Preparation method of gadotetrol impurity compound, prepared compound and application thereof

Abstract

The invention belongs to the field of detection and analysis, and particularly relates to a method for preparing a compound as shown in a formula I. The method comprises the following steps: mixing and reacting a compound as shown in a formula II and M1-C (O)-CH2-M2 in a solvent to obtain an intermediate product; mixing the intermediate product with alkali liquor in a solvent, and reacting to obtain a reaction product; and separating the reaction product by preparative liquid chromatography, and collecting the components at the spectral peak of the compound shown in the formula I. The invention further relates to the compound shown in the formula I and application thereof. The compound prepared by the method disclosed by the invention can be used as a standard substance and is used for effectively controlling the content of impurities in gadotetrol or raw materials thereof; # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the field of detection and analysis, and specifically relates to a method for preparing a gadoteridol impurity compound, and also relates to the prepared gadoteridol impurity compound and its application. Background Art

[0002] Gadoteridol is used for enhanced magnetic resonance imaging (MR) examinations of lesions in the brain, spine, and surrounding tissues. Gadoteridol is primarily used to shorten the T1 relaxation time. On T1-weighted images, gadoteridol selectively enhances the signal of tissues in areas where it can be distributed, such as the pituitary gland and meningeal structures without any blood-brain barrier, the choroid plexus, and low-flow venous regions, as well as central nervous system lesions with altered blood-brain barrier permeability. Gadoteridol is also used for whole-body MR examinations, including those of the head, neck, liver, breast, musculoskeletal system, and soft tissue.

[0003] The impurities of gadoteridol listed in the United States Pharmacopoeia that require strict control include the impurities shown in the following formula. However, there is currently a lack of relevant preparation methods for these impurities, making it impossible to effectively control the content of the impurities shown in the following formula in gadoteridol or its raw materials by providing impurity standards. Therefore, there is an urgent need for methods to prepare high-purity impurities to effectively control the content of the impurities shown in the following formula in gadoteridol or its raw materials:

[0004] Summary of the Invention

[0005] One of the purposes of the present application is to provide a method for preparing the compound represented by formula I to obtain a high-purity gadoteridol impurity compound, which can be used as a standard to effectively control the impurity content in gadoteridol or its raw materials.

[0006] To achieve the above objectives, the present application provides a method for preparing the compound represented by formula I, comprising the following steps:

[0007] The compound represented by formula II and M1-C(O)-CH2-M2 are mixed and reacted in a solvent to obtain an intermediate product;

[0008] mixing the intermediate product with an alkali solution in a solvent and reacting the mixture to obtain a reaction product;

[0009] The reaction product is separated by preparative liquid chromatography, and the components at the peak of the compound represented by formula I are collected;

[0010]

[0011] in,

[0012] M1, M2 and X are each independently selected from halogen, cyano, nitro, sulfonyl;

[0013] R1, R2 and R3 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 alkynyl, halogenated C2-C6 alkynyl.

[0014] In any embodiment, the main peak of the preparative liquid chromatography of the reaction product is the peak of the compound represented by Formula I.

[0015] In any embodiment, M1, M2 and X are each independently selected from halogen.

[0016] In any embodiment, M1, M2 and X are each independently selected from fluorine, chlorine, bromine and iodine.

[0017] In any embodiment, the M1-C(O)-CH2-M2 is selected from 1,2-dibromoacetyl, 1,2-dichloroacetyl, 1,2-difluoroacetyl, and 1,2-diiodoacetyl.

[0018] In any embodiment, the M1-C(O)-CH2-M2 is 1,2-dibromoacetyl.

[0019] In any embodiment, X is bromine.

[0020] In any embodiment, R1, R2 and R3 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkyl.

[0021] In any embodiment, R1, R2 and R3 are each independently selected from C2-C5 alkyl and halogenated C2-C5 alkyl.

[0022] In any embodiment, R1, R2 and R3 are each independently selected from C1-C6 alkyl.

[0023] In any embodiment, R1, R2 and R3 are each independently selected from C2-C5 alkyl.

[0024] In any embodiment, R1, R2 and R3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.

[0025] In any embodiment, R1, R2 and R3 are tert-butyl groups.

