Deuterium-labeled quetiapine fumarate isotope compound as well as preparation method and food detection method thereof

Abstract

The invention provides a deuterium-labeled quetiapine fumarate isotope compound, a preparation method thereof and a food detection method, and relates to the technical field of food detection. The deuterium-labeled quetiapine fumarate isotope compound is obtained by introducing deuterated Boc piperazine to react with 11-chlorodibenzo [b, f] [1, 4] thiazepine, then removing a protecting group and grafting 2-chloroethoxyethanol. According to the preparation method provided by the invention, by screening proper reaction reagents and optimizing the reaction temperature and the reaction duration, the product conversion rate is greatly improved, and stable mass production in the industry is facilitated. The chemical purity of the deuterium-labeled quetiapine fumarate obtained by the preparation method provided by the invention can reach 98.3% or above, the isotope abundance exceeds 97%, and the deuterium-labeled quetiapine fumarate can be used as an internal standard substance in the field of food quality inspection, and has important practical application value.

Description

Technical Field

[0001] The present invention relates to the technical field of food detection, and in particular to a deuterium-labeled quetiapine fumarate isotope compound, a preparation method thereof, and a food detection method. Background Art

[0002] Quetiapine belongs to the dibenzoxazepine class of atypical antipsychotics and has an affinity for 5-HT, dopamine D2, histamine, H1- and α1-, α2-receptors, and exerts a positive effect by antagonizing various neurotransmitter receptors in the human body. However, quetiapine has the effect of blocking α1-adrenergic receptors, and some people who accidentally ingest quetiapine may experience side effects such as orthostatic hypotension and dizziness. At present, for the detection of quetiapine, the known related detection methods at home and abroad have defects such as too high cost, complex sample treatment, cumbersome operation, and low detection efficiency.

[0003] Isotope dilution mass spectrometry (IDMS) uses a stable isotope-labeled compound as an internal standard reagent, which combines the separation ability of chromatography and the qualitative ability of mass spectrometry well. By detecting the ratio of ions with corresponding mass numbers and comparing it with the standard ratio, the purpose of accurate quantification can be achieved, and at the same time, the matrix effect and recovery difference caused in the sample pretreatment process can be effectively eliminated, improving the detection accuracy. This method is an analytical method with relatively high accuracy and precision.

[0004] At present, there are few reports at home and abroad on the method for detecting quetiapine using IDMS technology, and an appropriate internal standard is a key factor for accurate detection using IDMS technology. Therefore, it is of great significance to study the preparation of a deuterium-labeled quetiapine fumarate isotope compound for accurate and efficient detection of quetiapine. Summary of the Invention

[0005] The purpose of the present invention is to provide a deuterium-labeled quetiapine fumarate isotope compound, a preparation method thereof, and a food detection method to solve the technical problems of high production cost, complex operation, more reaction by-products, and low product conversion rate in the prior art.

[0006] To solve the above technical problems, a preparation method of a deuterium-labeled quetiapine fumarate isotope compound provided by the present invention is as follows:

[0007] Step 1: Fully mix dibenzo[b,f][1,4]thiazepine-11-[10H]one with a first solvent, and continuously stir for 8-10 hours at a reaction temperature of 70-90°C under a nitrogen protection environment to obtain 11-chlorodibenzo[b,f][1,4]thiazepine;

[0008] The reaction temperature in Step 1 is preferably 80°C;

[0009] Step 2: Dissolve the 11-chlorodibenz[b,f][1,4]thiazepine in a second solvent; then successively add deuterated Boc-piperazine and N,N-diisopropylethylamine, and the molar ratio of the feed is 1:(1 - 1.3):2; react fully at the first reaction temperature under a nitrogen protection environment to obtain a first intermediate product;

[0010] Preferably, the molar ratio of the feed in Step 2 is 1:1:2;

[0011] Step 3: Dissolve the first intermediate product in a third solvent, and add a first catalyst, and react fully at the first reaction temperature to obtain a second intermediate product;

[0012] Step 4: Dissolve the second intermediate product in a fourth solvent, successively add 2-chloroethoxyethanol and a second catalyst, and react at a reaction temperature of 100 - 120 °C for 20 - 26 hours to obtain a third intermediate product; the reaction temperature is preferably 105 °C;

[0013] Step 5: Add the third intermediate product and fumaric acid to a fifth solvent, reflux at the second reaction temperature, spin-dry and then filter to obtain the deuterium-labeled quetiapine fumarate isotope compound.

