A process for the preparation of an edoxaban intermediate

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an edoxaban intermediate. The method takes 2,5-dimethyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine (compound 1) as raw material, and first performs an oxidation reaction with an oxidant to obtain 5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine-2-methanal (compound 2), then performs a reaction with chlorite to obtain 5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine-2-carboxylic acid (compound 3), and finally performs a salt formation in an organic solution of hydrochloric acid to obtain the edoxaban intermediate (compound 4). The reaction route of the application is short, the material is cheap and easy to obtain, the reaction condition is mild, the atomic economy is high, the obtained product has high purity, the product quality can meet the subsequent requirements, and the yield is high.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis. Specifically relates to a kind of preparation method of edoxaban intermediate. BACKGROUND

[0002] Edoxaban, (Edoxaban, trade name Lixiana) is developed by Japan's first sanwa company, the principle of action is to inhibit the new type of oral anticoagulant of coagulation factor Xa, chemical name: N 1 -(5-chloro-2-pyridyl)-N 2 -[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]oxalamide, CAS No.: 480449-70-5, molecular weight: 548.06, molecular formula: C 24 H 30 ClN7O4S. The drug was approved for marketing in Japan in July 2011, mainly used for preventing venous thromboembolism after total knee replacement, total hip replacement and hip fracture surgery. In January 2015, it was approved by FDA for marketing in the United States (trade name Savaysa). Studies have shown that the use of edoxaban is more effective than enoxaparin in preventing venous thrombosis after joint replacement surgery, and the incidence of adverse reactions of edoxaban is much lower than that of rivaroxaban and apixaban. Edoxaban can be used as the first choice drug for preventing venous thromboembolism after surgery, with great market prospect.

[0003]

[0004] In the synthesis of edoxaban, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid and its hydrochloride are important intermediates of edoxaban, which play an important role in the synthesis of edoxaban. There are some problems in the production process of edoxaban intermediate, and it is of great significance to improve the synthesis process.

[0005]

[0006] 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride

[0007] In 2003, the original research company of edoxaban, First Chemical Co., Ltd. reported in WO2003000657 that 4-aminopyridine (compound 5) was used as the starting material, the amino group was first protected with di-tert-butyl dicarbonate to obtain compound 6, under the action of n-butyllithium, ortho-lithiation was carried out, then a mercapto group was introduced at the ortho position of the amino group to obtain compound 7, then intramolecular cyclization was carried out under the action of formic acid to obtain compound 8, then sodium borohydride reduction and methylation were carried out to obtain compound 9, compound 9 was subjected to lithium salt of carboxylic acid under the action of n-butyllithium and carbon dioxide to obtain compound 10, and finally hydrochloric acid was used for acidification and salt formation to obtain 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride 4.

[0008]

[0009] This route has a long reaction step, and the selectivity of introducing a mercapto group after ortho-lithiation is poor, and there are isomers that are difficult to separate, and the yield of the product is low, only 46%; in addition, because the n-butyllithium reagent is active, flammable and explosive, the reaction needs to be carried out at -78℃ and under anhydrous and anaerobic conditions, the reaction conditions are harsh. Industrialization is difficult to achieve, the methylation step of this route uses expensive, low boiling point and toxic iodomethane, the production cost is high, and there are certain safety risks for industrialization production.

[0010] Subsequently, First Chemical Co., Ltd. improved the original research route, using 1-tert-butoxycarbonyl-4-piperidinone (compound 11) as the starting material, under the catalysis of pyrrolidine, enamination was carried out with cyanamide and sulfur to obtain compound 12, diazotization was carried out with tert-butyl nitrite, and then Sandmeyer reaction was carried out with copper bromide to obtain compound 13, tert-butoxycarbonyl was removed under the action of trifluoroacetic acid to obtain compound 14, reductive amination was carried out with formaldehyde and sodium triacetoxyborohydride to obtain compound 15, then halogen-lithium exchange was carried out with n-butyllithium, and carbon dioxide gas was introduced to introduce a carboxyl group to obtain lithium salt of carboxylic acid compound 10, and then hydrochloric acid was used for acidification and salt formation to obtain compound 4.

