Preparation method of edoxaban intermediate

Abstract

The invention belongs to the technical field of organic synthesis. The invention particularly relates to a preparation method of an edoxaban intermediate. The method comprises the following steps: by taking 2, 5-dimethyl-4, 5, 6, 7-tetrahydrothiazole [5, 4-c] pyridine (compound 1) as a raw material, firstly carrying out oxidation reaction with an oxidizing agent to obtain 5-methyl-4, 5, 6, 7-tetrahydrothiazole [5, 4-c] pyridine-2-formaldehyde (compound 2), then carrying out reaction with chlorite to obtain 5-methyl-4, 5, 6, 7-tetrahydrothiazole [5, 4-c] pyridine-2-formic acid (compound 3), and finally, carrying out reaction on the 5-methyl-4, 5, 6, 7-tetrahydrothiazole [5, 4-c] pyridine-2-formic acid (compound 3) to obtain 5-methyl-4, 5, 6, 7-tetrahydrothiazole [5, 4-c] pyridine-2-formic acid (compound 3). And finally salifying in an organic solution of hydrochloric acid to obtain the edoxaban intermediate (compound 4). The method has the advantages of short reaction route, cheap and easily available materials, mild reaction conditions, high atom economy, high product purity, product quality meeting subsequent requirements, and high yield. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and specifically relates to a method for preparing an edoxaban intermediate. Background Art

[0002] Edoxaban (trade name Lixiana) is a new oral anticoagulant drug developed by Daiichi Sankyo Co., Ltd. of Japan, which works by inhibiting coagulation factor Xa. Its chemical name is N 1 -(5-chloro-2-pyridinyl)-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]ethanediamide, 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, and is mainly used to prevent venous thromboembolism after total knee replacement, total hip replacement, and hip fracture. It was approved by the FDA for marketing in the United States in January 2015 (trade name Savaysa). Studies have shown that the use of edoxaban is more effective than enoxaparin in preventing venous thrombosis after joint replacement. In addition, the incidence of adverse reactions of edoxaban is much lower than that of rivaroxaban and apixaban. Edoxaban can be used as the first choice for preventing venous thromboembolism after surgery, and has huge market prospects.

[0003]

[0004] In the synthesis of edoxaban, it was found that 5-methyl-4,5,6,7-tetrahydrothiazolidine [5,4-c] pyridine-2-carboxylic acid and its hydrochloride are important intermediates of edoxaban and play an important role in the synthesis of edoxaban. At present, there are some problems in the production process of edoxaban intermediates, 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 developer of edoxaban, Daiichi Sankyo 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-butyl lithium, the compound was lithiated at the ortho position and then a thiol group was introduced at the ortho position of the amino group to obtain compound 7. Compound 8 was then intramolecularly cyclized under the action of formic acid to obtain compound 8. Compound 9 was reduced with sodium borohydride and methylated to obtain compound 9. Compound 9 was treated with n-butyl lithium and carbon dioxide to obtain a lithium carboxylate salt compound 10. Finally, the compound was acidified with hydrochloric acid and salified to obtain 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride 4.

[0008]

[0009] The reaction steps of this route are relatively long. The selectivity of the process of introducing thiol groups after ortho-lithiation is relatively poor, and isomers that are difficult to separate are generated. The product yield is low, only 46%. In addition, due to the active nature of n-butyl lithium reagents, which are flammable and explosive, the reaction needs to be carried out at -78°C in the absence of water and oxygen, and the reaction conditions are harsh. Industrialization is difficult to achieve. The methylation step of this route uses expensive, low-boiling-point and highly toxic iodomethane, which has high production costs and certain safety and environmental risks, which is not conducive to industrial production.