[0014] Furthermore, the first solvent in Step 1 is selected from thionyl chloride, toluene, and tetrahydrofuran;

[0015] The second solvent in Step 2 is selected from dichloromethane, xylene, tetrahydrofuran, and potassium vinyltrifluoroborate;

[0016] The third solvent in Step 3 is selected from toluene, tetrahydrofuran, and dichloromethane; preferably dichloromethane;

[0017] The fourth solvent in Step 4 is selected from toluene, tetrahydrofuran, and dichloromethane; preferably toluene;

[0018] The fifth solvent in Step 5 is selected from acetone, toluene, and tetrahydrofuran.

[0019] Furthermore, the first catalyst in Step 3 is selected from a hydrochloric acid solution of 1,4-dioxane, palladium acetate, tris(dibenzylideneacetone)dipalladium, and bis(triphenylphosphine)palladium dichloride.

[0020] Furthermore, the second catalyst in Step 4 is selected from sodium bicarbonate, palladium acetate, sodium iodide, and tetrabutylammonium bromide.

[0021] Furthermore, the molar ratio of the first intermediate product to the first catalyst in Step 3 is 1:(1 - 2).

[0022] Further, the molar ratio of the second intermediate, 2-chloroethoxyethanol, and the second catalyst described in step 4 is 1:(1 - 2):0.1, and the preferred molar ratio is 1:1.2:0.1.

[0023] Further, the molar ratio of the third intermediate and fumaric acid described in step 5 is 1:(1 - 1.2).

[0024] Further, the first reaction temperature is 100 - 120 °C; preferably 120 °C;

[0025] The second reaction temperature is 40 - 60 °C, preferably 50 °C.

[0026] The present invention also provides a deuterium-labeled quetiapine fumarate isotope compound obtained by the above preparation method, and the structural formula is as follows:

[0027]

[0028] On the other hand, the present invention also provides a method for food detection, mainly using the deuterium-labeled quetiapine fumarate isotope compound obtained by the above preparation method as an internal standard.

[0029] Adopting the above technical solutions, the present invention has the following beneficial effects:

[0030] The deuterium-labeled quetiapine fumarate isotope compound, its preparation method and food detection method provided by the present invention react deuterated Boc piperazine with 11-chlorodibenzo[b,f][1,4]thiazepine, then remove the protecting group and connect 2-chloroethoxyethanol to obtain the deuterium-labeled quetiapine fumarate isotope compound. The preparation method provided by the present invention selects appropriate reaction reagents, optimizes the reaction temperature and reaction duration, and greatly improves the conversion rate in the large-scale production process. Compared with the method for synthesizing quetiapine by thiourea, quinoxaline and chloroacetyl chloride in the prior art, the preparation method provided by the present invention is simpler, easier to operate, the reaction process is easy to control, the chemical purity of the obtained deuterium-labeled quetiapine fumarate isotope compound can reach more than 98.3%, and the isotope abundance exceeds 97%, which can be used as an internal standard in the field of food quality inspection and has important practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0032] Figure 1 A schematic diagram of the synthetic route of the preparation method of the deuterium-labeled quetiapine fumarate isotope compound provided by the present invention;

[0033] Figure 2 This is the hydrogen spectrum of the deuterium-labeled quetiapine fumarate isotope compound prepared in Example 1. DETAILED DESCRIPTION

[0034] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] The present invention is further explained below in conjunction with specific implementation modes.

