Chlorpromazine-d6 compound as well as hydrochloride, preparation method and application thereof

Abstract

The invention discloses a chlorpromazine-d6 compound as well as hydrochloride, a preparation method and application thereof, and belongs to the technical field of organic synthesis and analysis detection, the chlorpromazine-d6 compound is 3-(2-chloro-10-phenothiazinyl)-N, N-bis (methyl-d3)-1-propylamine, and the preparation method comprises the following steps: taking 2-chlorophenothiazine as a raw material, adding a catalyst, and reacting at the temperature of 60-80 DEG C for 1-2 hours to obtain the chlorpromazine-d6 compound. Carrying out aza-Michael addition and reductive amination reaction to finally obtain chlorpromazine-d6; the obtained chlorpromazine-d6 is subjected to hydrochloric acid acidification, such that chlorpromazine-d6 hydrochloride is obtained; the invention provides a novel deuterated internal standard substance for analysis and detection. In addition, the invention provides a new process for preparing chlorpromazine-d6 and hydrochloride thereof with proprietary intellectual property rights, the preparation method is novel, and has the advantages of simple operation, mild reaction conditions, short process route, high efficiency, low cost, environmental protection and the like; the obtained chlorpromazine-d6 and the hydrochloride thereof have the advantages of high chemical purity, high deuteration rate, high deuterium atom stability and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis and analytical detection technology, and in particular to a chlorpromazine-d6 compound, its hydrochloride salt, its preparation method, and its application. Background Technology

[0002] Chlorpromazine, with the structure shown in Formula VI, belongs to the phenothiazine class of drugs and has strong sedative and hypnotic effects. It is a controlled psychotropic substance in China. Currently, forensic toxicology identification in such cases faces a dual technical bottleneck: on the one hand, a lack of standardized reference materials; on the other hand, insufficient precision of detection methods. These two major problems severely restrict the efficiency of judicial determination in chlorpromazine poisoning cases.

[0003] .

[0004] In the field of forensic toxicology analysis, the internationally accepted internal standard detection technology has formed a mature system. This technology, which uses deuterated derivatives of the analyte as internal standards, can significantly improve the accuracy and precision of quantitative analysis. Based on this, the synthesis technology of deuterated chlorpromazine compounds has become a key research focus for standard reagent companies. Currently, there are no reports on the synthesis of such deuterated compounds, and the required deuterated chlorpromazine standards are entirely dependent on imports. This supply situation not only drives up testing costs but also affects the efficiency of case investigation due to factors such as logistics cycles and international controls. Summary of the Invention

[0005] One of the objectives of this invention is to provide a chlorpromazine-d6 compound to solve the above-mentioned problems.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a chlorpromazine-d6 compound, chemically named 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propanamine, with the following structural formula (Ⅳ):

[0007] .

[0008] This invention also provides a chlorpromazine-d6 compound hydrochloride, chemically named 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propanamine hydrochloride, with the following structural formula (V):

[0009] .

[0010] The second objective of this invention is to provide a method for preparing the above-mentioned chlorpromazine-d6 compound or its hydrochloride, using 2-chlorophenthiazide as a raw material, undergoing aza-Michael addition and reductive amination reactions to finally obtain chlorpromazine-d6, followed by acidification with hydrochloric acid to obtain chlorpromazine-d6 hydrochloride, specifically including the following steps:

[0011] ;

[0012] (1) Under the action of alkali, compound (I) 2-chlorophenthiazide and compound (II) acrolein undergo an aza-Michael addition reaction to give compound (III) 3-(2-chloro-10-phenthiazinyl)-propanal;

[0013] (2) In the presence of a reducing agent, compound (III) 3-(2-chloro-10-phenthiazinyl)-propanal undergoes reductive amination with deuterated dimethylamine hydrochloride to obtain compound (IV) 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propanamine, i.e. chlorpromazine-d6;

[0014] (3) Acidify compound (IV) 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propane with hydrochloric acid solution to obtain chlorpromazine-d6 hydrochloride.

[0015] The traditional method for synthesizing chlorpromazine involves reacting 1-chloro-3-bromopropane with dimethylamine to obtain N,N-dimethyl-3-chloropropane, which is then reacted with 2-chlorophenthiazide to yield chlorpromazine. Both steps of this method require more than three equivalents of the strong base sodium hydroxide and generate a large amount of solid waste. It is costly and not environmentally friendly.