[0011]

[0012] The total yield of this route is improved compared with the original research route, the starting material is relatively low in price, and methylization of the amine is carried out with formaldehyde and sodium triacetoxyborohydride, avoiding the use of iodomethane, but expensive tert-butyl nitrite and flammable n-butyllithium reagent are needed, the reaction conditions are still harsh, and there are still problems of production cost and safety.

[0013] In 2005, Sankyo Co., Ltd. reported in patent WO2005047296 that 1-methyl-4-piperidone 16 was used as a starting material to react with cyanamide and sulfur to obtain amino-thiazole compound 17, and then compound 17 was used as a raw material to derive three routes. In the first route, compound 17 was diazotized with sodium nitrite and hydrobromic acid solution to obtain compound 15, and then halogen-lithium exchange was carried out with n-butyllithium reagent to react with carbon dioxide to generate lithium carboxylate compound 10; in the second route, compound 17 was deaminated with hyposulfurous acid by Griess to obtain compound 9, and then acylated with trichloroacetyl chloride by Friedel-Crafts reaction, and then hydrolyzed to obtain lithium carboxylate compound 10; in the third route, compound 15 was reacted with sodium cyanide to generate cyan compound 18, and then the cyan group was hydrolyzed under the action of lithium hydroxide to obtain lithium carboxylate compound 10, and finally salt formation generated compound 4.

[0014]

[0015] The starting material is easy to obtain, and all three routes reduce the reaction steps. In the first route, aqueous nitrous acid and hydrobromic acid are used instead of tert-butyl nitrite as the diazotizing reagent, which reduces the cost, but n-butyllithium is still used to introduce the carboxyl group; In the second route, trichloroacetyl chloride is used instead of n-butyllithium to introduce the carboxyl group, which is safer and more efficient, but a large amount of sulfuric acid and hypophosphorous acid are used to remove the amino group, which is difficult to handle and produces waste liquid that is not environmentally friendly, and the yield of the purified product is low; In the third route, the toxic substance sodium cyanide is used to replace bromine, which limits its industrial application.

[0016] In 2015, Ueda et al. used 1-methyl-4-piperidone as a starting material to obtain compound 15 by enamine, diazotization and bromination, and then in the presence of carbon monoxide, palladium and phosphine ligand as catalyst, compound 19 was generated with phenol, and then compound 4 was obtained by hydrolysis with lithium hydroxide and salt formation with hydrochloric acid.

[0017]

[0018] This method avoids the use of n-butyllithium and ultra-low temperature reaction conditions, and the yield of compound 4 is as high as 86%, but the cost of palladium catalyst and ligand is too high, and in addition, the reaction requires anhydrous and oxygen-free environment, which can be prepared in small scale in the laboratory, and is not suitable for large-scale production.

[0019] In 2020, Lv Guanfeng et al. reported that 1-methyl-4-piperidone 16 was used as a starting material to react with liquid bromine to generate compound 20, and compound 20 was reacted with thiourea by Hantzsch thiazole synthesis to obtain compound 17, which was diazotized to obtain compound 15, and then reduced with sodium thiosulfate to remove bromine to obtain compound 9, which was acylated with trichloroacetyl chloride by Friedel-Crafts reaction to obtain compound 21, and then hydrolyzed to obtain lithium carboxylate compound 10, and then acidified with hydrochloric acid to obtain compound 4.

[0020]

[0021] The route is relatively simple as a whole, and there are no harsh reaction conditions, wherein the thiazole is synthesized by reacting an a-bromoketone with thiourea, which is safer than using cyanamide and sulfur, but increases the reaction steps and does not significantly improve the product yield, and the atomic economy is poor.

[0022] In 2020, Lv Guanfeng et al. reported a method for synthesizing compound 4 by using 1-methyl-4-piperidone 16 as a starting material, undergoing enamine reaction, diazotization bromination, debromination, Friedel-Crafts acylation and hydrolysis reaction, and finally acidifying to form a salt.

