Synthesis method of 3-hydroxyazetidine hydrochloride

Abstract

The invention discloses a synthesis method of 3-hydroxyazetidine hydrochloride, and belongs to the technical field of organic synthesis. According to the method, tert-butylamine and epichlorohydrin are used as starting raw materials, and a target product is prepared through three-step reaction of cyclization, acetylation and deacetylation in sequence. The method is characterized in that in the acetylation reaction step, a step-by-step strategy that hydroxyl is subjected to monoacetylation at low temperature, and then tert-butyl acetylation is carried out by heating under the conditions that Lewis acid is used for catalysis and sodium hydrosulfite is used as a binding agent is adopted; the binding agent can effectively capture fallen tert-butyl, and side reaction between the fallen tert-butyl and the intermediate is avoided. By optimizing the synthesis route and the purification process, the problems of high raw material cost, high hydrogenation deprotection safety risk, more side reactions, difficulty in intermediate purification, poor product crystallization effect and the like in the prior art are solved. The obtained product is high in purity (greater than or equal to 98%) and good in crystal form, and the whole process is good in safety, simple and convenient to operate and more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of 3-hydroxyazetidine hydrochloride and belongs to the technical field of organic synthesis. BACKGROUND

[0002] 3-hydroxyazetidine hydrochloride is a light yellow to white powder, the molecular formula of which is C3H8ClNO, the molecular weight is 109.55, the CAS number is 18621-18-6, and the melting point is 86.5 DEG C (85-90 DEG C). The compound is easily soluble in dimethyl sulfoxide (DMSO), methanol and water, is a key intermediate for synthesizing baricitinib, and needs to be finally prepared into a target drug through multiple reaction steps.

[0003] In the prior art, the method for synthesizing 3-hydroxyazetidine hydrochloride generally uses benzylamine, diphenylamine or triphenylamine as a starting material (for example, a synthesis method of 3-hydroxyazetidine hydrochloride disclosed in Chinese Patent Application Publication No. CN111825592A). However, the cost of these raw materials is high, and the synthesis route generally involves a hydrogenation deprotection step, and hydrogen is used in the reaction, so there is a high safety risk.

[0004] In addition, in the acetylation reaction step in the prior art, there are generally problems of poor reaction selectivity and low purity. Various side reactions are prone to occur in the reaction process, especially the t-butyl group is prone to fall off under high-temperature conditions and react with the product (1-acetyl-3-acetyloxyazetidine) to generate complex-structure byproducts or tar-like impurities, thereby reducing the product purity and yield. The byproducts and impurities increase the difficulty of subsequent separation and purification. In order to obtain high-purity intermediate N-acetyl-3-acetyloxyazetidine, high-temperature and high-vacuum distillation is generally used for purification. This method has high energy consumption, high requirements for equipment, and decomposition risks in high-boiling-point and heat-sensitive compounds, and thus is not suitable for large-scale industrial production.

[0005] Finally, in the precipitation and purification stage of the finished product 3-hydroxyazetidine hydrochloride, the existing method uses a methanol / ethyl acetate mixed solvent for crystallization, which is easy to form black oily substances that are difficult to handle, resulting in large loss of crystallization yield; and the crystal form of the obtained product is poor and the purity is not high.

[0006] Specifically, the prior art mainly has the following defects:

[0007] 1. The cost of the starting material is high, and a dangerous hydrogenation reaction is involved, so the safety risk is high.

[0008] 2. The acetylation reaction has many side reactions, the reaction selectivity is difficult to control, complex-structure byproducts and tar-like impurities are easy to form, and the reaction yield and purity are low.

[0009] 3. The intermediate purification relies on high-temperature distillation, which has high energy consumption, strict equipment requirements and is difficult to implement on a large scale.

