Method for preparing thiamine hydrochloride

Abstract

The invention relates to the field of compound preparation, in particular to a method for preparing thiamine hydrochloride. The method comprises the following steps: carrying out contact reaction on thiamine nitrate, ammonium chloride and hydrogen chloride under the condition of an organic solvent, and separating reaction liquid to obtain thiamine hydrochloride solid. Compared with the prior art, ammonium chloride is used for replacing part of hydrochloric acid to participate in the reaction in the thiamine hydrochloride production process, so that the dosage of hydrochloric acid is reduced, equipment corrosion can be reduced, subsequent wastewater treatment steps are simplified, the product yield is not influenced, the content of other impurities is not increased, new production equipment is not added, and the production cost is effectively saved; furthermore, the materials are recycled, so that a more environment-friendly and cost-saving process route can be realized.

Description

Method for preparing thiamine hydrochloride Technical Field

[0001] This invention relates to the field of compound preparation, and more specifically to a method for preparing thiamine hydrochloride. Background Technology

[0002] Vitamin B1 hydrochloride, also known as thiamine hydrochloride, is an essential substance for humans and animals to maintain normal physiological functions. It participates in the synthesis of coenzymes in the body, maintains carbohydrate metabolism and the functions of the nervous and digestive systems, and is used to prevent and treat beriberi. It is also used as an adjunct treatment for neuritis and indigestion. In addition to its medicinal uses, it can also be used as a food additive and animal feed additive.

[0003] CN103387573A discloses a process for preparing thiamine hydrochloride, comprising: heating concentrated hydrochloric acid to release hydrogen chloride gas, which is then cooled, dried, and dehydrated to obtain hydrogen chloride gas; passing the dried hydrogen chloride gas into a methanol solution to obtain an acidic methanol solution containing hydrogen chloride; adding the acidic methanol solution dropwise to a methanol solution of thiamine nitrate for reaction; and then filtering, washing, and drying to obtain thiamine hydrochloride. This method only provides a methanol solution containing hydrogen chloride for salt conversion. On the one hand, hydrogen chloride is corrosive to equipment; on the other hand, the wastewater and waste liquid obtained after conversion are costly and difficult to treat.

[0004] CN104817551A discloses a method for preparing vitamin B1 hydrochloride by reacting vitamin B1 sulfate (thiamine sulfate) with a saturated aqueous solution of calcium chloride. This method is suitable for preparing vitamin B1 hydrochloride from vitamin B1 sulfate. However, it is not suitable for preparation processes using thiamine nitrate as a raw material, and the overall purification steps are relatively complex, increasing process costs, resulting in limited yield, and increasing the risk of calcium ions being impurities in the product.

[0005] Existing methods for preparing thiamine hydrochloride still require technological improvements. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the existing methods for preparing thiamine hydrochloride and to provide a method for preparing thiamine hydrochloride and a method for continuously preparing thiamine hydrochloride.

[0007] To achieve the above objectives, the first aspect of the present invention provides a method for preparing thiamine hydrochloride, the method comprising: reacting thiamine nitrate, ammonium chloride and hydrogen chloride in an organic solvent under conditions, and obtaining solid thiamine hydrochloride after separation of the reaction solution.

[0008] The second aspect of the present invention provides a method for the continuous preparation of thiamine hydrochloride, the method comprising the following steps: (1) mixing thiamine sulfate solution and nitrate, preferably adjusting the pH to neutral and then crystallizing to obtain thiamine nitrate; (2) under organic solvent conditions, reacting the thiamine nitrate prepared in step (1) with ammonium chloride and hydrogen chloride, and obtaining thiamine hydrochloride solid and mother liquor after separation of the reaction solution; (3) separating the mother liquor to obtain an organic phase and ammonium nitrate, wherein at least part of the ammonium nitrate is recycled back to step (1) as nitrate, and at least part of the organic phase is recycled back to step (2) as organic solvent.

[0009] Through the above technical solution, the present invention has the following advantages: Compared with the prior art, the present invention uses ammonium chloride to replace part of the hydrochloric acid in the production process of thiamine hydrochloride, which reduces the amount of hydrochloric acid used, reduces equipment corrosion, simplifies the subsequent wastewater treatment steps, does not affect the product yield or increase the content of other impurities, does not add new production equipment, effectively saves production costs, and further recycles materials, thereby achieving a greener and more cost-effective process route. Detailed Implementation

[0010] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0011] This invention provides a method for preparing thiamine hydrochloride, the method comprising: reacting thiamine nitrate, ammonium chloride and hydrogen chloride in an organic solvent under contact conditions, and obtaining solid thiamine hydrochloride after separation of the reaction solution.