[0023]

[0024] The above reported synthesis of edoxaban intermediates has problems such as long route, poor reaction selectivity, harsh reaction conditions, and potential safety and environmental protection problems. Therefore, it is of great significance to seek a method for preparing edoxaban intermediates with low cost, mild reaction conditions, easy control and safety and environmental protection. SUMMARY

[0025] In order to solve the above-mentioned problems in the prior art, the present application discloses a method for preparing an edoxaban intermediate and its application. The process conditions adopted by the present application are mild, and the process can be easily realized without special equipment. The entire process has good atomic economy, high green degree, simple product separation and purification, low overall cost, good safety, and good prospects for industrial production.

[0026] The present application provides a method for preparing an edoxaban intermediate, comprising the following steps:

[0027]

[0028] The method uses 2,5-dimethyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine (compound 1) as a raw material, first undergoes oxidation reaction with an oxidizing agent to obtain 5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine-2-carboxaldehyde (compound 2), then undergoes reaction with chlorite to obtain 5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine-2-carboxylic acid (compound 3), and finally is salted in an organic solution of hydrochloric acid to obtain the edoxaban intermediate (compound 4).

[0029] The method comprises the following steps:

[0030] Step 1): Compound 1 undergoes oxidation reaction with an oxidizing agent in a solvent to generate compound 2;

[0031] The oxidizing agent is selenium dioxide, tin dioxide, manganese dioxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, dibenzoyl peroxide, etc., but is not limited to these oxidizing agents, and is preferably selenium dioxide.

[0032] Step 2): Compound 2 is oxidized in a solvent with chlorite in an acidic solution to generate compound 3;

[0033] Step 3): Compound 3 is reacted in an organic solution of hydrochloric acid to generate the hydrochloride salt 4 of the edoxaban thiazole intermediate.

[0034] In the step 1), the molar ratio of compound 1 to the oxidizing agent is 1:(0.5-5), preferably 1:(2-5);

[0035] In the step 1), the solvent is one or more of water, benzene, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, dioxane, preferably tetrahydrofuran;

[0036] In the step 1), the reaction temperature is 0-120℃, preferably 70-90℃; and the reaction time is 0.5-24 hours, preferably 8-18 hours.

[0037] In the step 2), the solvent is one or more of water, methanol, ethanol, n-butanol, isobutyl alcohol, tert-butyl alcohol, isopropyl alcohol, n-butanol, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, dioxane, preferably water.

[0038] In the step 2), the acidic solution is a dihydrogen phosphate solution selected from sodium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, lithium dihydrogen phosphate solution, ammonium dihydrogen phosphate solution, aluminum dihydrogen phosphate solution, etc.

[0039] In the step 2), the molar ratio of compound 2 to chlorite is 1:(1-10), preferably 1:(1.5-10);

[0040] In the step 2), the reaction temperature is 0-90℃, preferably 10-25℃; and the reaction time is 0.5-10 hours.

[0041] In the step 3), the organic solvent in the organic solution of hydrochloric acid is one or more of methanol, ethanol, isopropyl alcohol, ethyl acetate, dichloromethane, preferably ethanol.

[0042] The preparation method of the present application is a new synthesis method for preparing the edoxaban intermediate, and has not been reported in the literature so far.

[0043] The technical features and excellent effects of the present application are as follows:

[0044] 1. The raw materials used in this invention are inexpensive, readily available, and widely sourced.

[0045] 2. The process conditions of this invention are mild, avoiding the use of flammable and explosive reagents such as n-butyllithium, as well as harsh reaction conditions such as low temperature, making the reaction safer and easier to achieve.

[0046] 3. The oxidation method used in this invention has good atom economy, uses less organic solvent, and is more environmentally friendly.

[0047] Compared with the prior art, the advantages of this invention are: the reaction route of this invention is shorter, the materials are inexpensive and readily available, the reaction conditions are mild, the atom economy is high, the purity of the obtained product is high, the product quality can meet the subsequent requirements, and the yield is high. Attached Figure Description

[0048] Figure 1 This is the mass spectrum of compound 2;

[0049] Figure 2 This is the mass spectrum of the intermediate of edoxaban (compound 4).