[0010] 4. The crystallization process of the product hydrochloride salt is low in efficiency, has large product loss and unsatisfactory purification effect. SUMMARY

[0011] The purpose of the present application is to provide a synthesis method of 3-hydroxyazetidine hydrochloride, which uses sodium dithionite to bind the detached tert-butyl group, thereby avoiding the reaction of the tert-butyl group with the product (1-acetyl-3-acetyloxyazetidine). Meanwhile, the problems of high raw material cost, high equipment requirement and difficult purification in the prior art are solved.

[0012] In order to achieve the above technical purposes, the technical scheme of the present application is as follows:

[0013] A synthesis method of 3-hydroxyazetidine hydrochloride, comprising the following steps:

[0014] (1) Cyclization reaction

[0015] Under the protection of nitrogen, tert-butylamine, epichlorohydrin and isopropyl alcohol are added to a reaction container, and the temperature is controlled at 30-35℃ for reaction; after the reaction is completed, a base is added to the system, and then the system is heated to 80-85℃ for continuous reaction; after the reaction is completed, the reaction mixture is cooled to room temperature, and the solid is removed by filtration; the filtrate is concentrated under reduced pressure to obtain N-tert-butyl-3-hydroxyazetidine crude product.

[0016] Preferably, the base is sodium bicarbonate, the molar ratio of the tert-butylamine to the epichlorohydrin is 1:1-2, and the molar ratio of the base to the epichlorohydrin is 1:1-2.

[0017] (2) Acetylation reaction

[0018] Under the protection of nitrogen, the N-tert-butyl-3-hydroxyazetidine crude product obtained in step (1) is added to a reaction container, and after cooling to 0℃, acetic anhydride is added dropwise for single acetylation reaction, and the temperature is controlled to maintain at 0-5℃ during the dropwise addition; after the reaction is completed, a Lewis acid catalyst and a binding agent are added to the reaction system, and acetic anhydride is supplemented, and then the system is heated to 110-120℃ for reaction; after the reaction is completed, the reaction liquid is filtered through diatomite, adsorbed and decolorized by activated carbon, and filtered through a silica gel pad; finally, the filtrate is concentrated under reduced pressure to remove the solvent, thereby obtaining 1-acetyl-3-acetyloxyazetidine crude product.

[0019] Preferably, the amount of acetic anhydride used each time is 3-6 equivalents of N-tert-butyl-3-hydroxyazetidine, the Lewis acid is boron trifluoride etherate, and the binding agent is sodium dithionite (sodium hydrosulfite), which is used in an amount of more than 0.2 equivalents of N-tert-butyl-3-hydroxyazetidine.

[0020] The amount of the activated carbon is 5% of the mass of the crude N-tert-butyl-3-hydroxyazetidine.

[0021] (3) Deacetylation reaction:

[0022] The crude 1-acetyl-3-acetyloxyazetidine obtained in step (2) is added into an aqueous hydrochloric acid solution with a concentration of 2-10%, and the reaction is carried out by heating to 90-100°C. After the reaction is completed, the reaction solution is cooled to room temperature, activated carbon is added for adsorption and decolorization, and then filtration is performed to obtain a crude product solution. The crude product solution is concentrated to dryness to obtain a crude product solid. The solid is dissolved by heating with ethanol, and then recrystallized by cooling. After filtration and drying, a white solid is obtained, which is 3-hydroxyazetidine hydrochloride.

[0023] Preferably, the concentration of the aqueous hydrochloric acid solution is 5-10%, and the amount of the activated carbon is 5% of the mass of the crude 1-acetyl-3-acetyloxyazetidine.

[0024] To further remove residual moisture, after being concentrated to dryness, ethanol is used for azeotropic water removal operation twice to ensure that the water content in the final product is ≤0.5%.

[0025] The synthetic route of the present application is as shown below:

[0026] (1) Cyclization reaction:

[0027] (2) Acetylation reaction:

[0028] (3) Deacetylation reaction:

[0029] The product prepared by the method of the present application is a white solid, and the structure is confirmed to be correct by nuclear magnetic resonance spectroscopy, with a purity (detected by CAD) of more than 98% and no obvious impurities.