[0010] Subsequently, Daiichi Sankyo Co., Ltd. improved the original research route, using 1-tert-butoxycarbonyl-4-piperidone (compound 11) as the starting material, and reacting it with cyanamide and sulfur under the catalysis of pyrrolidine to produce compound 12 through enamination. Compound 12 and tert-butyl nitrite were diazotized and then reacted with copper bromide to produce compound 13. The tert-butoxycarbonyl group was removed under the action of trifluoroacetic acid to obtain compound 14, which was then reduced and aminated in formaldehyde and sodium triacetoxyborohydride to obtain compound 15. Finally, n-butyl lithium was used to exchange halogen with lithium and carbon dioxide gas was introduced to introduce the carboxyl group to obtain the lithium carboxylate compound 10, which was then acidified with hydrochloric acid and salified to obtain compound 4.

[0011]

[0012] The total yield of this route is higher than that of the original research route, the price of the starting materials is relatively low, and formaldehyde and sodium triacetoxyborohydride are used to methylate the amine, avoiding the use of iodomethane. However, expensive tert-butyl nitrite and flammable n-butyl lithium reagents are required, and the reaction conditions are still harsh, and there are still production cost and safety issues.

[0013] In 2005, Daiichi Sankyo Co., Ltd. reported in patent WO2005047296 that 1-methyl-4-piperidone 16 was used as the starting material, reacted with cyanamide and sulfur to obtain aminothiazole compound 17, and then three routes were derived from 17 as the raw material. In the first route, compound 17 was subjected to diazotization reaction with sodium nitrite and hydrobromic acid solution to obtain compound 15, and then the halogen was exchanged with n-butyl lithium reagent and reacted with carbon dioxide to generate carboxylic acid lithium salt compound 10; the second route was to react compound 17 with hypophosphorous acid through Griess deamination to obtain compound 9, and then reacted with trichloroacetyl chloride through Friedel-Crafts acylation, and then hydrolyzed to obtain carboxylic acid lithium salt compound 10; the third route: compound 15 was reacted with sodium cyanide to generate cyano compound 18, and then the cyano group was hydrolyzed under the action of lithium hydroxide to obtain carboxylic acid lithium salt compound 10, and finally salified to generate compound 4.

[0014]

[0015] The starting materials are readily available, and the three routes all reduce the number of reaction steps. The first route uses aqueous nitrous acid and hydrobromic acid instead of tert-butyl nitrite as diazotization reagents, which reduces costs, but still requires the use of n-butyl lithium to introduce carboxyl groups; the second route uses trichloroacetyl chloride instead of n-butyl lithium to introduce carboxyl groups, which is safer and more efficient, but uses a large amount of sulfuric acid and hypophosphorous acid to remove amino groups, which makes post-treatment difficult, and the waste liquid generated is not environmentally friendly, and the yield of the purified product is low; the third route uses the highly toxic substance sodium cyanide to replace bromine, and its industrial application is limited.

[0016] In 2015, Ueda et al. used 1-methyl-4-piperidone as the raw material, obtained compound 15 through enamination and diazotization bromination, and then reacted with phenol to generate compound 19 under a carbon monoxide atmosphere with palladium and phosphine ligands as catalysts, and then hydrolyzed with lithium hydroxide to form a hydrochloric acid salt to obtain compound 4.

[0017]

[0018] This method avoids the use of n-butyl lithium and ultra-low temperature reaction conditions. The yield of compound 4 is as high as 86%. However, the cost of palladium catalyst and ligand is too high. In addition, the reaction needs to ensure an anhydrous and oxygen-free environment. It can be prepared on a small scale in the laboratory, but is not suitable for large-scale production.

[0019] In 2020, Lu Guanfeng et al. reported that 1-methyl-4-piperidone 16 was used as the starting material, which reacted with liquid bromine to generate compound 20. Compound 20 reacted with thiourea via the Hantzsch thiazole synthesis reaction to obtain compound 17, which was then subjected to diazotization reaction to obtain compound 15. Sodium thiosulfate was used for reduction and debromination to obtain compound 9. Compound 9 reacted with trichloroacetyl chloride via Friedel-Crafts acylation to obtain compound 21, which was then hydrolyzed to obtain the carboxylate lithium salt compound 10, and then acidified with hydrochloric acid to obtain compound 4.