[0036] like Figure 1 As shown, the preparation method of the deuterium-labeled quetiapine fumarate isotope compound provided by the present invention comprises the following specific steps:

[0037] Step 1: fully mix dibenzo[b,f][1,4]thiazepine-11-[10H]one with the first solvent, and continuously stir at 70-90° C. for 8-10 hours in a nitrogen atmosphere to obtain 11-chlorodibenzo[b,f][1,4]thiazepine;

[0038] The first solvent is selected from thionyl chloride, toluene, and tetrahydrofuran;

[0039] Step 2: dissolving the 11-chlorodibenzo[b,f][1,4]thiazepine in a second solvent; then sequentially adding deuterated Boc piperazine and N,N-diisopropylethylamine, with a molar ratio of 1:(1-1.3):2; fully reacting at 100-120° C. in a nitrogen protection environment to obtain a first intermediate product;

[0040] The second solvent is selected from dichloromethane, xylene, tetrahydrofuran, and potassium ethylene trifluoroborate;

[0041] Step 3: dissolving the first intermediate product in a third solvent, adding the first catalyst in a molar ratio of the first intermediate product: the first catalyst = 1: (1-2), and fully reacting at 100-120° C. to obtain a second intermediate product;

[0042] The third solvent is selected from toluene, tetrahydrofuran, and dichloromethane;

[0043] The first catalyst is selected from 1,4-dioxane-hydrochloric acid solution, palladium acetate, tris(dibenzylideneacetone)dipalladium, and bistriphenylphosphine palladium dichloride;

[0044] Step 4: Dissolve the second intermediate in a fourth solvent, and then successively add 2-chloroethoxyethanol and a second catalyst in a molar ratio of 1:(1 - 2):0.1, and react at 100 - 120 °C for 20 - 26 hours to obtain a third intermediate;

[0045] The fourth solvent is selected from toluene, tetrahydrofuran, and dichloromethane;

[0046] The second catalyst is selected from sodium bicarbonate, palladium acetate, sodium iodide, and tetrabutylammonium bromide;

[0047] Step 5: Add the third intermediate and fumaric acid to a fifth solvent in a molar ratio of 1:(1 - 1.2), reflux at 40 - 60 °C, spin-dry, and then filter to obtain the deuterium-labeled quetiapine fumarate isotope compound;

[0048] The fifth solvent is selected from acetone, toluene, and tetrahydrofuran.

[0049] Example 1

[0050] As Figure 2 shown, the deuterium-labeled quetiapine fumarate isotope compound is prepared by using the method provided by the present invention.

[0051] S1. Dissolve 4 g of dibenzo[b,f][1,4]thiazepin-11-[10H]one in 100 ml of thionyl chloride, and raise the temperature to 80 °C. Under nitrogen protection, continuously stir for 8 hours. After the reaction is completed, quench with water, then extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure. The crude product is purified by Flash column chromatography to obtain 3 g of 11-chlorodibenzo[b,f][1,4]thiazepine.

[0052] S2. Take 1.5 g of 11-chlorodibenzo[b,f][1,4]thiazepine and dissolve it in 10 mL of xylene. Add 1.5 g of deuterated Boc piperazine, raise the temperature to 120 °C, add 2 g of N,N-diisopropylethylamine. Under nitrogen protection, after the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure. The crude product is purified by Flash column chromatography to obtain 1.1 g of the first intermediate.

[0053] S3. Take 1.1 g of the first intermediate and dissolve it in 20 mL of dichloromethane. Dropwise add an equimolar amount of a hydrochloric acid solution of dioxane, and after reacting at 120 °C for a continuous period, spin-dry the solvent to obtain the second intermediate.

[0054] S4. Weigh the second intermediate product, 2-chloroethoxyethanol, and sodium iodide in a molar ratio of 1:1:0.1 in sequence. Then dissolve the second intermediate product and 2-chloroethoxyethanol in toluene, add sodium iodide, and react at 105 °C for 24 hours to obtain deuterated quetiapine.

[0055] S5. Dissolve deuterated quetiapine and fumaric acid in acetone in a ratio of 1:1, reflux at 50 °C, and spin-dry to obtain the target product. It can be calculated from the Figure 2 hydrogen nuclear magnetic resonance spectrum that for the 300 mg of deuterium-labeled quetiapine fumarate isotope compound obtained in this example, the chemical purity is above 98.3%.