[0012] Compared with existing technologies, this invention uses ammonium chloride to replace a portion of hydrochloric acid in the production of thiamine hydrochloride, reducing the amount of hydrochloric acid used, thus reducing equipment corrosion, simplifying subsequent wastewater treatment steps, without affecting product yield or increasing the content of other impurities, without adding new production equipment, effectively saving production costs, and further recycling materials to achieve a greener and more cost-effective process route.

[0013] The present invention provides a method for continuous preparation of thiamine hydrochloride, the method comprising the following steps: (1) mixing thiamine sulfate solution and nitrate, preferably adjusting the pH to neutral and then crystallizing to obtain thiamine nitrate; (2) under organic solvent conditions, reacting the thiamine nitrate prepared in step (1) with ammonium chloride and hydrogen chloride, and obtaining thiamine hydrochloride solid and mother liquor after separation of the reaction solution; (3) separating the mother liquor to obtain organic phase and ammonium nitrate, wherein at least part of the ammonium nitrate is recycled back to step (1) as nitrate, and at least part of the organic phase is recycled back to step (2) as organic solvent.

[0014] The above method of the present invention enables the green, efficient, continuous, and low-cost synthesis of high-quality thiamine hydrochloride.

[0015] In this invention, the method of pH adjustment is not particularly limited, and it is usually adjusted by adding a pH adjuster such as ammonia.

[0016] In this invention, the method and conditions for separating the reaction solution are not particularly required and can be carried out using conventional techniques, such as filtration, vacuum filtration, and centrifugation. The mother liquor is separated by distillation. The distillation temperature and time can be adjusted according to the physical properties of the organic solvent to be recovered from the mother liquor; for example, in this invention, the mother liquor is distilled at 45°C.

[0017] In this invention, thiamine nitrate of any structure is applicable to the method of this invention, and there is no particular limitation on the structure of thiamine nitrate. The following is an illustrative description, but it does not limit the scope of this invention. According to a preferred embodiment of this invention, the structural formula of the thiamine nitrate is as follows: In the structural formula, R1 and R2 are alkyl groups; R3 is a hydroxyl or hydroxyalkyl group; and Y is a hydroxyl, hydroxyalkyl, amino, or aminoalkyl group.

[0018] According to a preferred embodiment of the present invention, in the structural formula of the thiamine nitrate, R1 and R2 are each independently C1-C6 alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl; more preferably, R1 and R2 are both methyl.

[0019] According to a preferred embodiment of the present invention, in the structural formula of the thiamine nitrate, R3 is -(CH2). p -OH, where p is a natural number, preferably an integer from 0 to 6, including but not limited to hydroxymethyl, hydroxyethyl, n-hydroxypropyl, isohydroxypropyl, n-hydroxybutyl, sec-hydroxybutyl, tert-hydroxybutyl, hydroxypentyl, and more preferably, R3 is hydroxyethyl.

[0020] According to a preferred embodiment of the present invention, in the structural formula of the thiamine nitrate, Y is -(CH2). n -NH2 or -(CH2)m -OH, wherein n and m are each independent natural numbers, preferably integers from 0 to 6, including but not limited to aminomethyl, aminoethyl, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-pentylamino, hydroxymethyl, hydroxyethyl, n-hydroxypropyl, isohydroxypropyl, n-hydroxybutyl, sec-hydroxybutyl, tert-hydroxybutyl, hydroxypentyl, and more preferably, Y is an amino group.

[0021] According to a preferred embodiment of the present invention, the thiamine nitrate is 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolonium nitrate.

[0022] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the hydrogen chloride is fed in the form of an organic solution, and the concentration of hydrogen chloride in the organic solution is 3-20 mol / L. By adopting the aforementioned preferred scheme, the contact reaction is more thorough and the solvent recovery is more economical.

[0023] According to a preferred embodiment of the present invention, the solvent for dissolving hydrogen chloride is selected from at least one of alcohols, ketones, esters, carboxylic acids, ethers, amines, halogenated aliphatic hydrocarbons, amides, imidazoles, sulfones, and aromatic hydrocarbons, more preferably selected from at least one of alcohols, ketones, esters, carboxylic acids, ethers, and halogenated aliphatic hydrocarbons, even more preferably alcohols, and more preferably C1-C3 alcohols. By adopting the aforementioned preferred embodiment, the contact reaction is more thorough, ensuring the crystal form and purity of the product, and solvent recovery is more economical.