[0050] Figure 3 The 1H NMR spectrum of edoxaban intermediate (compound 4) is shown. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0052] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly used in the field to which this invention pertains.

[0053] The solvents used in this article are commercially available.

[0054] The following are merely some specific embodiments of the present invention. The present invention is not limited to these embodiments, and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the content disclosed in this invention should be considered within the scope of protection of this invention.

[0055] Example 1: Edoxaban intermediate was prepared according to the following method:

[0056] Step 1)

[0057]

[0058] Into a 250 mL three-necked round-bottom flask, equipped with a stirring device and a thermometer, 16.8 g of compound 1 (100 mmol, 1 eq), 22.2 g of selenium dioxide (200 mmol, 2 eq), and 150 mL of tetrahydrofuran were placed under nitrogen protection. The reaction device was moved into an oil bath pot, and the temperature was kept at 80°C for about 18 hours. After the reaction was completed, the reaction was allowed to cool to room temperature, and the black insoluble substance was filtered off. The filter cake was washed with 50 mL of tetrahydrofuran three times, and the filter cake was discarded. The filtrate was concentrated under reduced pressure to remove the solvent, and 15.11 g of a yellow liquid (compound 2) was obtained, with a yield of 89%.

[0059] Step 2)

[0060]

[0061] Into a 250 mL three-necked round-bottom flask, equipped with a stirring device and a thermometer, 16.8 g of compound 1 (100 mmol, 1 eq), 22.2 g of selenium dioxide (200 mmol, 2 eq), and 150 mL of tetrahydrofuran were placed under nitrogen protection. The reaction device was moved into an oil bath pot, and the temperature was kept at 80°C for about 18 hours. After the reaction was completed, the reaction was allowed to cool to room temperature, and the black insoluble substance was filtered off. The filter cake was washed with 50 mL of tetrahydrofuran three times, and the filter cake was discarded. The filtrate was concentrated under reduced pressure to remove the solvent, and 15.11 g of a yellow liquid (compound 2) was obtained, with a yield of 89%.

[0062] Step 3)

[0063]

[0064] Into a 250 mL three-necked round-bottom flask, equipped with a stirring device and a thermometer, 16.8 g of compound 1 (100 mmol, 1 eq), 22.2 g of selenium dioxide (200 mmol, 2 eq), and 150 mL of tetrahydrofuran were placed under nitrogen protection. The reaction device was moved into an oil bath pot, and the temperature was kept at 80°C for about 18 hours. After the reaction was completed, the reaction was allowed to cool to room temperature, and the black insoluble substance was filtered off. The filter cake was washed with 50 mL of tetrahydrofuran three times, and the filter cake was discarded. The filtrate was concentrated under reduced pressure to remove the solvent, and 15.11 g of a yellow liquid (compound 2) was obtained, with a yield of 89%.

[0065] 1 H NMR (CDCI3) δ 9.09 (s, 1H), 4.58 (s, 2H), 3.59 (s, 2H), 3.19 (m, 2H), 2.90 (s, 3H); MS (ESI + )m / z 198.97 [M+H]. The purity was detected by high performance liquid chromatography, and the content was 98.5%.

[0066] Example 2 refers to the preparation method of Example 1, and the oxidant in step 1) of Example 1 is changed to obtain compound 2 prepared by different oxidants, and the yield and purity are shown in Table 1:

[0067] Table 1 Effect of different oxidants on yield and purity of compound 2

[0068] Oxidizing agent Selenium dioxide Tin dioxide Manganese dioxide Tert-butyl hydroperoxide Purity (%) 93.5％ 70.8％ 67.4％ 75.6％ Yield (%) 89％ 58％ 75％ 69％

[0069] The results show that different oxidizing agents have different effects on the yield of compound 2. When selenium dioxide is used as the oxidizing agent, the purity and yield of compound 2 are optimal.