[0016] Furthermore, if chlorpromazine-d6 is prepared using the current method, deuterated dimethylamine must be used in the first step to introduce deuterium atoms before proceeding with the subsequent reactions. Since deuteration reagents are relatively expensive, low conversion rates during subsequent reactions or loss of intermediates during purification will significantly increase the cost of synthesizing chlorpromazine-d6.

[0017] Specifically, according to the inventors' comparative experiments, the first step of the conventional method for synthesizing chlorpromazine—the reaction of 1-chloro-3-bromopropane with dimethylamine-d6, followed by distillation purification—yields only 56% for the intermediate N,N-dimethyl-3-chloropropane-d6. The subsequent reaction with 2-chlorophenthiazide also yields only 69% chlorpromazine-d6; the total yield for both steps is 38.6%. Based on market prices of various reagents, the chemical cost of synthesizing 10g of chlorpromazine-d6 is approximately 4353 yuan, with dimethylamine-d6 accounting for 97% of the total cost. However, the chemical cost of synthesizing 10g of chlorpromazine-d6 using the method of this invention, such as according to Example 1 described later, is approximately 2420 yuan, with dimethylamine-d6 again accounting for 95% of the total cost.

[0018] If the compound chlorpromazine-d6 of this invention is synthesized using the synthetic method of chlorpromazine-d2 reported in the existing literature (J. Cymerman Craig et al., SYNTHESISOF DEUTERIUM-LABELLED CHLORPROMAZINE AND CHLORPROMAZINE METABOLITES), then two deuterated methyl groups (CD3) need to be attached to the primary amino group (NH2) of the intermediate. This method has at least two drawbacks: (1) In the process of deuteration of primary amines, conventional deuteration methylation reagents (such as iodomethane-d3, dimethyl sulfate-d6, etc.) are used, which can easily produce quaternary ammonium salt byproducts, thereby greatly reducing the product yield and increasing the difficulty of product purification, or almost not being able to stop at the tertiary amine step, resulting in no product being obtained; (2) Even if the deuteration of primary amines is successful, this method requires four steps to achieve the synthesis of chlorpromazine. The increase in steps means increased cost and reduced efficiency; and among the deuteration methylation reagents, the cheapest is deuterated iodomethane. Based on its market price and the required molar mass, its cost is comparable to that of deuterated dimethylamine.

[0019] The method provided by this invention is a novel synthetic route for chlorpromazine, using inexpensive and readily available acrolein as a raw material, and employing a deuteration reagent in the final step, greatly reducing the cost increase brought about by the deuteration reagent. This route only requires two steps to obtain chlorpromazine-d6. The entire route is low-cost, environmentally friendly, has few side reactions, high reaction efficiency, high product purity, and high utilization rate of the deuteration reagent.

[0020] As a preferred technical solution, in step (1): the molar ratio of compound 2-chlorophenthiazide of formula (I) to compound acrolein of formula (II) is 1:1 to 1:5; more preferably, the molar ratio is 1:3, which results in a higher reaction yield and fewer byproducts;

[0021] The base used is selected from one or more of the following: triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, K2CO3, Cs2CO3, LiOH, NaOH, and KOH; DBU or potassium tert-butoxide are further preferred, as they produce fewer reaction byproducts and have a higher yield.

[0022] The molar ratio of compound 2-chlorophenthiazide of formula (I) to the base is 1:0.1 to 1:1; a further preferred molar ratio is 1:0.5, which results in a high reaction yield, fewer byproducts, and higher efficiency.

[0023] The organic solvent used is selected from one or more of the following: dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, and N,N-dimethylformamide; N,N-dimethylformamide is further preferred due to its good solubility and rapid reaction.

[0024] The separation and purification methods used are one or more combined methods of recrystallization and column chromatography; column chromatography is further preferred, resulting in higher purity of the product.

[0025] The solvents used for separation and purification are selected from one or a mixture of petroleum ether, n-hexane, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, methanol, ethanol, and isopropanol; a mixture of petroleum ether, n-hexane, dichloromethane, and ethyl acetate is further preferred, as it results in higher purity of the product.