[0024] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the molar ratio of ammonium chloride to thiamine nitrate is 1-8, preferably 1-3. By adopting the aforementioned preferred scheme, the contact reaction is more complete, and inorganic salt residues are avoided.

[0025] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the molar ratio of hydrogen chloride to thiamine nitrate is 1-8, preferably 1-3. By adopting the aforementioned preferred scheme, the contact reaction is more thorough, it is more equipment-friendly, and the process cost is reduced.

[0026] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the weight ratio of the organic solvent to thiamine nitrate is 1-20, preferably 1-8. By adopting the aforementioned preferred scheme, the contact reaction is more thorough, and the crystal purity of the product is guaranteed.

[0027] According to a preferred embodiment of the present invention, the molar ratio of hydrogen chloride to ammonium chloride in the preparation method of the present invention is 0.5-2. By adopting the aforementioned preferred scheme, the contact reaction is more thorough, inorganic salt residues are avoided, equipment is more user-friendly, and process costs are reduced.

[0028] According to a preferred embodiment of the present invention, the contact reaction conditions in the preparation method of the present invention include: a reaction temperature of 10-120°C, preferably 20-70°C. By adopting the aforementioned preferred scheme, the contact reaction is more thorough, and the crystal purity of the product is guaranteed.

[0029] According to a preferred embodiment of the present invention, the contact reaction conditions in the preparation method of the present invention include a reaction time of 20-420 min, preferably 150-320 min. By adopting the aforementioned preferred scheme, the contact reaction is made more thorough, and the crystal purity of the product is guaranteed.

[0030] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the contact reaction is carried out by first performing a first contact reaction and then performing a second contact reaction, wherein the temperature of the second contact reaction is 10-30°C higher than the temperature of the first contact reaction. By adopting the aforementioned preferred scheme, the contact reaction is more thorough, and the crystal purity of the product is guaranteed.

[0031] According to a preferred embodiment of the present invention, the temperature rise from the temperature of the first contact reaction to the temperature of the second contact reaction is achieved by a programmed continuous temperature rise at a rate of 0.5-5 °C / min; for example, the temperature rise rate can be set to 0.5, 1.5, 2.5, 3 °C / min, etc. By adopting the aforementioned preferred scheme, the contact reaction is made more thorough, and the crystal purity of the product is guaranteed.

[0032] According to a preferred embodiment of the present invention, the conditions for the first contact reaction include: a reaction temperature of 10-100°C, preferably 20-50°C; and / or a reaction time of 10-300 min, preferably 120-220 min.

[0033] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the contact reaction is carried out by first performing a first contact reaction and then performing a second contact reaction, wherein the conditions for the second contact reaction include: a temperature of 30-120°C, preferably 40-70°C.

[0034] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the contact reaction is carried out by first performing a first contact reaction and then performing a second contact reaction, wherein the conditions for the second contact reaction include: the reaction time is 10-120 min, preferably 30-100 min.

[0035] According to a preferred embodiment of the present invention, in the preparation method of the present invention, the organic solvent is at least one selected from alcohol organic solvents, ester organic solvents, ketone organic solvents, and ether organic solvents, preferably an alcohol organic solvent, more preferably a C1-C4 alcohol organic solvent, more preferably methanol, and even more preferably the organic solvent is the same as the solvent in the organic solution of hydrogen chloride. By adopting the aforementioned preferred scheme, it is beneficial to recover materials and simplify the processing technology without increasing new solvent residues.

[0036] The present invention will be described in detail below through examples and comparative examples. The reagents are sourced from: thiamine nitrate: Jiangxi Tianxin Pharmaceutical Co., Ltd., purity ≥99.0% (HPLC), content ≥98.0% (potentiometric titration), structural formula: .

[0037] Hydrochloric acid: Commercially available product from the Electrochemical Plant of Zhejiang Juhua Co., Ltd., with a content of 32.0 wt% (chemical titration).

[0038] Ammonium chloride: Commercially available from Zhejiang Dayang Biotechnology Group Co., Ltd., with a content ≥ 99.0% (chemical titration).

[0039] Methanol: Commercially available from Anhui Haoyuan Chemical Group Co., Ltd., with a content of ≥99.9% (GC).

[0040] The method for preparing hydrochloric acid methanol is as follows: 32% hydrochloric acid is heated to produce HCl gas, which is then condensed and dried, and then absorbed into methanol to prepare hydrochloric acid methanol solution.

