PREPARATION METHOD OF INTERMEDIATE OF GADOLINIUM-BASED IONIC CONTRAST AGENT AND USE THEREOF

Abstract

A preparation method and application of an intermediate of gadolinium-based ionic contrast agent comprises the following step: allowing a substance represented by the general formula (II) to react a substance represented by the general formula (III) or a substance represented by the general formula (IV) in the presence of a basic catalyst to generate an intermediate of gadolinium-based ionic contrast agent containing the structure represented by the general formula (I) or the general formula (V), wherein R represents C.sub.1-C.sub.5 alkyl, benzyl or benzyl derivative, R.sub.1 represents H or CH.sub.2OH, and R.sub.2 represents CH.sub.3 or OH. When preparing an intermediate of gadolinium-based ionic contrast agent having the structure represented by the general formula (I) using the above-mentioned preparation method, it can provide the advantages of simple reaction, fewer steps, controllable reaction, a yield up to 99% or more, and a purity greater than 99.5% for the obtained product.

Claims

1. A preparation method of an intermediate of gadolinium-based ionic contrast agent, wherein, the reaction equation for the preparation method is as follows: ##STR00007## the preparation method comprises the following step: allowing a substance represented by the general formula (II) to react with a substance represented by the general formula (III) or a substance represented by the general formula (IV) in the presence of a basic catalyst to generate an intermediate of gadolinium-based ionic contrast agent having the structure represented by the general formula (I) or the general formula (V); wherein, R represents C.sub.1-C.sub.5 alkyl, benzyl or benzyl derivative, R.sub.1 represents H or CH.sub.2OH, and R.sub.2 represents CH.sub.2OH, CH.sub.3 or OH.

2. The preparation method of an intermediate of gadolinium-based ionic contrast agent according to claim 1, wherein R represents C.sub.1-C.sub.5 alkyl, R.sub.1 represents H or CH.sub.2OH, and R.sub.2 represents CH.sub.2OH, CH.sub.3 or OH.

3. The preparation method of an intermediate of gadolinium-based ionic contrast agent according to claim 1, wherein R represents tert-butyl, R.sub.1 represents H, and R.sub.2 represents CH.sub.3, or R represents tert-butyl, R.sub.1 represents CH.sub.2OH, and R.sub.2 Represents CH.sub.2OH.

4. The preparation method according to claim 1, wherein the basic catalyst is an inorganic basic catalyst or an organic basic catalyst; the inorganic basic catalyst is one or more selected from potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate and lithium bicarbonate; the organic basic catalyst is an organic amine catalyst, and the organic amine catalyst is one or more selected from trimethylamine, tripropylamine, tributylamine, dimethylaniline, diethylaniline, pyridine, pyridine derivative and compounds similar to the above-mentioned structures.

5. The preparation method according to claim 1, wherein the mass ratio of the substance represented by the general formula (II), the substance represented by the general formula (III) or the general formula (IV), and the basic catalyst is (10-100):(1-10):1.

6. The preparation method according to claim 1, wherein the reaction temperature is 40 to 180 C. and the reaction time is 6 to 18 h.

7. The preparation method according to claim 1, wherein toluene or isopropanol is used as a solvent in the reaction.

8. An intermediate of gadolinium-based ionic contrast agent, wherein, the intermediate has a structure represented by the general formula (V): ##STR00008##

9. Use of the preparation method according to claim 1 in the preparation of a gadolinium-based ionic contrast agent, wherein the intermediate of gadolinium-based ionic contrast agent is subjected to hydrolysis and prepared into salt to obtain the gadolinium-based ionic contrast agent.

10. The use according to claim 9, wherein the hydrolysis specifically comprises: hydrolyzing the intermediate of gadolinium-based ionic contrast agent in the presence of a catalyst; wherein the preparation method of the catalyst comprises the following steps: subjecting zirconia and titanium tetrachloride to reaction in the presence of sulfuric acid and water at 60 C. to 90 C. until solids are dissolved, adding silica to perform reaction for 1 to 5 h, filtering to obtain solids, washing and calcining the solids.