[0030] Compared with the prior art, the present application has the following beneficial effects:

[0031] 1. The present application uses inexpensive tert-butylamine as a starting material, avoiding the use of expensive benzylamine and diphenylamine, thereby significantly reducing production costs. At the same time, the entire synthetic route avoids the dangerous catalytic hydrogenolysis step, improving the safety of the production process and being more suitable for industrialization.

[0032] 2. The present application adopts a step-by-step strategy of acetylating hydroxyl group at low temperature first and then acetylating tert-butyl group at elevated temperature, which can avoid the side reactions such as hydrolysis, elimination or intramolecular cyclization of acetyl group on hydroxyl group under the catalysis of Lewis acid at high temperature, protect the integrity of hydroxyl acetyl group and avoid its "deterioration" or impurity generation.

[0033] 3. The present application uses sodium hyposulfite as a binding agent during the acetylation of tert-butyl group, which can effectively capture the detached tert-butyl group and prevent it from reacting with the product (1-acetyl-3-acetyloxyazetidine), thereby reducing the generation of complex by-products or tar-like impurities and improving the reaction purity.

[0034] 4. The present application significantly reduces the types and amounts of impurities and improves the purity of the product by using "step-by-step acetylation strategy" and "application of sodium hyposulfite as a tert-butyl binding agent", which is more suitable for industrial production.

[0035] 5. In the final product purification stage, the present application uses ethanol for recrystallization instead of the methanol / ethyl acetate system, which is simple to operate, has good product crystal form and high purity. BRIEF DESCRIPTION OF DRAWINGS

[0036] The present application will be further described in detail below in combination with the drawings and specific embodiments.

[0037] Figure 1 The chromatogram of the product obtained in Example 2.

[0038] Figure 2 The chromatogram of the product obtained in Example 4.

[0039] Figure 3 The chromatogram of the product obtained in Example 5.

[0040] Figure 4 The chromatogram of the product obtained in Comparative Example 1.

[0041] Figure 5 The chromatogram of the product obtained in Comparative Example 2.

[0042] Figure 6 The chromatogram of the product obtained in Example 7.

[0043] Figure 7 The chromatogram of the product obtained in Example 8.

[0044] Figure 8 The chromatogram of the product obtained in Example 9.

[0045] Figure 9 The nuclear magnetic resonance spectrum of the product obtained in Example 9. DETAILED DESCRIPTION

[0046] Example 1 (cyclization reaction)

[0047] Under nitrogen protection, tert-butylamine (100.0 g, 1.36 mol), epichlorohydrin (151.8 g, 1.63 mol) and isopropyl alcohol (500 mL) were added into a reaction vessel, then the temperature of the reaction liquid was raised to 30-35°C, and the reaction was carried out at this temperature range. After the reaction was completed, the reaction liquid was cooled to room temperature, then sodium bicarbonate (126 g, 1.50 mol) was added into the reaction system, then the reaction system was heated to 80-85°C, and the reaction was continued at this temperature.

[0048] After the reaction was completed, the reaction liquid was cooled to room temperature (20-25°C), and the insoluble solid salt was removed by filtration, then the filtrate was concentrated under reduced pressure to obtain N-tert-butyl-3-hydroxyazetidine crude product, which was analyzed by gas chromatography (GC) and the purity was about 85%.

[0049] Example 2 (cyclization reaction)

[0050] Under nitrogen protection, tert-butylamine (100.0 g, 1.36 mol), epichlorohydrin (126.5 g, 1.36 mol) and isopropyl alcohol (500 mL) were added into a reaction vessel, then the temperature of the reaction liquid was raised to 30-35°C, and the reaction was carried out at this temperature range. After the reaction was completed, the reaction liquid was cooled to room temperature, then sodium bicarbonate (126 g, 1.50 mol) was added into the reaction system, then the reaction system was heated to 80-85°C, and the reaction was continued at this temperature.

