
KR1020197021751A KR102265637B1 (ko) 2016-12-30 2017-09-18 1,4,7,10-테트라아자시클로도데칸-1,4,7,10-테트라아세트산의 제조 방법
EP17889406.9A EP3564218B1 (en) 2016-12-30 2017-09-18 Method for preparing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
CN201780080570.8A CN110198931B (zh) 2016-12-30 2017-09-18 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法
ES17889406T ES2865297T3 (es) 2016-12-30 2017-09-18 Método para la preparación de ácido 1,4,7,10-tetraazaciclododecano-1,4,7,10-tetraacético
MX2019007798A MX2019007798A (es) 2016-12-30 2017-09-18 Metodo para preparar acido 1,4,7,10-tetraazaciclododecano-1,4,7,10 -tetraacetico.

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CN113087680A (zh) * 2020-01-08 2021-07-09 威智医药有限公司 Dota晶型及其制备方法
WO2021250163A1 (en) * 2020-06-10 2021-12-16 Justesa Imagen S.A.U. Procedure for obtaining gadoterate meglumine from high-purity tetraxetan (dota) and its use in the preparation of injectable galenical formulations
CN113429362A (zh) * 2021-06-01 2021-09-24 南昌大学 环胺高氯酸可逆相变材料及其制备方法
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