Hydrolysis method for tert-butyl ester in gadolinium-based contrast agent

Abstract

A hydrolysis method for tert-butyl ester in gadolinium-based contrast agent comprises hydrolyzing the tert-butyl ester with a catalyst. 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. This hydrolysis method does not introduce other substances that are difficult to remove, such as acids, and provides high hydrolysis efficiency and high purity of the obtained product.

Claims

1. A method for preparing a catalyst for hydrolyzing tert-butyl ester in gadolinium-based contrast agent, the method comprising 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, performing a reaction for 1 to 5 h, filtering to obtain solids, washing and calcining the solids.

Description

DETAILED DESCRIPTION

(1) 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.

(2) 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

(3) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(4) ##STR00002##

(5) The hydrolysis method provided in the present Example comprises the following steps:

(6) The compound represented by formula (III) was added into a 500 mL reaction flask containing 200 mL distilled water, and a catalyst was added under stirring (the mass ratio of the compound represented by formula (III) to the catalyst was 1:100) to perform reaction at 90° C. for 12 h, and then 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.

(7) Wherein, the catalyst was prepared by the following method: 5 g ZrO.sub.2 and 3 g TiCl.sub.4 were added to 100 mL distilled water, and 10 mL sulfuric acid was added; the mixture was heated at about 80° C. until the solid were completely dissolved, and then 60 ml SiO.sub.2 was added to perform adsorption for 2 h; and 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.

(8) The purity of the teridol obtained in the present Example is 99.8%, and the yield is 96%. The elemental analysis results of the product obtained in the present Example are 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%; wherein, both the infrared spectrum and the nuclear magnetic resonance hydrogen spectrum of the product obtained in the present Example indicate that the obtained substance is teridol.

Example 2

(9) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(10) ##STR00003##

(11) The steps were the same as those in Example 1, except that the tert-butyl ester was a compound represented by formula (II); and the solvent for recrystallization was ethanol/acetone (6:4). 21 g butrol was obtained in the present Example.

(12) The purity of the butrol obtained in the present Example is 99.7%, and the yield is 95%. The elemental analysis results of the product obtained in the present Example are 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%; wherein, both the infrared spectrum and the nuclear magnetic resonance hydrogen spectrum of the product obtained in the present Example indicate that the obtained substance is butrol.

Example 3

(13) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(14) ##STR00004##

(15) The steps were the same as those in Example 1, except that the tert-butyl ester was a compound represented by formula (I).

(16) The purity of the product obtained in the present Example is 99%, and the yield is 96%. 1H-NMR (400 MHZ) (DMSO-d6) δ: 1.31 (t (7 Hz), 2.47 (dd (14.7 Hz), 1H), 2.78-2.90 (m, 4H), 2.90-3.10 (m, 3H), 3.20-3.50 (m, 9H), 3.60-3.75 (m, 2H), 3.99 (q (7 Hz), 2H), 6.80-6.85 (m, 2H), 7.10-7.15 (m, 2H), 8-12 (m, 5H).

Example 4

(17) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(18) ##STR00005##

(19) The hydrolysis method provided in the present Example comprises the following steps:

(20) The compound represented by formula (III) was added into a 500 mL reaction flask containing 200 mL distilled water, and a catalyst was added under stirring (the mass ratio of the compound represented by formula (III) to the catalyst was 1:1) to perform reaction at 70° C. for 24 h, and then the resultant was filtered, washed with a small amount of water, concentrated to dry under reduced pressure, and recrystallized with 95% ethanol to obtain a white solid, wherein the catalyst used was the same as that used in Example 1. The elemental analysis results, the infrared spectrum, and the nuclear magnetic resonance hydrogen spectrum of the teridol obtained in the present Example are the same as those in Example 1. The purity of the teridol obtained in the present Example is 99%, and the yield is 90%.

Example 5

(21) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(22) ##STR00006##

(23) The hydrolysis method provided in the present Example comprises the following steps:

(24) The compound represented by formula (III) was added into a 500 mL reaction flask containing 200 mL distilled water, and a catalyst was added under stirring (the mass ratio of the compound represented by formula (III) to the catalyst is 1:50) to perform reaction at 90° C. for 15 h, and then the resultant was filtered, washed with a small amount of water, concentrated to dry under reduced pressure, and recrystallized with 95% ethanol to obtain a white solid, wherein the catalyst used was the same as that used in Example 1. The elemental analysis results, the infrared spectrum, and the nuclear magnetic resonance hydrogen spectrum of the teridol obtained in the present Example are the same as those in Example 1. The purity of the teridol obtained in the present Example is 99.5%, and the yield is 92%.

Example 6

(25) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(26) ##STR00007##

(27) The steps were the same as those in Example 5, except that the tert-butyl ester was a compound represented by formula (II); and the solvent for recrystallization was ethanol/acetone (6:4). The purity of the butrol obtained in the present Example is 99.5%, and the yield is 93%. The elemental analysis results, the infrared spectrum, and the nuclear magnetic resonance hydrogen spectrum of the product obtained in the present Example are the same as those in Example 2.

Example 7

(28) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The reaction equation is as follows:

(29) ##STR00008##

(30) The steps were the same as those in Example 5, except that the tert-butyl ester was a compound represented by formula (I). The purity of the product obtained in the present Example is 99%, and the yield is 90%. The elemental analysis results, the infrared spectrum, and the nuclear magnetic resonance hydrogen spectrum of the product obtained in the present Example are the same as those in Example 3.

Example 8

(31) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The steps are the same as those in Example 1, except that the catalyst used in the present Example was prepared by the following method: 5 g ZrO.sub.2 and 0.76 g TiCl.sub.4 were added to 100 mL distilled water, and 5 mL sulfuric acid was added; the mixture was heated at about 80° C. until the solid was completely dissolved, 50 ml SiO.sub.2 was added to perform adsorption for 2 h; and 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 500° C. to obtain the catalyst.

(32) The elemental analysis results, the infrared spectrum, and the nuclear magnetic resonance hydrogen spectrum of the teridol obtained in the present Example are the same as those in Example 1. The purity of the teridol obtained in the present Example is 99%, and the yield is 88%.

Example 9

(33) The present Example provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The steps were the same as those in Example 1, except that the catalyst used in the present Example was prepared by the following method: 5 g ZrO.sub.2 and 7.59 g TiCl.sub.4 was added to 100 mL distilled water, and 30 mL sulfuric acid was added; the mixture was heated at about 80° C. until the solid was completely dissolved, 100 ml SiO.sub.2 was added to perform adsorption for 2 h; and 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 700° C. to obtain the catalyst.

(34) The elemental analysis results, the infrared spectrum, and the nuclear magnetic resonance hydrogen spectrum of the teridol obtained in the present Example are the same as those in Example 1. The purity of the teridol obtained in the present Example is 98.5%, and the yield is 90%.

(35) Finally, the methods described in the embodiments 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

(36) The present disclosure provides a hydrolysis method for tert-butyl ester in gadolinium-based contrast agent. The hydrolysis method includes the step of hydrolyzing the tert-butyl ester with a catalyst, wherein the the catalyst is prepared by a method including 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 the solids is dissolved, adding silica to perform reaction for 1 to 5 h, filtering to obtain the solid, washing and calcining the solid. The hydrolysis 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 hydrolysis efficiency.