11. The preparation method according to claim 2, wherein the mass ratio of the substance represented by the general formula (II), the substance represented by the general formula (III) or the general formula (IV), and the basic catalyst is (10-100):(1-10): 1.

12. The preparation method according to claim 3, wherein the mass ratio of the substance represented by the general formula (II), the substance represented by the general formula (III) or the general formula (IV), and the basic catalyst is (10-100):(1-10): 1.

13. The preparation method according to claim 4, wherein the mass ratio of the substance represented by the general formula (II), the substance represented by the general formula (III) or the general formula (IV), and the basic catalyst is (10-100):(1-10): 1.

14. The preparation method according to claim 2, wherein the reaction temperature is 40 to 180 C. and the reaction time is 6 to 18 h.

15. The preparation method according to claim 3, wherein the reaction temperature is 40 to 180 C. and the reaction time is 6 to 18 h.

16. The preparation method according to claim 4, wherein the reaction temperature is 40 to 180 C. and the reaction time is 6 to 18 h.

17. The preparation method according to claim 5, wherein the reaction temperature is 40 to 180 C. and the reaction time is 6 to 18 h.

18. The preparation method according to claim 2, wherein toluene or isopropanol is used as a solvent in the reaction.

19. The preparation method according to claim 3, wherein toluene or isopropanol is used as a solvent in the reaction.

20. The preparation method according to claim 4, wherein toluene or isopropanol is used as a solvent in the reaction.

Description

DETAILED DESCRIPTION

[0038] The specific embodiments of the present disclosure will be described in further detail in combination with the Examples below. The following Examples are used to illustrate the present disclosure, but not to limit the scope of the present disclosure.

[0039] Unless otherwise specified, the technical means used in the Examples are conventional means well known to a person skilled in the art, and the raw materials used are all commercially available products.

Example 1

[0040] The present Example provides a preparation method of an intermediate of gadolinium-based ionic contrast agent. The reaction equation for the preparation method is as follows:

##STR00003##

[0041] the preparation method comprises the following steps: [0042] 26 g of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate, 2 g of potassium carbonate, 300 mL of isopropanol, and 10 g of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane were added into a 1 L reaction flask to perform reaction at 60 C. for 12 h, then isopropanol was recovered, 300 mL of toluene was added, the resulting reaction solution was washed with water, dried with anhydrous magnesium sulfate, and then toluene was recovered under reduced pressure to obtain 33 g of a light yellow oily substance with a yield greater than 99% and a purity greater than 99.8%.

[0043] The elemental analysis results of the light yellow oily substance obtained in the present Example were as follows: C: 60.12%, N: 8.48%, and H: 9.46% (C.sub.33H.sub.62N.sub.4O.sub.9 theoretical values: C: 60.18%, H: 9.43%, and N: 8.51%). From the above data, it can be proved that the above intermediate was successfully synthesized in the present Example.

Example 2

[0044] The present Example provides a preparation method of an intermediate of gadolinium-based ionic contrast agent. The reaction equation of the preparation method is as follows:

##STR00004##

[0045] the preparation method comprises the following steps: [0046] 30 g of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate hydrobromide, 20 g of potassium carbonate, 300 mL of toluene, 10 mL of propylene oxide were added into a 1 L reaction flask to perform reaction at 60 C. for 12 h, then the resulting reaction solution was washed with water, dried with anhydrous magnesium sulfate, and toluene was recovered under reduced pressure to obtain 28 g of a light yellow oily substance with a yield greater than 99% and a purity greater than 99.5%;

[0047] wherein, in the intermediate of gadolinium-based ionic contrast agent (I) obtained in the present Example, R represents tert-butyl, R.sub.1 represents H, and R.sub.2 represents CH.sub.3.

[0048] The elemental analysis results of the light yellow oily substance obtained in the present Example were as follows: C: 59.76%, N: 9.62%, and H: 9.79% (C.sub.29H.sub.56N.sub.4O.sub.7 theoretical values: C: 59.97%, N: 9.65%, and H: 9.72%). From the above data, it can be proved that the above intermediate was successfully synthesized in the present Example.