[0026] In any embodiment, in the step of preparing the intermediate product, the reaction temperature is 0°C-40°C, preferably 5°C-30°C, more preferably 10°C-30°C, for example 10°C, 15°C, 20°C, 25°C, 35°C.

[0027] In any embodiment, in the step of preparing the intermediate product, the reaction time is 0.5-10 hours, preferably 1-4 hours, such as 2, 3, 5, 6, 7, 8, or 9 hours.

[0028] In any embodiment, in the step of preparing the intermediate product, the molar ratio of the compound represented by formula II to the M1-C(O)-CH2-M2 is 1:10-1:0.5, preferably 1:5-1:1, for example 1:8, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1.5.

[0029] In any embodiment, in the step of preparing the intermediate product, the compound represented by formula II is dissolved in a solvent, and M1-C(O)-CH2-M2 is added to the obtained solution to react to obtain the intermediate product.

[0030] In any embodiment, M1-C(O)-CH2-M2 is slowly added to the solution.

[0031] In any embodiment, M1-C(O)-CH2-M2 is added dropwise to the solution.

[0032] In any embodiment, the dropping speed is 0.5-4.0 mL / min, preferably 0.5-2.0 mL / min, such as 1, 1.5 mL / min.

[0033] In any embodiment, in the step of preparing the reaction product, the reaction temperature is 30°C-90°C, preferably 30°C-70°C, preferably 30°C-60°C, for example 35°C, 40°C, 45°C, 50°C, 55°C, 65°C, 75°C, 80°C, 85°C.

[0034] In any embodiment, in the step of preparing the reaction product, the reaction time is 0.5-10 hours, preferably 1-6 hours, for example 2, 3, 4, 5, 6, 7, 8, or 9 hours.

[0035] In any embodiment, in the step of preparing the reaction product, the molar ratio of the intermediate product to the alkali in the alkali solution is 1:1-1:10, preferably 1:3-1:8, for example 1:2, 1:4, 1:5, 1:6, 1:7, 1:9.

[0036] In any embodiment, the operating conditions of the preparative liquid chromatography include one or more of the following:

[0037] The chromatographic column is a C18 chromatographic column, preferably a YCM AQ C18 chromatographic column;

[0038] The column temperature is 15°C-35°C, preferably 20°C-30°C, for example 25°C;

[0039] The mobile phase consists of mobile phase A and mobile phase B, wherein mobile phase A is a trifluoroacetic acid aqueous solution with a concentration of 0.05 wt%-0.2 wt% (0.1 wt%, 0.15 wt%), and mobile phase B is acetonitrile;

[0040] The elution program of the mobile phase is as follows: from 0 min to 18 min, the proportion of mobile phase A is 100 vol%; from 18 min to 22 min, the proportion of mobile phase A is uniformly reduced from 100 vol% to 95-99 vol% (e.g., 96 vol%, 97 vol%, 98 vol%); from 22 min to 30 min, the proportion of mobile phase A is 95-99 vol% (e.g., 96 vol%, 97 vol%, 98 vol%);

[0041] The flow rate of the mobile phase is 20-100 mL / min, for example, 30, 40, 50, 60, 70, 80, 90 mL / min;

[0042] The injection volume is 1-10 mL, for example, 5 or 10 mL;

[0043] The detector is an ultraviolet detector;

[0044] The detection wavelength is 200-220 nm, for example 210 nm.

[0045] In any embodiment, in the step of preparing the intermediate product, an acid binding agent is added to the reaction system before or during the reaction.

[0046] In any embodiment, in the step of preparing the intermediate product, after the reaction, the obtained reaction product is dried to obtain the intermediate product.

[0047] In any embodiment, in the step of preparing the intermediate product and the step of preparing the reaction product, the solvent is independently selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetone, methanol, and ethanol.

[0048] In any embodiment, in the step of preparing the intermediate product, the ratio of the weight of the compound represented by Formula II to the volume of the solvent is 1:20-1:5 g / mL, for example, 1:8 g / mL, 1:10 g / mL, 1:15 g / mL, 1:18 g / mL.

[0049] In any embodiment, in the step of preparing the intermediate product, the molar ratio of the compound represented by formula II to the acid binding agent is 1:3-1:1.5, for example, 1:2, 1:2.5, or 1:2.8.