[0070] Example 3 is prepared according to the preparation method of Example 1, the molar ratio of compound 1 to selenium dioxide in step 1) of Example 1 is changed, and other conditions remain unchanged. The yield and purity of compound 2 obtained are shown in Table 2:

[0071] Table 2 Effect of molar ratio of compound 1 to selenium dioxide on yield and purity of compound 2

[0072] Compound 1 : Selenium dioxide 1：0.5 1：1 1：2 1：5 Purity (%) 81.5％ 85.4％ 94.8％ 88.7％ Yield (%) 44％ 72％ 90％ 85％

[0073] The results show that the molar ratio of compound 1 to selenium dioxide has different effects on the yield and purity of compound 2. When the molar ratio of compound 1 to selenium dioxide is 1:2, the purity and yield of compound 2 are optimal.

[0074] Example 4 is prepared according to the preparation method of Example 1, the reaction solvent in step 1) of Example 1 is changed, and different reaction solvents are used to prepare compound 2. The purity and yield of compound 2 are shown in Table 3:

[0075] Table 3 Effect of different reaction solvents on purity and yield of compound 2

[0076] Reaction solvent 1,4-Dioxane Tetrahydrofuran Acetic acid N-Methyl pyrrolidone Purity (%) 84.2％ 93.8％ 80.9％ 77.6％ Yield (%) 72％ 89％ 60％ 55％

[0077] The results show that different reaction solvents have different effects on the purity and yield of compound 2. When tetrahydrofuran is used as the reaction solvent, the purity of compound 2 can reach more than 90%, and the yield is optimal.

[0078] Example 5 is prepared according to the preparation method of Example 1, the reaction temperature in step 1) of Example 1 is changed, and different reaction temperatures are used to prepare compound 2. The purity and yield of compound 2 are shown in Table 4:

[0079] Table 4 Effect of different reaction temperatures on purity and yield of compound 2

[0080] Reaction temperature 60℃ 70℃ 80℃ 90℃ Purity (%) 80.8％ 84.5％ 95.5％ 92.3％ Yield (%) 66％ 75％ 89％ 83％

[0081] The results show that different reaction temperatures have different effects on the purity and yield of compound 2. When the reaction temperature is 80-90℃, the purity of compound 2 can reach more than 90%, and the yield is optimal.

[0082] In addition, the reaction time is also investigated, and the results show that the reaction time has little effect on the yield and purity of compound 2, i.e. when the reaction time is 0.5-24 hours, the yield and purity of compound 2 have no obvious change, and when the reaction time is 8-18 hours, the reaction is more complete, and the yield and purity are relatively higher.

[0083] Example 6 is prepared according to the preparation method of Example 1, the molar ratio of compound 2 to sodium chlorite in step 2) of Example 1 is changed, and other conditions are unchanged, to prepare compound 3, and the yield and purity are shown in Table 5:

[0084] Table 5 Effect of molar ratio of compound 2 to sodium chlorite on yield and purity of compound 3

[0085] Compound 2: Sodium chlorite 1：1 1：1.5 1：5 1：10 Purity (%) 92.7％ 97.6％ 96.3％ 95.6％ Yield (%) 89％ 98％ 98％ 98％

[0086] The results show that the molar ratio of compound 2 to sodium chlorite has different effects on the yield and purity of compound 3, when the molar ratio of compound 2 to sodium chlorite is 1:1.5-10, the purity and yield of compound 3 have no obvious change, and can reach the best, and in consideration of the whole, the molar ratio of compound 2 to sodium chlorite is preferably 1:1.5-10.

[0087] Example 7 is prepared according to the preparation method of Example 1, the acidic buffer reagent in step 2) of Example 1 is changed to obtain different acidic buffer reagents, and other conditions are unchanged, to prepare compound 3, and the yield and purity are shown in Table 6:

[0088] Table 6 Effect of different acidic buffer reagents on purity and yield of compound 3

[0089] Acidic buffer reagent Lithium dihydrogen phosphate Sodium dihydrogen phosphate Potassium dihydrogen phosphate Ammonium dihydrogen phosphate Purity (%) 93.1％ 96.8％ 94.6％ 91.5％ Yield (%) 90％ 98％ 88％ 92％

[0090] The results show that different acidic buffer reagents have different effects on the purity and yield of compound 3, and the purity of compound 3 prepared by different acidic buffer reagents has little change, and the yield is more than 85%, and when sodium dihydrogen phosphate is used as the acidic buffer reagent, the purity and yield of compound 3 reach the best.