Example 3

[0049] The present Example provides a preparation method of an intermediate of gadolinium-based ionic contrast agent. The reaction equation is the same as that in Example 1. The preparation method comprises the following steps: [0050] 26 g of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate, 2 g of sodium carbonate, 300 mL of isopropanol, and 10 g of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane were added into a 1 L reaction flask to perform reaction at 40 C. for 18 h, then isopropanol was recovered, 300 mL of toluene were added, the resulting reaction solution was washed with water, dried with anhydrous magnesium sulfate, and then toluene was recovered under reduced pressure to obtain a light yellow oily substance with a yield greater than 98.6% and a purity greater than 99.5%.

[0051] The elemental analysis results of the light yellow oily substance obtained in the present Example were the same as those of the product obtained in Example 1, which can prove that the above intermediate was successfully synthesized in the present Example.

Example 4

[0052] The present Example provides a preparation method of an intermediate of gadolinium-based ionic contrast agent. The reaction equation is the same as that in Example 1. The preparation method comprises the following steps: [0053] 40 g of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate, 2 g of dimethylaniline, 300 mL of isopropanol, and 20 g of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane were added into a 1 L reaction flask to perform reaction at 180 C. for 4 h, then isopropanol was recovered, 300 mL of toluene was added, the resulting reaction solution was washed with water, dired with anhydrous magnesium sulfate, and then toluene was recovered under reduced pressure to obtain a light yellow oily substances with a yield greater than 98.2% and a purity greater than 99.3%.

[0054] The elemental analysis result of the light yellow oily substances obtained in the present Example is the same as that of the product obtained in Example 1, which can prove that the above intermediate was successfully synthesized in the present Example.

Example 5

[0055] The present Example provides a preparation method of an intermediate of gadolinium-based ionic contrast agent. The reaction equation is the same as that in Example 1. The preparation method comprises the following steps: [0056] 100 g of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate, 1 g of potassium carbonate, 300 mL of isopropanol, and 10 g of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane were added into a 1 L reaction flask to perform reaction at 60 C. for 12 h, then isopropanol was recovered, 300 mL of toluene was added, the resulting reaction solution was washed with water, dried with anhydrous magnesium sulfate, and then toluene was recovered under reduced pressure to obtain a light yellow oily substance with a yield greater than 98% and a purity greater than 99%.

[0057] The elemental analysis results of the light yellow oily substance obtained in the present Example were the same as those of the product obtained in Example 1, which can prove that the above intermediate was successfully synthesized in the present Example.

Example 6

[0058] The present Example provides a preparation method of an intermediate of gadolinium-based ionic contrast agent, and the reaction equation is the same as that in Example 2. The preparation method comprises the following steps: [0059] 30 g of tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate hydrobromide, 20 g of trimethylamine, 300 mL of toluene, and 10 mL of propylene oxide were added into a 1 L reaction flask to perform reaction at 60 C. for 12 h, then the resulting reaction solution was washed with water, dried with anhydrous magnesium sulfate, and then toluene was recovered under reduced pressure to obtain 28 g of a light yellow oily substance with a yield greater than 98% and a purity greater than 99%;

[0060] wherein, in the intermediate of gadolinium-based ionic contrast agent (I) obtained in the present Example, R represents tert-butyl, R.sub.1 represents H, and R.sub.2 represents CH.sub.3.

[0061] The elemental analysis results of the light yellow oily substances obtained in the present Example were the same as those of the product obtained in Example 2, which can prove that the above intermediate was successfully synthesized in the present Example.

Example 7

[0062] The present Example provides a preparation method of a gadolinium-based ionic contrast agent. The reaction equation is as follows:

##STR00005##

[0063] The preparation method comprises the following steps: [0064] 1) the intermediate of gadolinium-based ionic contrast agent obtained in Example 1 was added into a 500 mL reaction flask containing 200 mL distilled water, and 0.5 g of a catalyst was added under stirring to perform reaction at 85 to 90 C. for 12 h, the resultant was filtered, washed with a small amount of water, concentrated to dry under reduced pressure, and recrystallized with ethanol/acetone (6:4) to obtain 21 g white solid of butrol (the elemental analysis results were as follows: C: 47.82%, N: 12.32%, and H: 7.64%, C.sub.18H.sub.34N.sub.4O.sub.9 theoretical values: C: 47.97%, N: 12.43%, and H: 7.62%);