[0050] In any embodiment, in the step of preparing the intermediate product, the acid binding agent is selected from one or more of triethylamine, pyridine, and N-methylmorpholine.

[0051] In any embodiment, in the step of preparing the intermediate product, M1-C(O)-CH2-M2 is added to the solution at 0°C-40°C (preferably 5°C-30°C, more preferably 10°C-30°C, such as 15°C, 20°C, 25°C).

[0052] In any embodiment, in the step of preparing the intermediate product, before drying, the obtained reaction product is washed and the organic phase is separated for drying.

[0053] In any embodiment, in the step of preparing the intermediate product, washing is performed with water.

[0054] In any embodiment, in the step of preparing the intermediate product, washing is performed 1-3 times.

[0055] In any embodiment, in the step of preparing the intermediate product, the volume ratio of water used in each washing to the solvent used is 1:1-3:1, for example, 2:1.

[0056] In any embodiment, in the step of preparing the intermediate product, during drying, a desiccant is first used to remove water, and then the product is evaporated to dryness.

[0057] In any embodiment, in the step of preparing the intermediate product, the desiccant is selected from one or more of anhydrous sodium sulfate and anhydrous magnesium sulfate.

[0058] In any embodiment, in the step of preparing the reaction product, the collected components at the peak of the compound represented by Formula I are dried.

[0059] In any embodiment, in the step of preparing the reaction product, the ratio of the weight of the intermediate product to the volume of the solvent is 1:20-1:5 g / mL, for example 1:8 g / mL, 1:10 g / mL, 1:15 g / mL, 1:17 g / mL.

[0060] In any embodiment, in the step of preparing the reaction product, the alkali solution is an inorganic alkali solution.

[0061] In any embodiment, in the step of preparing the reaction product, the alkali solution is selected from one or more solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate.

[0062] In any embodiment, in the step of preparing the reaction product, the concentration of the alkali solution is 10 wt % to 60 wt %, for example, 20 wt %, 30 wt %, 40 wt %, or 50 wt %.

[0063] In any embodiment, the collected fractions at the peak of the compound represented by Formula I are lyophilized; preferably, the lyophilization temperature is -85°C to -75°C, for example -80°C.

[0064] In some embodiments, the spectral peak of the compound represented by Formula I is determined by liquid chromatography-mass spectrometry.

[0065] In any embodiment, the operating conditions of the liquid chromatography include one or more of the following:

[0066] The chromatographic column is a C18 column, which can be Waters X Bridge C18;

[0067] The column temperature is 30°C-50°C, preferably 35°C-45°C, for example 40°C;

[0068] The mobile phase consists of mobile phase A and mobile phase B, wherein mobile phase A is 0.005 mol / L-0.02 mol / L (e.g., 0.01 mol / L, 0.015 mol / L) NH4HCO3 aqueous solution, and mobile phase B is acetonitrile;

[0069] The elution program of the mobile phase is as follows: 0 min-1.6 min, mobile phase B is uniformly increased from 3-6 vol% (e.g., 5 vol%) to 93-97 vol% (e.g., 94 vol%, 95 vol%), 1.6 min-3 min, mobile phase B accounts for 93-97 vol% (e.g., 94 vol%, 95 vol%);

[0070] The flow rate of the mobile phase is 1-5 mL / min, for example, 2, 3, or 4 mL / min;

[0071] The injection volume is 1-10 μL, for example, 5 μL;

[0072] The detector is an ultraviolet detector;

[0073] The detection wavelengths are 214 nm and 254 nm.

[0074] In any embodiment, the operating conditions of the mass spectrometer include one or more of the following:

[0075] The quadrupole temperature is 90-110°C, for example, 95°C, 100°C;

[0076] The ion source temperature is 280-320°C, for example 300°C;

[0077] An atmospheric pressure spray ion source was used;

[0078] Detection was performed in positive ion mode;

[0079] Use full scan mode;

[0080] The scanning range was 100–1200 m / z;

[0081] The input voltage at the capillary outlet is 3500-4500V, for example 4000V.