[0051] After the reaction was completed, the reaction liquid was cooled to room temperature (20-25°C), and the insoluble solid salt was removed by filtration, then the filtrate was concentrated under reduced pressure to obtain N-tert-butyl-3-hydroxyazetidine crude product, which was analyzed by gas chromatography (GC) and the purity was about 91.4% (its chromatogram is shown in Figure 1 ).

[0052] Example 3 (cyclization reaction)

[0053] Under nitrogen protection, tert-butylamine (100.0 g, 1.36 mol), epichlorohydrin (252.9 g, 2.72 mol) and isopropyl alcohol (500 mL) were added into a reaction vessel, then the temperature of the reaction liquid was raised to 30-35°C, and the reaction was carried out at this temperature range. After the reaction was completed, the reaction liquid was cooled to room temperature, then sodium bicarbonate (126 g, 1.50 mol) was added into the reaction system, then the reaction system was heated to 80-85°C, and the reaction was continued at this temperature.

[0054] After the reaction was completed, the reaction solution was cooled to room temperature (20-25°C), insoluble solid salt was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain N-tert-butyl-3-hydroxyazetidine crude product, which was analyzed by gas chromatography (GC) and had a purity of about 88%.

[0055] Examples 1, 2, and 3 were compared, and the comparison results are as follows:

[0056] As can be seen from the purity data, the purity of Example 2 is higher than that of Examples 1 and 3, and therefore, the molar ratio of tert-butylamine to epichlorohydrin is preferably 1:1.

[0057] Example 4 (acetylation reaction)

[0058] Under nitrogen protection, N-tert-butyl-3-hydroxyazetidine crude product (181 g, about 0.95 mol of N-tert-butyl-3-hydroxyazetidine) obtained in Example 2 was added to a reaction vessel. After cooling to 0°C, acetic anhydride (350 mL, about 3.72 mol) was added dropwise, and the dropwise addition rate was controlled to maintain the reaction solution temperature at 0-5°C. After the dropwise addition was completed, the reaction solution was warmed to 20-30°C, and the reaction was carried out at this temperature to complete the monoacetylation. After the reaction was completed, boron trifluoride etherate (56 g, 0.39 mol) and sodium hydrosulfite (34 g, 0.19 mol) were added to the reaction solution, and then, acetic anhydride (302 g, 2.95 mol) was added. Then, the reaction system was warmed to 110-120°C, and the reaction was carried out at this temperature.

[0059] After the reaction was completed, the reaction solution was filtered through celite, and granular activated carbon (9.05 g) was added to the filtrate and stirred for adsorption and decolorization. After decolorization, the clear filtrate was filtered through a 4 cm silica gel pad. Finally, the obtained clear filtrate was concentrated under reduced pressure to recover most of the acetic anhydride, and a brownish red oily liquid was obtained as a residue, which was 1-acetyl-3-acetyloxyazetidine crude product, which was analyzed by gas chromatography (GC) and had a purity of about 66.4% (its chromatogram is shown in FIG. 1). Figure 2

[0060] Example 5 (acetylation reaction)

[0061] ​Under nitrogen protection, the N-tert-butyl-3-hydroxyazetidine crude product (181 g, about 0.95 mol based on N-tert-butyl-3-hydroxyazetidine) obtained from Example 2 was added into a reaction vessel. After cooling to 0°C, acetic anhydride (350 mL, about 3.72 mol) was added dropwise, and the dropping speed was controlled to maintain the temperature of the reaction liquid between 0-5°C. After the addition was completed, the reaction liquid was warmed to 20-30°C, and reacted at this temperature to complete the mono-acetylation. After the reaction was completed, boron trifluoride etherate (84 g, 0.59 mol) and sodium hydrosulfite (34 g, 0.19 mol) were added into the reaction liquid, and then, acetic anhydride (408 g, 3.99 mol) was added again. Then, the reaction system was warmed to 110-120°C, and reacted at this temperature.