[0026] As a preferred technical solution, in step (2): the molar ratio of the compound 3-(2-chloro-10-phenthiazinyl)-propanal of formula (III) to deuterated dimethylamine hydrochloride is 1:1 to 1:5; further, the molar ratio is 1:1.5, resulting in higher reaction yield and lower cost;

[0027] The reducing agent used is selected from one of H2 / palladium on carbon, H2 / Raney nickel, H2 / platinum, CO / rhodium, NaBH4, NaBH3CN, and NaBH(OAc)3;

[0028] The organic solvent used is selected from one or more of the following: dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, and N,N-dimethylformamide; methanol is further preferred for higher yield.

[0029] The separation and purification methods used are one or more combined methods of recrystallization and column chromatography; the solvents used for separation and purification are selected from one or more of petroleum ether, n-hexane, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, methanol, ethanol, and isopropanol.

[0030] As a preferred technical solution, in step (3): the molar ratio of the compound (Ⅳ) chlorpromazine-d6 to hydrochloric acid is 1:1 to 1:5; more preferably, the molar ratio is 1:2, which yields a higher yield;

[0031] In step (3): the concentration of the hydrochloric acid solution used is 1 mol / L to 12 mol / L;

[0032] Further optimization of the hydrochloric acid solution concentration to 12 mol / L resulted in faster reaction, higher yield, and more convenient post-processing.

[0033] The solvent used is selected from one or more of the following: dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, water, and N,N-dimethylformamide; tetrahydrofuran is further preferred because it is easier to process and has a higher yield.

[0034] The separation and purification methods used were recrystallization and pulping.

[0035] A third objective of this invention is to provide the use of the above-mentioned compounds in analytical detection.

[0036] The preparation method of this invention breaks through the technical barriers in the synthesis of deuterated chlorpromazine compounds, and is of strategic significance for building an independent and controllable forensic toxicology identification system. This breakthrough in the localization of this key technology will directly promote the alignment of domestic toxicology testing standards with advanced international methods, laying the foundation for improving the scientific rigor and authority of judicial determinations in poisoning cases.

[0037] Compared with the prior art, the advantages of this invention are as follows: This invention provides a new process for synthesizing chlorpromazine-d6 and its hydrochloride with independent intellectual property rights, achieving high yield, high purity, and high deuteration rate of chlorpromazine-d6 compound and its hydrochloride; in addition, this invention provides a new deuterated internal standard for chlorpromazine for analytical detection; this method has the advantages of simple operation, mild reaction conditions, few side reactions, and easy purification of reaction intermediates and final products, and the obtained chlorpromazine-d6 and its hydrochloride have the advantages of high chemical purity, high deuteration rate, and high deuterium atom stability. Attached Figure Description

[0038] Figure 1 The hydrogen nuclear magnetic resonance spectrum of the compound of formula III obtained in Example 1;

[0039] Figure 2 The carbon NMR spectrum of the compound of formula III obtained in Example 1;

[0040] Figure 3 The 1H NMR spectrum of chlorpromazine-d6 prepared in Example 1;

[0041] Figure 4 The image shows the carbon NMR spectrum of chlorpromazine-d6 obtained in Example 1.

[0042] Figure 5 The image shows the high-performance liquid chromatogram of chlorpromazine-d6 prepared in Example 1. Detailed Implementation

[0043] To explain the technical content, objectives, and effects of the present invention in detail, the following specific embodiments are provided to further illustrate the content of the present invention. However, the content of the present invention is far more than the following examples.

[0044] Example 1: A method for preparing chlorpromazine-d6 (compound of formula IV), specifically including the following steps:

[0045] Step (1): Preparation of 3-(2-chloro-10-phenthiazinyl)-propanal (Compound III) Under inert gas protection, 2-chlorophenthiazide (Compound I, 1 mmol, 0.234 g) was dissolved in N,N-dimethylformamide (DMF, 2 mL), followed by the addition of potassium tert-butoxide (0.5 mmol, 0.056 g), with the reaction temperature controlled not to exceed 25 °C. Next, a DMF solution of acrolein (Compound II, 3 mmol, 0.168 g) was slowly added dropwise. After the addition was complete, the reaction temperature was controlled not to exceed 25 °C, and the reaction was monitored by TLC. After the reaction was complete (approximately 3 h), the mixture was cooled in an ice-water bath, and water (5 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with water (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The compound was then purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 0.22 g of pure compound III as a white solid, with a yield of 76%. The yields under different reaction conditions in this step are shown in Table 1.