[0082] In another aspect, the present application provides a compound of formula I, which is prepared by the method of the first aspect of the present application; wherein X is as defined in the first aspect of the present application; preferably, the purity of the compound of formula I is ≥95%, for example, ≥96%, ≥97%, ≥98%, ≥99%;

[0083]

[0084] In another aspect, the present application provides the use of the compound of formula I prepared by the method of the first aspect of the present application or the compound of formula I of the second aspect of the present application in the purity detection or purity control of gadoteridol or its raw materials; wherein, X is defined as described in the first aspect of the present application;

[0085]

[0086] In this application, unless otherwise specified, the terms involved are defined as follows:

[0087] The term "halogen" refers to atoms of Group VIIA elements, including fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and the like.

[0088] The term "cyano" refers to a -CN group.

[0089] The term "nitro" refers to a -NO2 group.

[0090] The term "sulfonyl" refers to a -S(O)2 group.

[0091] The term "C1-C6 alkyl" refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, specifically including C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.

[0092] The term "halogenated C1-C6 alkyl" refers to a C1-C6 alkyl group in which one or more H groups are replaced by a halogen, wherein "C1-C6 alkyl" and "halogen" are as defined above. Specifically, it includes halogenated C1-C4 alkyl, halogenated C1-C3 alkyl, halogenated C1-C2 alkyl, and halogenated C2-C4 alkyl, such as monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromomethyl, 2,2,2-trifluoroethyl, 1,2,3-tribromo-n-propyl, and 1,2,3-tribromo-n-butyl.

[0093] The term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 6 carbon atoms and having at least one unsaturated carbon-carbon double bond, specifically including C2-C5 alkenyl, C2-C4 alkenyl, such as ethenyl, propenyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, etc.

[0094] The term "halogenated C2-C6 alkenyl" refers to a C2-C6 alkenyl group in which one or more H atoms are replaced by a halogen, wherein "C2-C6 alkenyl" and "halogen" are as defined above. Specifically, it includes halogenated C2-C5 alkenyl, halogenated C2-C4 alkenyl, and halogenated C2-C3 alkenyl groups, such as 1,2-dichlorovinyl, 1,3-dibromopropenyl, 1,2-dichloro-n-butenyl, 1,4-dibromo-n-butenyl, 1,3-dibromoisobutenyl, and 1,5-dichloro-n-pentenyl.

[0095] The term "C2-C6 alkynyl" refers to a straight or branched hydrocarbon group containing 2 to 6 carbon atoms and having at least one unsaturated carbon-carbon triple bond, specifically including C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, such as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, etc.

[0096] The term "halogenated C2-C6 alkynyl" refers to a C2-C6 alkynyl group in which one or more H atoms are replaced by a halogen, wherein "C2-C6 alkynyl" and "halogen" are as defined above. Specifically, it includes halogenated C2-C5 alkynyl, halogenated C2-C4 alkynyl, and halogenated C2-C3 alkynyl, such as dichloroethynyl, 1,3-dibromopropynyl, 1,3-dichloro-1-butynyl, 1,4-dichloro-2-butynyl, 1,3-dibromo-1-pentynyl, 1,4-dichloro-2-pentynyl, and 1,4-dichloro-3-methyl-1-butynyl.

[0097] Beneficial effects achieved by this application:

[0098] The impurity compound prepared by the method of the present application has a high purity of more than 95%, and can be used as a standard to effectively control the impurity content in gadoteridol or its raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] In order to make the content of this application easier to understand, the following is a further detailed description of this application based on the specific embodiments of this application and in conjunction with the accompanying drawings, wherein

[0100] Figure 1 The mass spectrum and characteristic ion peak magnification of the intermediate of Example 1 of the present application are shown.

[0101] Figure 2 This is a liquid chromatogram of the reaction product of Example 1 of the present application with a detection wavelength of 214 nm.

[0102] Figure 3 This is a liquid chromatogram of the reaction product of Example 1 of the present application with a detection wavelength of 254 nm.

[0103] Figure 4 This is a total ion current chromatogram of the reaction product of Example 1 of the present application.

[0104] Figure 5 This is the mass spectrum corresponding to the maximum chromatographic peak retention time of the reaction product of Example 1 of the present application.

[0105] Figure 6 This is a preparative liquid chromatogram of the reaction product of Example 1 of the present application.

[0106] Figure 7 The target product of Example 1 of the present application 1 HNMR spectrum.