[0091] Example 8 is prepared according to the preparation method of Example 1, the reaction solvent in step 3) of Example 1 is changed to obtain different reaction solvents to prepare compound 4, and the purity and yield are shown in Table 7:

[0092] Table 7 Effect of different reaction solvents on purity and yield of compound 4

[0093]

[0094]

[0095] The results show that different reaction solvents have different effects on the purity and yield of compound 4, and different reaction solvents have little effect on the purity of compound 4, and the yield can reach more than 75%. When the reaction solvent is ethanol, the purity and yield of compound 4 are best.

Claims

1. A method for preparing an intermediate of edoxaban, characterized in that, 。 2. The preparation method according to claim 1, characterized in that, Includes the following steps: Step 1) Compound 1 undergoes an oxidation reaction with an oxidizing agent in a solvent to generate compound 2; Step 2) Compound 2 undergoes an oxidation reaction with chlorite in an acidic solution in a solvent to generate compound 3; Step 3) Compound 3 is reacted in an organic solution of hydrochloric acid to form hydrochloride 4, which is an intermediate of edoxabanthiazole.

3. The preparation method according to claim 2, characterized in that, In step 1), the oxidant is one or more of selenium dioxide, tin dioxide, manganese dioxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, or benzoyl peroxide.

4. The preparation method according to claim 2, characterized in that, In step 1), the oxidant is selenium dioxide.

5. The preparation method according to claim 2, characterized in that, In step 1), the molar ratio of compound 1 to oxidant is 1:(0.5~5).

6. The preparation method according to claim 2, characterized in that, In step 1), the molar ratio of compound 1 to oxidant is 1:(2~5).

7. The preparation method according to claim 2, characterized in that, In step 1), the solvent is one or more of water, benzene, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and dioxane; in step 2), the solvent is one or more of water, methanol, ethanol, n-butanol, isobutanol, tert-butanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and dioxane.

8. The preparation method according to claim 2, characterized in that, In step 1), the solvent is tetrahydrofuran; in step 2), the solvent is water.

9. The preparation method according to claim 2, characterized in that, In step 1), the reaction temperature is 0~120℃ and the reaction time is 0.5~24 hours; in step 2), the reaction temperature is 0-90℃ and the reaction time is 0.5-10 hours.

10. The preparation method according to claim 2, characterized in that, In step 1), the reaction temperature is 70~90 ℃, and in step 2), the reaction temperature is 10-25 ℃.

11. The preparation method according to claim 2, characterized in that, In step 2), the chlorite is sodium chlorite, potassium chlorite, or calcium chlorite; the acidic solution is a dihydrogen phosphate solution.

12. The preparation method according to claim 2, characterized in that, In step 2), the acidic solution is a dihydrogen phosphate solution, which may be a sodium dihydrogen phosphate solution, potassium dihydrogen phosphate solution, lithium dihydrogen phosphate solution, ammonium dihydrogen phosphate solution, or aluminum dihydrogen phosphate solution.

13. The preparation method according to claim 2, characterized in that, In step 2), the molar ratio of compound 2 to chlorite is 1:(1~10).

14. The preparation method according to claim 2, characterized in that, In step 2), the molar ratio of compound 2 to chlorite is 1:(1.5~10).

15. The preparation method according to claim 2, characterized in that, In step 3), the organic solvent in the hydrochloric acid organic solution is one or more of methanol, ethanol, isopropanol, ethyl acetate, and dichloromethane.

16. Use of the preparation method according to any one of claims 1-15 in the preparation of 5-methyl-4,5,6,7-tetrahydrothiazolium[5,4-c]pyridine-2-carboxylic acid or its hydrochloride.

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