[0046] Table 1: Yields of step (1) under different reaction conditions

[0047]

[0048] Structural identification of compounds of formula III, such as Figure 1 and Figure 2 As shown:

[0049] 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.22 – 7.14 (m, 2H), 7.06 (d,J = 8.2 Hz, 1H), 7.00 – 6.96 (m, 1H), 6.93 (dd, J = 8.2, 2.0 Hz, 1H), 6.88 –6.81 (m, 2H), 4.21 (t, J = 6.8 Hz, 2H), 2.99 (td, J = 6.9, 1.0 Hz, 2H);

[0050] 13 C NMR (101 MHz, CDCl3) δ 200.1, 146.2, 144.1, 133.5, 128.3, 127.9,127.7, 125.6, 124.3, 123.5, 122.9, 115.9, 115.7, 41.8, 40.5.;

[0051] Step (2): Preparation of chlorpromazine-d6 (compound of formula IV)

[0052] At room temperature, compound III (1.0 mmol, 0.29 g), deuterated dimethylamine hydrochloride (1.5 mmol, 0.105 g), sodium acetate (1.5 mmol, 0.123 g), and methanol (10 mL) were added sequentially to a dry round-bottom flask. After stirring thoroughly, sodium cyanoborohydride (2.0 mmol, 0.125 g) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water (5 mL), concentrated under reduced pressure, and methanol was removed. The remaining aqueous layer was adjusted to pH 8–9 with 1N NaOH solution, then extracted with CH2Cl2 (10 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Subsequently, the crude product was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 0.23 g of light pink colloidal solid chlorpromazine-d6, yield 70.8%, purity 99.82%. Figure 5 As shown; HPLC conditions were as follows: column: Agilent InfinityLab ZORBAXSB-C18 column, 21.2 × 250 mm, 5 µm; mobile phase: acetonitrile: 0.5% trifluoroacetic acid (adjusted to pH 5.3 with tetramethylethylenediamine) (50:50); detection wavelength: 254 nm; injection concentration: 2 mg / L; injection volume: 10 uL.

[0053] Structural identification of chlorpromazine-d6, such as Figure 3 and Figure 4 As shown: 1 H NMR (400 MHz, CDCl3) δ 7.21 –7.08 (m, 2H), 7.01 (d, J = 8.7 Hz, 1H), 6.96 – 6.84 (m, 4H), 3.87 (t, J = 7.0Hz, 2H), 2.39 (t, J = 7.0 Hz, 2H), 1.93 (p, J = 7.0 Hz, 2H);

[0054] 13 C NMR (101 MHz, CDCl3) δ 146.7, 144.6, 133.3, 128.0, 127.6, 127.5,124.9, 123.6, 123.0, 122.3, 116.0, 115.9, 57.0, 45.6, 44.7 (Heptet, J = 20.2Hz, 2Cf), 25.2.

[0055] Step (3): Preparation of chlorpromazine-d6 hydrochloride (compound V)

[0056] At room temperature, compound IV (3.1 mmol, 1.0 g) and tetrahydrofuran (10 mL) were added to a dry round-bottom flask. After stirring and clarifying, 12 mol / L hydrochloric acid (6.2 mmol, 0.52 mL) was slowly added dropwise. After the addition was complete, the reaction was stirred for 1 hour, and then cooled in an ice-water bath to crystallize for 2 hours. The mixture was filtered, and the filter cake was washed twice with ice-cold tetrahydrofuran and dried under vacuum to give 1.04 g of white solid chlorpromazine-d6 hydrochloride, yield 93%.