[0041] In the following examples, the detection methods used for various indicators of the obtained product are as follows: the thiamine hydrochloride content was detected by potentiometric titration, and the nitrate and total impurity content were detected by high performance liquid chromatography (HPLC) with external standard method. Among them, the total impurity is mainly thiamine impurity A.

[0042] In Example 1, 100 g (0.3 mol) of 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate, 600 g of methanol, and 32.1 g (0.6 mol) of ammonium chloride solid were added to a flask after the pH of the mixture of thiamine sulfate and ammonium nitrate was adjusted to 7 and crystallized. At 45 °C, 83 ml of 9 mol / L hydrochloric acid methanol was added dropwise. After reacting for 150 min, the temperature was continuously increased at a rate of 0.5 °C / min. After reaching the final temperature of 60 °C, the temperature was maintained for 75 min, and then the mixture was cooled and filtered to obtain the target product solid and mother liquor.

[0043] The obtained target product solid was dried, wherein the content of thiamine hydrochloride was 100.2 wt%, nitrate was 0.16 wt%, and total impurities were 0.01 wt%.

[0044] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0045] In Example 2, 0.3 mol of 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate, 800 g of methanol, and 0.3 mol of ammonium chloride solid were added to a flask. At 35°C, 100 ml of 9 mol / L hydrochloric acid methanol was added dropwise. After reacting for 150 min, the temperature was continuously increased at a rate of 5°C / min. After reaching the endpoint temperature of 60°C, the temperature was maintained for 75 min, and then cooled and filtered to obtain the target product solid and mother liquor.

[0046] The obtained target product solid was dried, wherein the content of thiamine hydrochloride was 100.5 wt%, nitrate was 0.18 wt%, and total impurities were 0.01 wt%.

[0047] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0048] In Example 3, 0.3 mol of 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate, 300 g of isopropanol, and 0.9 mol of ammonium chloride solid were added to a flask. At 25 °C, 35 ml of 9 mol / L hydrochloric acid methanol was added dropwise. After reacting for 150 min, the temperature was continuously increased at a rate of 2.5 °C / min. After reaching the endpoint temperature of 40 °C, the temperature was maintained for 75 min, and then the mixture was cooled and filtered to obtain the target product solid and mother liquor.

[0049] The obtained target product solid was dried, wherein the content of thiamine hydrochloride was 99.7 wt%, nitrate was 0.11 wt%, and total impurities were 0.04 wt%.

[0050] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0051] Example 4 was prepared in the same way as Example 1, except that: 83 ml of 9 mol / L hydrochloric acid methanol was added dropwise at 45 °C, and the reaction was carried out for 150 min. Then, the mixture was kept warm for 75 min, cooled down, and filtered to obtain the target product solid and mother liquor.

[0052] The obtained target product solid was dried, and the content of thiamine hydrochloride was 100.8 wt%, nitrate was 0.22 wt%, and the total impurity content was 0.04 wt%.

[0053] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0054] Example 5 was prepared in the same way as Example 1, except that 0.33 mol of ammonium chloride solid was added dropwise to 110 ml of 9 mol / L hydrochloric acid methanol at 45 °C.

[0055] The obtained target product solid was dried, wherein the content of thiamine hydrochloride was 100.7 wt%, nitrate was 0.23 wt%, and total impurities were 0.05 wt%.

[0056] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0057] Example 6 was prepared in the same way as Example 1, except that: 83 ml of 9 mol / L hydrochloric acid methanol was added dropwise at 45 °C. After the reaction was carried out for 150 min, the temperature was continuously increased at a rate of 0.5 °C / min. After reaching the final temperature of 50 °C, the temperature was maintained for 75 min. Then the temperature was lowered and filtered to obtain the target product solid and mother liquor.

[0058] The obtained target product solid was dried, and the content of thiamine hydrochloride was 100.7 wt%, nitrate was 0.23 wt%, and the total impurity content was 0.04 wt%.

[0059] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0060] Example 7 is prepared in the same way as Example 1, except that: the methanol hydrochloric acid is replaced with ethyl acetate hydrochloric acid and the methanol is replaced with ethyl acetate.

[0061] The obtained target product solid was dried, and the content of thiamine hydrochloride was 99.3 wt%, nitrate was 0.2 wt%, and the total impurity content was 0.05 wt%.

[0062] The resulting mother liquor was distilled at 45°C, and the methanol fraction and the ammonium nitrate solid precipitated in the bottle were collected. The methanol fraction was then recycled as a solvent, and the ammonium nitrate was recycled as a nitrate donor for 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

[0063] Comparative Example 1 was prepared using the same method as Example 1, except that ammonium chloride was not added. To obtain the same yield of thiamine hydrochloride, 163 ml of 9 mol / L methanol hydrochloride was added. The large amount of hydrochloric acid used could corrode the equipment.