[0107] Figure 8 This is a liquid chromatogram of the test solution of Example 1 of the present application. DETAILED DESCRIPTION

[0108] The embodiments of the present application will be clearly and completely described below in conjunction with the examples. Obviously, the described examples are only some of the examples of the present application, rather than all of the examples. The following description of at least one exemplary embodiment is actually only illustrative and is in no way intended to limit the present application and its application or use. Based on the examples in this application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0109] Example 1 Preparation Method of Gadoterol Impurity

[0110]

[0111] t-Bu-DO3A hydrogen bromide salt (5.95g, 10mmol) was added to a 250mL three-necked flask, 50mL of dichloromethane was added to dissolve it completely, triethylamine (2.12g, 21mmol) was added, the temperature was controlled to below 20°C, bromoacetyl bromide (2.02g, 10mmol) was added dropwise at a rate of 1mL / min, and after the addition was completed, the reaction was maintained at 20°C for 4h to obtain the product. The product was washed twice with 100mL of purified water, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate to remove water, and evaporated to dryness to obtain 5.28g of the intermediate, whose mass spectrum is shown as follows Figure 1 As shown, M / E: 555.4[(M+H) + ].

[0112] To the intermediate (1.61 g, 2.9 mmol) was added 16 mL of anhydrous methanol, and 2.33 g of a 30 wt% sodium hydroxide solution was added, and the mixture was kept at 60° C. for 2 h to obtain a reaction product. The reaction product was detected by liquid chromatography-mass spectrometry, and the liquid chromatogram of the reaction product with detection wavelengths of 214 nm and 254 nm was obtained. Figure 2-3 The total ion current of the reaction products is shown in Figure 4 As shown, the mass spectrum corresponding to the maximum chromatographic peak retention time of the reaction product is as follows Figure 5 shown.

[0113] The peak of impurity F was determined to be M / E: 387 [(M+H) + ].

[0114] Among them, the operating conditions of liquid chromatography are: the chromatographic column is Waters X Bridge C18 (specifications are 50 mm×4.6 mm, ID3.5 μm); the column temperature is 40°C; the mobile phase consists of mobile phase A and mobile phase B, mobile phase A is 0.01 mol / L NH4HCO3 aqueous solution, and mobile phase B is acetonitrile; the elution program of the mobile phase is: 0 min-1.6 min, the mobile phase B increases uniformly from 5 volume % to 95 volume %, 1.6 min-3 min, and the proportion of mobile phase B is 95 volume %; the flow rate of the mobile phase is 2.0 mL / min; the injection volume is 5 μL; the detector is a UV detector; and the detection wavelengths are 214 nm and 254 nm.

[0115] The operating conditions of the mass spectrometer were as follows: quadrupole temperature of 100°C; ion source temperature of 300°C; ion source of ES-API (atmospheric pressure spray ion source); detection mode of Pos (positive ion mode); scan mode of Scan (full scan), with a scan range of 100–1200 m / z; and capillary outlet voltage input voltage (Frag) of 4000 V.

[0116] The reaction product was separated by preparative liquid chromatography and the impurity F component (retention time 7.34 min) was collected, and lyophilized at -80 ° C to obtain 0.62 g of the target product; wherein, the operating conditions of the preparative liquid chromatography are: the chromatographic column is YCM AQ C18 [specifications: 50×250 mm, 12 nm (pore size of filler particles), 10 μm (diameter of filler particles)]; the column temperature is 25 ° C; the mobile phase includes mobile phase A and B, mobile phase A is 0.1 wt% trifluoroacetic acid aqueous solution, and mobile phase B is acetonitrile; the elution program of the mobile phase is: 0 min-18 min, the proportion of mobile phase A is 100 volume%; 18 min-22 min, the proportion of mobile phase A decreases uniformly from 100 volume% to 98 volume%; 22 min-30 min, the proportion of mobile phase A is 98 volume%; the flow rate of the mobile phase is 50 mL / min; the injection volume is 8 mL; the detector is a UV detector, and the detection wavelength is 210 nm. The preparative liquid chromatography of the reaction product is shown in Figure 6 .

[0117] Target product 1 HNMR see Figure 7 , 1 HNMR(400MHz,D2O):2.8105-3.9407(m,16H),4.5354(s,2H),4.0761(s,6H).