[0062] After the reaction was completed, the reaction liquid was filtered through celite, and the filtrate was added with granular activated carbon (9.05 g) to stir and adsorb for decolorization. After the decolorization, the mixture was filtered through a 4 cm silica gel pad. Finally, the obtained clear filtrate was concentrated under reduced pressure to recover most of the acetic anhydride, and a brownish red oily liquid was obtained as the residue, which was the crude 1-acetyl-3-acetyloxyazetidine. The purity thereof was about 78.4% by gas chromatography (GC) analysis (its chromatogram is shown in Figure 1). Figure 3 ).

[0063] Example 6 (acetylation reaction)

[0064] Under nitrogen protection, the N-tert-butyl-3-hydroxyazetidine crude product (181 g, about 0.95 mol based on N-tert-butyl-3-hydroxyazetidine) obtained from Example 2 was added into a reaction vessel. After cooling to 0°C, acetic anhydride (350 mL, about 3.72 mol) was added dropwise, and the dropping speed was controlled to maintain the temperature of the reaction liquid between 0-5°C. After the addition was completed, the reaction liquid was warmed to 20-30°C, and reacted at this temperature to complete the mono-acetylation. After the reaction was completed, boron trifluoride etherate (84 g, 0.59 mol) and sodium hydrosulfite (34 g, 0.19 mol) were added into the reaction liquid, and then, acetic anhydride (408 g, 3.99 mol) was added again. Then, the reaction system was warmed to 110-120°C, and reacted at this temperature.

[0065] After the reaction was completed, the reaction liquid was filtered through celite, and the filtrate was added with granular activated carbon (9.05 g) to stir and adsorb for decolorization. After the decolorization, the mixture was filtered through a 4 cm silica gel pad. Finally, the obtained clear filtrate was concentrated under reduced pressure to recover most of the acetic anhydride, and a brownish red oily liquid was obtained as the residue, which was the crude 1-acetyl-3-acetyloxyazetidine. The purity thereof was about 78.4% by gas chromatography (GC) analysis (its chromatogram is shown in Figure 1).

[0066] Comparing Example 4, 5, 6, the results are as follows:

[0067] From the purity data, it can be seen that the purity of Example 5 is higher than that of Example 4 and 6, therefore, the molar ratio of boron trifluoride etherate to N-tert-butyl-3-hydroxyazetidine is preferably 1:0.62, and the molar ratio of additional acetic anhydride to N-tert-butyl-3-hydroxyazetidine is preferably 1:4.20.

[0068] Comparative Example 1 (acetylation reaction, without sodium dithionite)

[0069] Under nitrogen protection, N-tert-butyl-3-hydroxyazetidine crude product (181 g, about 0.95 mol based on N-tert-butyl-3-hydroxyazetidine) obtained from Example 2 was added to a reaction vessel. After cooling to 0°C, acetic anhydride (350 mL, about 3.72 mol) was added dropwise, and the dropwise addition rate was controlled to maintain the reaction liquid temperature between 0-5°C. After the dropwise addition was completed, the reaction liquid was warmed to 20-30°C and reacted at this temperature to complete the mono-acetylation. After the reaction was completed, boron trifluoride etherate (84 g, 0.59 mol) was added to the reaction liquid, and additional acetic anhydride (408 g, 3.99 mol) was added. Then the reaction system was warmed to 110-120°C and reacted at this temperature. After the reaction was completed, 1-acetyl-3-acetyloxyazetidine crude product was obtained, and its purity was about 55.3% by gas chromatography (GC) analysis (its chromatogram is shown in FIG. 1). Figure 4 ).

[0070] The product purity of Example 4 using sodium dithionite was about 10% higher than that of Comparative Example 1.

[0071] Comparative Example 2 (acetylation reaction, one-step method)

[0072] Under nitrogen protection, N-tert-butyl-3-hydroxyazetidine crude product (181 g, about 0.95 mol based on N-tert-butyl-3-hydroxyazetidine) and boron trifluoride etherate (84 g, 0.59 mol) were added to a reaction vessel, and acetic anhydride (786 g, about 7.7 mol) was added dropwise. After the dropwise addition was completed, the temperature was warmed to 110-120°C and reacted at this temperature to complete the di-acetylation. After the reaction was completed, 1-acetyl-3-acetyloxyazetidine crude product was obtained, and its purity was about 54.6% by gas chromatography (GC) analysis (its chromatogram is shown in FIG. 2). Figure 5 ).