[0056] Example 2

[0057] This example verified the effects of using different solvents on the yield, chemical purity, and isotope abundance of the target product, deuterium-labeled quetiapine fumarate isotope compound.

[0058] S1. Dissolve 12 g of dibenzo[b,f][1,4]thiazepin-11-[10H]one in 300 ml of thionyl chloride, and heat to 80 °C. Under nitrogen protection, stir continuously for 8 hours. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and then distill off the solvent under reduced pressure. The crude product is purified by Flash column chromatography to obtain 9 g of 11-chlorodibenzo[b,f][1,4]thiazepine.

[0059] S2. Take 4.5 g of 11-chlorodibenzo[b,f][1,4]thiazepine and dissolve it in 30 mL of xylene. Add deuterated Boc-piperazine, heat to 120 °C, add 6 g of N,N-diisopropylethylamine. Under nitrogen protection, after the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and then distill off the solvent under reduced pressure. The crude product is purified by Flash column chromatography to obtain 3.3 g of the first intermediate product.

[0060] S3. Take 3.3 g of the first intermediate product and dissolve it in 60 mL of dichloromethane. Dropwise add an equimolar amount of hydrochloric acid solution of 1,4-dioxane. After reacting at 120 °C continuously, spin-dry the solvent to obtain the second intermediate product.

[0061] S4. Weigh the second intermediate product, 2-chloroethoxyethanol, and sodium iodide in a molar ratio of 1:2:0.1 in sequence. First, mix the second intermediate product and 2-chloroethoxyethanol evenly and dissolve them in three solvents, namely toluene, isopropanol, and tetrahydrofuran, to obtain three groups of reaction solutions. Then add sodium iodide to the three groups of reaction solutions respectively, and react at 105 °C for 22 hours to obtain three groups of deuterated quetiapine.

[0062] S5. Dissolve deuterated quetiapine and fumaric acid in acetone in a ratio of 1:1, reflux at 50 °C, and evaporate to dryness to obtain three groups of deuterium-labeled isotopic compounds of quetiapine fumarate; among them, the deuterium-labeled isotopic compound of quetiapine fumarate prepared using toluene as the solvent is labeled as Example 2-1, the deuterium-labeled isotopic compound of quetiapine fumarate prepared using isopropanol as the solvent is labeled as Example 2-2, and the deuterium-labeled isotopic compound of quetiapine fumarate prepared using tetrahydrofuran as the solvent is labeled as Example 2-3.

[0063] Calculate the yields, chemical purities, and isotopic abundances of the three groups of deuterium-labeled isotopic compounds of quetiapine fumarate obtained in Example 2 as shown in Table 1:

[0064] Table 1. Determination results of yields, chemical purities, and isotopic abundances of three groups of deuterium-labeled isotopic compounds of quetiapine fumarate in Example 2

[0065] Sample Yield (%) Chemical purity (%) Isotope abundance (% atom) Example 2-1 56.4 99.3 97.35 Example 2-2 20.3 98.6 97.15 Example 2-3 58.6 98.5 97.28

[0066] As can be seen from Table 1, when isopropanol is selected as the fourth solvent in Step 4, on the premise that other preparation conditions are the same, the yield of the deuterium-labeled isotopic compound of quetiapine fumarate is only 20.3%; when, according to the preparation method provided by the present invention, toluene and tetrahydrofuran are preferably used as the fourth solvent in Step 4, the yields of the deuterium-labeled isotopic compounds of quetiapine fumarate can both reach more than 56%. Although the selection of the type of the fourth solvent has a significant impact on the yield of the target isotopic compound, it has no obvious impact on the chemical purity and isotopic abundance of the already generated target isotopic compound. The chemical purities of the three groups of isotopic compounds can all reach more than 98.3%, and the isotopic abundances are above 97%.

[0067] Example 3

[0068] S1. Dissolve 4 g of dibenzo[b,f][1,4]thiazepin-11-[10H]one in 100 ml of tetrahydrofuran, and heat to 80 °C. Under nitrogen protection, stir continuously for 10 hours. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure. The crude product is purified by Flash column chromatography to obtain 3 g of 11-chlorodibenzo[b,f][1,4]thiazepine.