[0020]

[0021] The route is relatively simple as a whole and does not require harsh reaction conditions. The synthesis of thiazole by the reaction of α-bromoketone with thiourea is safer than the reaction using cyanamide and sulfur, but it adds reaction steps and does not significantly increase the product yield, resulting in poor atom economy.

[0022] In 2020, Lü Guanfeng et al. reported a method for synthesizing compound 4 using 1-methyl-4-piperidone 16 as the starting material, through enamination, diazotization bromination, debromination, Friedel-Crafts acylation and hydrolysis, and finally acidification to form a salt. This route has simple steps and is currently widely used.

[0023]

[0024] The synthesis of the edoxaban intermediates reported above has the problems of long routes, low reaction selectivity, harsh reaction conditions, hidden dangers in safety and environmental protection, etc. Therefore, it is of great significance to seek a method for preparing edoxaban intermediates with low cost, mild reaction conditions, easy control, safety and environmental protection. Summary of the invention

[0025] In order to solve the above problems existing in the prior art, the present invention discloses a method for preparing an edoxaban intermediate and its application. The process conditions adopted in this route are mild, without harsh reaction conditions such as high temperature and low temperature, and can be easily realized without special equipment. The whole process has good atom economy, high green degree, simple separation and purification of the obtained product, low overall cost, good safety, and has a good prospect for industrial production.

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

[0027]

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

[0029] The method comprises the following steps:

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

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

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

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

[0034] In the step 1), the molar ratio of compound 1 to the oxidant 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, and dioxane, preferably tetrahydrofuran;

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

[0037] In the 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, 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 the compound 2 to chlorite is 1:(1-10), preferably 1:(1.5-10);

[0040] In the step 2), the reaction temperature is 0-90°C; preferably 10-25°C; 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, isopropanol, ethyl acetate, and dichloromethane, preferably ethanol.

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

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

[0044] 1. The raw materials used in the present invention are cheap, easily available and widely available.

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

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

[0047] Compared with the prior art, the present invention has the following advantages: the reaction route is shorter, the materials are cheap and readily available, the reaction conditions are mild, the atom economy is high, the obtained product has high purity, the product quality can meet subsequent requirements, and the yield is high. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0050] Figure 3 This is the H NMR spectrum of the edoxaban intermediate (Compound 4). DETAILED DESCRIPTION

[0051] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation to the present invention.

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

[0053] The solvent used herein is commercially available.

[0054] The following are only some specific embodiments of the present invention, and the present invention is not limited to the following embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by ordinary technicians in this field should be considered as the protection scope of the present invention.

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

[0056] Step 1)

[0057]

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

[0059] Step 2)

[0060]

[0061] 9.1 g of compound 2 (50 mmol, 1 eq) was added to 50 mL of water, 50 mL of 20% disodium hydrogen phosphate solution was added, 40.7 mL (75 mmol, 1.5 eq) of 25% sodium chlorite aqueous solution was slowly added dropwise, and the reaction was completed at room temperature. 60 mL of saturated sodium carbonate was added, and after stirring for 15 minutes, 60 mL of ethyl acetate was added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, and the ethyl acetate was evaporated to obtain 9.72 g of a yellow oil (compound 3) with a yield of 98%.

[0062] Step 3)

[0063]

[0064] Under nitrogen protection, 5.00 g of compound 3 was added into a 50 ml three-necked round-bottom flask equipped with a stirring device and a thermometer. Ethanol solution (20 mL) was added, and 2 M hydrochloric acid was slowly added dropwise and stirred at room temperature for 20 hours. A white solid was precipitated, the solvent was filtered off, and dichloromethane was added for washing to obtain 5.2 g of a white solid (compound 4), with a yield of 92%.