[0073] The product purity of Comparative Example 2 (one-step method) was significantly lower than that of Example 5, and was also lower than that of Example 4 and 6.

[0074] Example 7 (deacetylation reaction)

[0075] In a reaction vessel, 1-acetyl-3-acetoxyazetidine (108.0 g, 0.68 mol) obtained in Example 5 and an aqueous hydrochloric acid solution having a concentration of 2% (500 mL) were added, and the temperature was raised to 90-100°C, and the reaction was carried out at this temperature. After the completion of the reaction, the reaction solution was cooled to room temperature, granular activated carbon (5.4 g) was added, and stirring was carried out for 2 hours to adsorb and decolorize, and then filtration was carried out, to obtain a clear filtrate having a light yellow color. This filtrate was concentrated to dryness under reduced pressure at 50°C, to obtain a light yellow viscous solid.

[0076] To further remove residual moisture, ethanol (100 mL) was added to the solid, and heating was carried out under reflux to dissolve it, and then most of the ethanol (water-carrying) was distilled off under reduced pressure at 50°C, and this water-carrying operation was repeated once to ensure that the moisture content in the final product was ≤0.5%. Finally, ethanol (100 mL) was added, heated to 50°C, and stirring was carried out to completely dissolve it. Then, the solution was slowly cooled to 15-20°C, and stirring was carried out at this temperature for 3 hours to crystallize. After the crystals were precipitated, filtration was carried out under nitrogen, and vacuum drying (35-45°C) was carried out, to obtain a white solid (56 g), which was 3-hydroxyazetidine hydrochloride, and the purity thereof was 92.07% as determined by CAD (see the chromatogram thereof in Fig. 2). The yield in this step was about 50.4%. Figure 6

[0077] Example 8 (deacetylation reaction)

[0078] In a reaction vessel, 1-acetyl-3-acetoxyazetidine (108.0 g, 0.68 mol) obtained in Example 5 and an aqueous hydrochloric acid solution having a concentration of 5% (500 mL) were added, and the temperature was raised to 90-100°C, and the reaction was carried out at this temperature. After the completion of the reaction, the reaction solution was cooled to room temperature, granular activated carbon (5.4 g) was added, and stirring was carried out for 2 hours to adsorb and decolorize, and then filtration was carried out, to obtain a clear filtrate having a light yellow color. This filtrate was concentrated to dryness under reduced pressure at 50°C, to obtain a light yellow viscous solid.

[0079] ​To further remove the residual moisture, add ethanol (100 mL) to the solid, heat to reflux to dissolve, then evaporate most of the ethanol (with water) at 50°C under reduced pressure, repeat this operation once to ensure the moisture content of the final product is <0.5%. Finally, add ethanol (100 mL), heat to 50°C and stir to completely dissolve. Then, slowly cool the solution to 15-20°C, and stir at this temperature for 3 hours to allow the crystals to precipitate. After the crystals precipitate, filter under nitrogen protection, and vacuum dry (35-45°C) to obtain a white solid (56 g), which is 3-hydroxyazetidine hydrochloride. The purity is 99.18% as determined by CAD (see its chromatogram in Figure 7 ). The yield of this step is about 60.5%.

[0080] Example 9 (deacetylation reaction)

[0081] In a reaction vessel, add 1-acetyl-3-acetyloxyazetidine (108.0 g, 0.68 mol) obtained in Example 5 and 10% concentrated hydrochloric acid aqueous solution (500 mL), heat to 90-100°C, and react at this temperature. After the reaction is complete, cool the reaction liquid to room temperature, add granular activated carbon (5.4 g), stir for 2 hours to adsorb and decolorize, then filter to obtain a light yellow clear filtrate. Concentrate the filtrate to dryness at 50°C under reduced pressure to obtain a light yellow viscous solid.