[0069] S2. Dissolve 1.5 g of 11-chlorodibenzo[b,f][1,4]thiazepine in 10 mL of xylene, add deuterated Boc-piperazine, heat to 120 °C, add 2 g of N,N-diisopropylethylamine. Under nitrogen protection, after the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and then distill off the solvent under reduced pressure. The crude product is purified by flash column chromatography to obtain 1.1 g of the first intermediate product.

[0070] S3. Dissolve 1.1 g of the first intermediate product obtained in step S2 in 20 mL of dichloromethane, dropwise add an equimolar amount of a hydrochloric acid solution of 1,4-dioxane, react at 120 °C continuously, and then spin-dry the solvent to obtain the second intermediate product.

[0071] S4. Weigh the second intermediate product, 2-chloroethoxyethanol, and sodium iodide in a molar ratio of 1:1:0.1 in sequence. Then dissolve the second intermediate product and 2-chloroethoxyethanol in toluene, add sodium iodide, and react at 105 °C for 25 hours to obtain deuterated quetiapine.

[0072] S5. Dissolve deuterated quetiapine and fumaric acid in acetone in a ratio of 1:1, reflux at 50 °C, and then spin-dry to obtain the target product, the deuterium-labeled fumarate quetiapine isotope compound.

[0073] Example 4

[0074] S1. Dissolve 4 g of dibenzo[b,f][1,4]thiazepine-11-[10H]one in 100 mL of tetrahydrofuran, heat to 80 °C. Under nitrogen protection, stir continuously for 10 hours. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and then distill off the solvent under reduced pressure. The crude product is purified by flash column chromatography to obtain 3 g of 11-chlorodibenzo[b,f][1,4]thiazepine.

[0075] S2. Dissolve 1.5 g of 11-chlorodibenzo[b,f][1,4]thiazepine in 10 mL of xylene, add deuterated Boc-piperazine, heat to 120 °C, add 2 g of N,N-diisopropylethylamine. Under nitrogen protection, after the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and then distill off the solvent under reduced pressure. The crude product is purified by flash column chromatography to obtain 1.1 g of the first intermediate product.

[0076] S3. Dissolve 1.1 g of the first intermediate product obtained in step S2 in 20 mL of dichloromethane, dropwise add an equimolar amount of a hydrochloric acid solution of 1,4-dioxane, react at 120 °C continuously, and then spin-dry the solvent to obtain the second intermediate product.

[0077] S4. Weigh the second intermediate product, 2-chloroethoxyethanol, and sodium iodide in a molar ratio of 1:1:0.1 in sequence. Then dissolve the second intermediate product and 2-chloroethoxyethanol in toluene, add sodium iodide, and react at 105 °C for 26 hours to obtain deuterated quetiapine.

[0078] S5. Dissolve deuterated quetiapine and fumaric acid in acetone in a ratio of 1:1, reflux at 50 °C, and spin-dry to obtain the target product, the deuterium-labeled isotopic compound of quetiapine fumarate.

[0079] The yields, chemical purities, and isotope abundances of the three groups of deuterium-labeled isotopic compounds of quetiapine fumarate obtained in Examples 1, 3, and 4 are calculated respectively as shown in Table 2:

[0080] Table 2 Measurement results of the yields, chemical purities, and isotope abundances of the isotopic compounds obtained in Examples 1, 3, 4, and 2-1

[0081]

[0082]

[0083] It can be seen from Table 2 that on the premise of the same other conditions, the yield of the isotopic compound obtained in Example 2-1 is significantly lower than that of other examples, indicating that increasing the polymerization reaction time in Step 4 can significantly improve the yield of the target product, the deuterium-labeled quetiapine fumarate; by comparing the yields of the three groups of isotopic compounds obtained in Examples 1, 3, and 4, it can be seen that when the reaction time reaches 25 hours, and then continue to increase the reaction time, the yield increase is less, proving that when the reaction time reaches 25 hours, the reaction is basically complete. Therefore, the reaction time in Step 4 of the preparation method provided by the present invention is 20 - 26 hours, and preferably 24 - 26 hours considering the cost.