[0057] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A chlorpromazine-d6 compound, characterized in that, Its chemical name is 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propane, and its structural formula is shown in formula (Ⅳ) below: 。 2. A chlorpromazine-d6 compound hydrochloride, characterized in that, Its chemical name is 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propanamine hydrochloride, and its structural formula is shown in formula (V) below: 。 3. The method for preparing the chlorpromazine-d6 compound or its hydrochloride salt according to claim 1 or 2, characterized in that, Using 2-chlorophenthiazide as a raw material, chlorpromazine-d6 is obtained through aza-Michael addition and reductive amination reactions, followed by acidification with hydrochloric acid to obtain chlorpromazine-d6 hydrochloride. The specific steps include the following: ； (1) Under the action of alkali, compound (I) 2-chlorophenthiazide and compound (II) acrolein undergo an aza-Michael addition reaction to give compound (III) 3-(2-chloro-10-phenthiazinyl)-propanal; (2) In the presence of a reducing agent, compound (III) 3-(2-chloro-10-phenthiazinyl)-propanal undergoes reductive amination with deuterated dimethylamine hydrochloride to obtain compound (IV) 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propanamine, i.e. chlorpromazine-d6; (3) Acidify compound (IV) 3-(2-chloro-10-phenthiazinyl)-N,N-bis(methyl-d3)-1-propane with hydrochloric acid solution to obtain chlorpromazine-d6 hydrochloride.

4. The method according to claim 3, characterized in that, In step (1): the molar ratio of compound 2-chlorophenthiazide of formula (I) to acrolein of formula (II) is 1:1 to 1:5; the base used is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, K2CO3, Cs2CO3, LiOH, NaOH, and KOH; the molar ratio of compound 2-chlorophenthiazide of formula (I) to the base is 1:0.1 to 1:1; the organic solvent used is selected from dichloromethane, chloroform, and methyl... The method of separation and purification is one or a mixture of multiple of the following: benzene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, and N,N-dimethylformamide; the method of separation and purification is one or a combination of recrystallization and column chromatography; the solvent used for separation and purification is selected from one or a mixture of multiple of the following: petroleum ether, n-hexane, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, methanol, ethanol, and isopropanol.

5. The method according to claim 3, characterized in that, In step (1): the molar ratio of compound 2-chlorophenthiazide of formula (I) to compound acrolein of formula (II) is 1:0.5; the organic solvent used is N,N-dimethylformamide; the separation and purification method is solid chromatography separation, and the solvent for separation and purification is selected from a mixture of ether, n-hexane, dichloromethane, and ethyl acetate.

6. The method according to claim 3, characterized in that, In step (2): the molar ratio of compound (III) 3-(2-chloro-10-phenthiazinyl)-propanal to deuterated dimethylamine hydrochloride is 1:1 to 1:5; the reducing agent used is selected from one of H2 / palladium on carbon, H2 / Raney nickel, H2 / platinum, CO / rhodium, NaBH4, NaBH3CN, and NaBH(OAc)3; the organic solvent used is selected from dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, and 1,4-dioxane. The solvent used for separation and purification is selected from one or more of the following: hexacyclohexane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, and N,N-dimethylformamide; the separation and purification method used is one or more of recrystallization and column chromatography; the solvent used for separation and purification is selected from one or more of the following: petroleum ether, n-hexane, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, methanol, ethanol, and isopropanol.

7. The method according to claim 6, characterized in that, In step (2): the molar ratio of compound (III) 3-(2-chloro-10-phenthiazinyl)-propanal to deuterated dimethylamine hydrochloride is 1:1.5; the reducing agent used is selected from one of NaBH4, NaBH3CN, and NaBH(OAc)3; the organic solvent used is selected from methanol; the separation method adopts column chromatography, and the solvent used for separation and purification is selected from a mixture of petroleum ether, n-hexane, dichloromethane, and ethyl acetate.

8. The method according to claim 3, characterized in that, In step (3): the molar ratio of the compound (Ⅳ) chlorpromazine-d6 to hydrochloric acid is 1:1 to 1:5; the solvent used is selected from one or more of the following: dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, water, and N,N-dimethylformamide; the separation and purification methods used are recrystallization and pulping.

9. The method according to claim 8, characterized in that, In step (3): the concentration of the hydrochloric acid solution used is 12 mol / L; the solvent used is tetrahydrofuran.

10. Use of the compound of claim 1 or 2 in analytical detection.

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