[0065] 1 H NMR(CDCl3)δ9.09(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 Referring to the preparation method of Example 1, the oxidant in step 1) of Example 1 was changed to obtain compound 2 prepared by different oxidants. The yield and purity are shown in Table 1:

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

[0068] Oxidants 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 showed that different oxidants had different yields for compound 2. When selenium dioxide was used as the oxidant, the purity and yield of compound 2 were optimal.

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

[0071] Table 2 Effect of the molar ratio of compound 1 to selenium dioxide on the 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 showed that the molar ratio of compound 1 to selenium dioxide had different effects on the yield and purity of compound 2. When the molar ratio of compound 1 to selenium dioxide was 1:2, the purity and yield of compound 2 reached the best.

[0074] Example 4 Referring to the preparation method of Example 1, the reaction solvent of step 1) in Example 1 was changed to obtain compound 2 with different reaction solvents. The purity and yield are shown in Table 3:

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

[0076] Reaction solvent 1,4-Dioxane Tetrahydrofuran acetic acid N-Methylpyrrolidone 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 its yield is optimal.

[0078] Example 5 Referring to the preparation method of Example 1, the reaction temperature of step 1) in Example 1 was changed to obtain compound 2 at different reaction temperatures. The purity and yield are shown in Table 4:

[0079] Table 4 Effect of different reaction temperatures on the 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°C, the purity of compound 2 can reach more than 90% and the yield can reach the best.

[0082] In addition, the present invention also investigated the reaction time, and the results showed that time had little effect on the yield and purity of compound 2, that is, when the reaction time was 0.5-24 hours, the yield and purity of compound 2 did not change significantly, and when the reaction time was 8-18 hours, the reaction was more complete, and the yield and purity were relatively higher.

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

[0084] Table 5 Effect of the molar ratio of compound 2 to sodium chlorite on the 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 basically no obvious changes, and both can reach the best. Taking all factors into consideration, the preferred molar ratio of compound 2 to sodium chlorite is 1:1.5-10.

[0087] Example 7 Referring to the preparation method of Example 1, the acidic buffer reagent in step 2) of Example 1 was changed to obtain a different acidic buffer reagent, and other conditions remained unchanged to prepare compound 3. The yield and purity are shown in Table 6:

[0088] Table 6 Effect of different acidic buffer reagents on the 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. The purity of compound 3 prepared by different acidic buffer reagents does not change much, and the yield is above 85%. When sodium dihydrogen phosphate is used as the acidic buffer reagent, the purity and yield of compound 3 reach the best.

[0091] Example 8 Referring to the preparation method of Example 1, the reaction solvent in step 3) of Example 1 was changed to obtain compound 4 with different reaction solvents. The purity and yield are shown in Table 7:

[0092] Table 7 Effect of different reaction solvents on the 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. 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 reach the best.

Claims

1. A method for preparing an edoxaban intermediate, characterized in that:

2. The preparation method according to claim 1, characterized in that The following steps are involved: Step 1) Compound 1 undergoes an oxidation reaction with an oxidant 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 generate the hydrochloride 4 of the edoxabanthiazole intermediate.

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

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

5. The preparation method according to claim 2, characterized in that: In the step 1), the solvent is one or more of water, benzene, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably tetrahydrofuran; 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, and dioxane, preferably water.

6. The preparation method according to claim 2, characterized in that: In the step 1), the reaction temperature is 0-120°C, preferably 70-90°C; the reaction time is 0.5-24 hours; in the step 2), the reaction temperature is 0-90°C; preferably 10-25°C; the reaction time is 0.5-10 hours.

7. The preparation method according to claim 2, characterized in that: In the step 2), the chlorite is sodium chlorite, potassium chlorite, or calcium chlorite; the acidic solution is a dihydrogen phosphate solution, preferably a sodium dihydrogen phosphate solution, a potassium dihydrogen phosphate solution, a lithium dihydrogen phosphate solution, an ammonium dihydrogen phosphate solution, or an aluminum dihydrogen phosphate solution.

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

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

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid or its hydrochloride.

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