[0082] To further remove the residual moisture, add ethanol (100 mL) to the solid, heat to reflux to dissolve, then evaporate most of the ethanol (with water) at 50°C under reduced pressure, repeat this operation once to ensure the moisture content of the final product is <0.5%. Finally, add ethanol (100 mL), heat to 50°C and stir to completely dissolve. Then, slowly cool the solution to 15-20°C, and stir at this temperature for 3 hours to allow the crystals to precipitate. After the crystals precipitate, filter under nitrogen protection, and vacuum dry (35-45°C) to obtain a white solid (56 g), which is 3-hydroxyazetidine hydrochloride. The purity is 98.33% as determined by CAD (see its chromatogram in Figure 8 ), and verified by NMR (see its NMR chart in Figure 9 ). The yield of this step is about 60.1%.

[0083] Compare Examples 7, 8, and 9, and the comparison results are as follows:

[0084] From the purity and yield data, the yield and purity of Example 7 are the lowest, and Examples 8 and 9 are significantly higher than Example 7, so the concentration of the hydrochloric acid aqueous solution is preferably 5-10%.

[0085] The above embodiments do not limit the present application in any way, and any technical solutions obtained by equivalent replacement or equivalent transformation fall within the protection scope of the present application.

Claims

1. A method for synthesizing 3-hydroxyazacyclobutane hydrochloride, characterized in that, Includes the following steps: (1) Cyclization reaction: tert-butylamine, epichlorohydrin and isopropanol were added to the reaction vessel and the temperature was controlled at 30~35℃ for the reaction. After the reaction was completed, sodium bicarbonate was added and the system was heated to 80~85℃ to continue the reaction. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain crude N-tert-butyl-3-hydroxyazacyclobutane. (2) Acetylation reaction: The crude N-tert-butyl-3-hydroxyazacyclobutane obtained in step (1) was added to a reaction vessel, and acetic anhydride was added dropwise under low temperature to carry out a monoacetylation reaction; after the reaction was completed, boron trifluoride diethyl ether and sodium dithionite were added, and acetic anhydride was added, and then the temperature was raised to 110~120℃ to carry out the reaction; after the reaction was completed, the crude 1-acetyl-3-acetoxyazacyclobutane was obtained by diatomaceous earth filtration, activated carbon adsorption decolorization, silica gel pad filtration and vacuum concentration; the sodium dithionite was used to prevent the detached tert-butyl group from reacting with 1-acetyl-3-acetoxyazacyclobutane; (3) Deacetylation reaction: The crude 1-acetyl-3-acetoxyazacyclobutane obtained in step (2) is added to a 2-10% hydrochloric acid aqueous solution and heated to 90-100℃ for reaction. After the reaction is completed, the product is decolorized by activated carbon adsorption, filtered, concentrated to obtain crude solid. The crude solid is dissolved by heating with ethanol and then cooled to recrystallize, to obtain 3-hydroxyazacyclobutane hydrochloride.

2. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (1), the molar ratio of tert-butylamine to epichlorohydrin is 1:1~2.

3. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (1), the molar ratio of the alkali to epichlorohydrin is 1:1~2.

4. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (2), the low temperature environment is 0~5℃.

5. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (2), the amount of acetic anhydride used each time is 3 to 6 equivalents of N-tert-butyl-3-hydroxyazacyclobutane.

6. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (2), the amount of sodium dithionite used is more than 0.2 equivalents of N-tert-butyl-3-hydroxyazine.

7. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (3), the concentration of the hydrochloric acid aqueous solution is 5~10%.

8. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (3), the amount of activated carbon used is 5% of the crude weight of 1-acetyl-3-acetoxyazacyclobutane.

9. The method for synthesizing 3-hydroxyazacyclobutane hydrochloride according to claim 1, characterized in that: In step (3), after concentration to dryness, azeotropic water removal is performed twice with ethanol to ensure that the moisture content in the final product is ≤0.5%.

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