[0118] Purity analysis of the product:

[0119] Weigh 20 mg of the target product, add 50 mmol / L ammonium phosphate aqueous solution (pH 7.0) to dissolve, dilute to 10 ml and shake well to obtain the test solution. Use high performance liquid chromatography to detect the test solution. The chromatogram is as shown below: Figure 8 As shown, the retention time of impurity F is 7.081 min (main peak).

[0120] The operating conditions of liquid chromatography were as follows: the chromatographic column was packing L18 (specifications: 25 cm × 4.6 mm); the column temperature was 20°C; the mobile phase consisted of mobile phase A and mobile phase B, wherein mobile phase A was a 50 mmol / L ammonium phosphate aqueous solution (pH 5.0), and mobile phase B was acetonitrile; the elution program of the mobile phase was: 0 min-30 min, with mobile phase A accounting for 87 volume% and mobile phase B accounting for 13 volume%; the flow rate of the mobile phase was 1 mL / min; the injection volume was 20 μL; the detector was an ultraviolet detector; and the detection wavelength was 220 nm.

[0121] The area normalization method was used to calculate the content of impurity F in the test solution, and then the content of impurity F in the target product was calculated, that is, the purity was 95.49%.

[0122] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of this application.

Claims

1. A method for preparing a compound represented by formula I, comprising the following steps: The compound represented by formula II and M1-C(O)-CH2-M2 are mixed and reacted in a solvent to obtain an intermediate product; mixing the intermediate product with an alkali solution in a solvent and reacting the mixture to obtain a reaction product; The reaction product is separated by preparative liquid chromatography, and the components at the peak of the compound represented by formula I are collected; in, M1, M2 and X are each independently selected from halogen, cyano, nitro, sulfonyl; R1, R2 and R3 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 alkynyl, halogenated C2-C6 alkynyl.

2. The method according to claim 1, characterized in that One or more of the following: Said M1, M2 and X are each independently selected from halogen; Said M1, M2 and X are each independently selected from fluorine, chlorine, bromine and iodine; The M1-C(O)-CH2-M2 is selected from 1,2-dibromoacetyl, 1,2-dichloroacetyl, 1,2-difluoroacetyl, and 1,2-diiodoacetyl; The M1-C(O)-CH2-M2 is 1,2-dibromoacetyl; Said X is bromine; Said R1, R2 and R3 are each independently selected from C1-C6 alkyl, halogenated C1-C6 alkyl; Said R1, R2 and R3 are each independently selected from C2-C5 alkyl, halogenated C2-C5 alkyl; Said R1, R2 and R3 are each independently selected from C1-C6 alkyl; Said R1, R2 and R3 are each independently selected from C2-C5 alkyl; Said R1, R2 and R3 are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; The R1, R2 and R3 are tert-butyl groups.

3. The method according to claim 1 or 2, wherein the step of preparing the intermediate product is characterized in that One or more of the following: The reaction temperature is 0°C-40°C; The reaction time is 0.5-10 hours; The molar ratio of the compound represented by formula II to the M1-C(O)-CH2-M2 is 1:10-1:0.

5.

4. The method according to any one of claims 1 to 3, wherein In the step of preparing the intermediate product, the compound represented by formula II is dissolved in a solvent, and M1-C(O)-CH2-M2 is added to the obtained solution to react to obtain the intermediate product.

5. The method according to claim 4, wherein Slowly add M1-C(O)-CH2-M2 to the solution; Preferably, M1-C(O)-CH2-M2 is added dropwise to the solution; More preferably, the dropping speed is 0.5-4.0 mL / min.

6. The method according to any one of claims 1 to 5, wherein the step of preparing the reaction product is characterized in that One or more of the following: The reaction temperature is 30°C-90°C; The reaction time is 0.5-10h; The molar ratio of the intermediate product to the alkali in the alkali solution is 1:1-1:

10.

7. The method according to any one of claims 1 to 6, wherein The operating conditions of the preparative liquid chromatography include one or more of the following: The chromatographic column is a C18 chromatographic column, preferably a YCM AQ C18 chromatographic column; Column temperature is 15°C-35°C; The mobile phase consists of mobile phase A and mobile phase B, wherein mobile phase A is a trifluoroacetic acid aqueous solution with a concentration of 0.05% by weight to 0.2% by weight, and mobile phase B is acetonitrile; The elution procedure of the mobile phase is as follows: 0 min-18 min, the proportion of mobile phase A is 100 vol%; 18 min-22 min, the proportion of mobile phase A decreases uniformly from 100 vol% to 95-99 vol%; 22 min-30 min, the proportion of mobile phase A is 95-99 vol%; The flow rate of the mobile phase is 20-100 mL / min; The injection volume is 1-10 mL; The detector is an ultraviolet detector; The detection wavelength is 200-220nm.