[0065] wherein, the catalyst was prepared by the following method: 5 g of ZrO.sub.2 and 3 g of TiCL.sub.4 were added to 100 mL of distilled water, and 10 mL of sulfuric acid was added, the mixture was heated at about 80 C. until the solids were completely dissolved, and then 60 ml of SiO.sub.2 were added to perform adsorption for 2 h, the resultant was filtered, washed twice with water, washed twice with 50 ml of 10% NaOH, and washed with distilled water to neutrality, and then calcined at 550 C. to obtain the catalyst; [0066] 2) the above-mentioned butrol was dissolved in 100 mL of distilled water, and 9.0 g of Gd.sub.2O.sub.3 was added to perform reaction at 85 C. until the solution was clear, then the reaction solution was filtered, concentrated, and recrystallized with 300 mL of 95% ethanol to obtain 28 g white crystal of gadobutrol with a yield greater than 99% and a purity greater than 99.5%;

[0067] wherein, the infrared spectrum (KBr, cm.sup.1) of the white crystal was provided as follows: 3560, 3280, 2975, 2940, 2920, 2880, 2870, 1650, 1600, 1380. It can be proved that the white crystal is gadobutrol.

Example 8

[0068] The present Example provides a preparation method of a gadolinium-based ionic contrast agent. The reaction equation is as follows:

##STR00006##

[0069] The preparation method comprises the following steps: [0070] 1) the intermediate of gadolinium-based ionic contrast agent obtained in Example 2 was added into a 500 mL reaction flask containing 200 mL distilled water, and 0.5 g of a catalyst was added under stirring to perform reaction at 85 to 90 C. for 12 h, the resultant was filtered, washed with a small amount of water, concentrated to dry under reduced pressure, and recrystallized with 95% ethanol to obtain 17 g white solid of teridol (the elemental analysis results were as follows: C: 50.37%, N: 13.80%, and H: 8.09%, C.sub.17H.sub.32N.sub.4O.sub.7 theoretical values: C: 50.44%, N: 13.85%, and H: 8.01%);

[0071] wherein, the catalyst was prepared by the following method: 5 g of ZrO.sub.2 and 3 g of TiCL.sub.4 were added to 100 mL of distilled water, and 10 mL of sulfuric acid was added, the mixture was heated at about 80 C. until the solids were completely dissolved, and then 60 ml of SiO.sub.2 was added to perform adsorption for 2 h, the resultant was filtered, washed twice with water, washed twice with 50 mL of 10% NaOH, and washed with distilled water to neutrality, and then calcined at 550 C. to obtain the catalyst; [0072] 2) the above-mentioned teridol was dissolved in 100 mL of distilled water, and 9.0 g of Gd.sub.2O.sub.3 was added to perform reaction at 85 C. until the solution was clear, then filtered, concentrated, and recrystallized with 200 mL of isopropanol to obtain 28 g white crystal of gadoteridol with a yield greater than 99% and a purity greater than 99.5%.

[0073] Finally, the methods described in the examples are only preferred embodiments, and are not intended to limit the protection scope of the present disclosure. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present disclosure shall be included in the protection scope of the present disclosure.

INDUSTRIAL APPLICABILITY

[0074] The present disclosure provides a preparation method and use of an intermediate of gadolinium-based ionic contrast agent. The preparation method includes the following steps: allowing a substance represented by the general formula (II) to react with a substance represented by the general formula (III) or a substance represented by the general formula (IV) in the presence of a basic catalyst to generate an intermediate of gadolinium-based ionic contrast agent having the structure represented by the general formula (I) or the general formula (V), wherein R represents C.sub.1-C.sub.5 alkyl, benzyl or benzyl derivative, R.sub.1 represents H or CH.sub.2OH, and R.sub.2 represents CH.sub.3 or OH. The preparation method provided by the present disclosure can be used for industrial large-scale production, and makes up for the shortcomings of the existing method such as suitability for small-scale production only, insufficient purity, and low yield.