[0084] Table 3 Comparison of the measurement results of the yields, chemical purities, and isotope abundances of the deuterium-labeled isotopic compounds of quetiapine fumarate obtained in Examples 1 - 4

[0085]

[0086] In summary, the present invention provides a deuterium-labeled quetiapine fumarate isotope compound, a preparation method thereof, and a food detection method. During the preparation process, deuterated Boc piperazine is introduced to react with 11-chlorodibenzo[b,f][1,4]thiazepine. By selecting an appropriate solvent and reaction time, the yield of the deuterium-labeled quetiapine fumarate isotope compound can be significantly improved. In addition, the chemical purity of the stable isotope compound prepared according to the method provided by the present invention can reach more than 98.3%, and the isotope abundance exceeds 97%. Compared with the existing industrial method for synthesizing quetiapine, the process is more stable and easy to operate, which is conducive to the large-scale production of the deuterium-labeled quetiapine fumarate isotope compound with high purity and high isotope abundance.

[0087] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features. These modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a deuterium-labeled quetiapine fumarate isotope compound, characterized in that: The specific steps are as follows: Step 1: fully mix dibenzo[b,f][1,4]thiazepine-11-[10H]one with the first solvent, and continuously stir at 70-90° C. for 8-10 hours in a nitrogen atmosphere to obtain 11-chlorodibenzo[b,f][1,4]thiazepine; Step 2: dissolving the 11-chlorodibenzo[b,f][1,4]thiazepine in a second solvent; then sequentially adding deuterated Boc piperazine and N,N-diisopropylethylamine in a molar ratio of 1:(1-1.3):2; reacting the mixture fully at a first reaction temperature in a nitrogen protection environment to obtain a first intermediate product; Step 3: dissolving the first intermediate product in a third solvent, adding a first catalyst, and reacting the mixture at a first reaction temperature to obtain a second intermediate product; Step 4: dissolving the second intermediate product in a fourth solvent, adding 2-chloroethoxyethanol and a second catalyst in sequence, and reacting at a reaction temperature of 100-120° C. for 20-26 hours to obtain a third intermediate product; Step 5: adding the third intermediate product and fumaric acid to the fifth solvent, refluxing at the second reaction temperature, spinning and filtering to obtain the deuterium-labeled quetiapine fumarate isotope compound.

2. The preparation method according to claim 1, characterized in that: In step 1, the first solvent is selected from thionyl chloride, toluene, and tetrahydrofuran; In step 2, the second solvent is selected from dichloromethane, xylene, tetrahydrofuran, and potassium ethylene trifluoroborate; The third solvent in step 3 is selected from toluene, tetrahydrofuran, and dichloromethane; The fourth solvent in step 4 is selected from toluene, tetrahydrofuran, and dichloromethane; The fifth solvent in step 5 is selected from acetone, toluene, and tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that: The first catalyst described in step 3 is selected from a hydrochloric acid solution of 1,4-dioxane, palladium acetate, tris(dibenzylideneacetone)dipalladium, and bistriphenylphosphine palladium dichloride.

4. The preparation method according to claim 1, characterized in that: The second catalyst described in step 4 is selected from sodium bicarbonate, palladium acetate, sodium iodide, and tetrabutylammonium bromide.

5. The preparation method according to claim 1, characterized in that: In step 3, the molar ratio of the first intermediate product to the first catalyst is 1:(1-2).

6. The preparation method according to claim 1, characterized in that: In step 4, the molar ratios of the second intermediate product, 2-chloroethoxyethanol and the second catalyst are 1:(1-2):0.1 respectively.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the third intermediate product to fumaric acid in step 5 is 1:(1-1.2).

8. The preparation method according to claim 1, characterized in that: The first reaction temperature is 100-120°C; The second reaction temperature is 40-60°C.

9. A deuterium-labeled quetiapine fumarate isotope compound, characterized in that: The compound is prepared by the method according to any one of claims 1 to 8, and the structural formula is as follows:

10. A method for food testing, characterized in that: The deuterium-labeled quetiapine fumarate isotope compound prepared according to the method according to any one of claims 1 to 8 or the compound according to claim 9 is used as the internal standard.

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