8. The method according to any one of claims 1 to 7, wherein In the step of preparing the intermediate product, an acid binding agent is added to the reaction system before or during the reaction.

9. The method according to any one of claims 1 to 8, characterized in that One or more of the following: In the step of preparing the intermediate product, after the reaction, the obtained reaction product is dried to obtain the intermediate product; In the step of preparing the intermediate product and the step of preparing the reaction product, the solvent is independently selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetone, methanol, and ethanol; In the step of preparing the intermediate product, the ratio of the weight of the compound represented by Formula II to the volume of the solvent is 1:20-1:5 g / mL; In the step of preparing the intermediate product, the molar ratio of the compound represented by formula II to the acid binding agent is 1:3-1:1.5; In the step of preparing the intermediate product, the acid binding agent is selected from one or more of triethylamine, pyridine, and N-methylmorpholine; In the step of preparing the intermediate product, M1-C(O)-CH2-M2 is added to the solution at 0°C-40°C; In the step of preparing the intermediate product, before drying, the obtained reaction product is washed and the organic phase is separated for drying; preferably, the washing is performed with water; preferably, the washing is performed 1-3 times; preferably, the volume ratio of water used in each washing to the solvent used is 1:1-3:1; In the step of preparing the intermediate product, during drying, water is first removed using a desiccant, and then evaporated to dryness; preferably, the desiccant is selected from one or more of anhydrous sodium sulfate and anhydrous magnesium sulfate; In the step of preparing the reaction product, the components at the peak of the compound represented by formula I are dried and collected; In the step of preparing the reaction product, the ratio of the weight of the intermediate product to the volume of the solvent is 1:20-1:5 g / mL; In the step of preparing the reaction product, the alkali solution is an inorganic alkali solution; preferably, the alkali solution is selected from one or more solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate; In the step of preparing the reaction product, the concentration of the alkali solution is 10% to 60% by weight; In the step of preparing the reaction product, the collected components at the spectrum peak of the compound represented by Formula I are freeze-dried; preferably, the freeze-drying temperature is -85°C to -75°C.

10. The method according to any one of claims 1 to 9, wherein The peak of the compound represented by formula I was determined by liquid chromatography-mass spectrometry.

11. The method according to claim 10, wherein: The operating conditions of the liquid chromatography include one or more of the following: The chromatographic column is a C18 column, which can be Waters X Bridge C18; Column temperature is 30℃-50℃; The mobile phase consists of mobile phase A and mobile phase B, wherein mobile phase A is 0.005 mol / L-0.02 mol / L NH4HCO3 aqueous solution and mobile phase B is acetonitrile; The elution program of the mobile phase was as follows: 0 min-1.6 min, mobile phase B increased uniformly from 3-6 vol% to 93-97 vol%, and 1.6 min-3 min, with mobile phase B accounting for 93-97 vol%; The flow rate of the mobile phase was 1-5 mL / min; The injection volume is 1-10 μL; The detector is an ultraviolet detector; The detection wavelengths are 214 nm and 254 nm.

12. The method according to claim 10, wherein: The operating conditions of the mass spectrometer include one or more of the following: The quadrupole temperature is 90-110°C; The ion source temperature is 280-320°C; An atmospheric pressure spray ion source was used; Detection was performed in positive ion mode; Use full scan mode; The scanning range was 100–1200 m / z; The input voltage at the capillary outlet is 3500-4500V.

13. The compound represented by formula I, which is prepared by the method according to any one of claims 1 to 12; wherein, The definition of X is as described in claim 1 or 2; preferably, the purity of the compound represented by formula I is ≥95%; 14. Use of the compound of formula I prepared by the method according to any one of claims 1 to 12 or the compound of formula I according to claim 13 in the purity detection or purity control of gadoteridol or its raw materials; wherein, X is as defined in claim 1 or 2;

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