[0064] Comparative Example 2 was prepared using the same method as Example 1, except that ammonium chloride was not added and the same amount of methanol hydrogen chloride was added. The resulting target product solid was dried, and the yield of thiamine hydrochloride decreased by 45% compared to Example 1.

[0065] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing thiamine hydrochloride, characterized in that, The method includes: reacting thiamine nitrate, ammonium chloride and hydrogen chloride in an organic solvent, and obtaining thiamine hydrochloride solid after separation of the reaction solution.

2. A method for the continuous preparation of thiamine hydrochloride, characterized in that, The method includes the following steps: (1) mixing thiamine sulfate solution and nitrate, preferably adjusting the pH to neutral and then crystallizing to obtain thiamine nitrate; (2) under organic solvent conditions, reacting thiamine nitrate prepared in step (1) with ammonium chloride and hydrogen chloride, and obtaining thiamine hydrochloride solid and mother liquor after separation of the reaction solution; (3) separating the mother liquor to obtain organic phase and ammonium nitrate, wherein at least part of the ammonium nitrate is recycled back to step (1) as nitrate, and at least part of the organic phase is recycled back to step (2) as organic solvent.

3. The method according to claim 1 or 2, wherein, The structural formula of thiamine nitrate is as follows: In the structural formula, R1 and R2 are alkyl groups; R3 is a hydroxyl or hydroxyalkyl group; and Y is a hydroxyl, hydroxyalkyl, amino, or aminoalkyl group.

4. The method according to claim 3, wherein, In the structural formula of the aforementioned thiamine nitrate: R1 and R2 are each independently a C1-C6 alkyl group; and / or R3 is -(CH2). p -OH, where p is a natural number, preferably an integer between 0 and 6; and / or Y is -(CH2). n -NH2 or -(CH2) m -OH, wherein n and m are each independent natural numbers, preferably integers from 0 to 6; preferably, thiamine nitrate is 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate.

5. The method according to any one of claims 1-4, wherein, The hydrogen chloride is fed in the form of an organic solution, and the concentration of hydrogen chloride in the organic solution is 3-20 mol / L. Preferably, the solvent for dissolving hydrogen chloride is selected from at least one of alcohols, ketones, esters, carboxylic acids, ethers, amines, halogenated aliphatic hydrocarbons, amides, imidazoles, sulfones and aromatic hydrocarbons. More preferably, it is selected from at least one of alcohols, ketones, esters, carboxylic acids, ethers and halogenated aliphatic hydrocarbons. More preferably, it is an alcohol, and more preferably, it is a C1-C3 alcohol.

6. The method according to any one of claims 1-5, wherein, During the contact reaction, the molar ratio of ammonium chloride to thiamine nitrate is 1-8:1, preferably 1-3:1; and / or the molar ratio of hydrogen chloride to thiamine nitrate is 1-8:1, preferably 1-3:1; and / or the weight ratio of the organic solvent to thiamine nitrate is 1-20:1, preferably 1-8:

1.

7. The method according to any one of claims 1-6, wherein, During the contact reaction, the molar ratio of hydrogen chloride to ammonium chloride is 0.5-2.

8. The method according to any one of claims 1-7, wherein, The conditions for the contact reaction include: a reaction temperature of 10-120℃, preferably 20-70℃; and / or a reaction time of 20-420 min, preferably 150-320 min.

9. The method according to any one of claims 1-8, wherein, The contact reaction is performed by first conducting a first contact reaction and then a second contact reaction, wherein the temperature of the second contact reaction is 10-30°C higher than the temperature of the first contact reaction. Preferably, the temperature rise from the temperature of the first contact reaction to the temperature of the second contact reaction is performed by a programmed continuous temperature rise at a rate of 0.5-5°C / min. More preferably, the conditions for the first contact reaction include: a reaction temperature of 10-100°C, preferably 20-50°C; and / or a reaction time of 10-300 min, preferably 120-220 min; and / or the conditions for the second contact reaction include: a temperature of 30-120°C, preferably 40-70°C; and / or a time of 10-120 min, preferably 30-100 min.

10. The method according to any one of claims 1-9, wherein, The organic solvent is at least one of alcohol organic solvents, ester organic solvents, ketone organic solvents and ether organic solvents, preferably an alcohol organic solvent, and more preferably a C1-C4 alcohol organic solvent.