Preparation method of (S)-oxetane-2-methylamine

Abstract

The invention provides a preparation method of (S)-oxetane-2-methylamine. The preparation method of (S)-oxetane-2-methylamine comprises the following steps: (1) carrying out ring closing reaction on a compound A under an alkaline condition to obtain a compound B; (2) reacting the compound B with dibenzylamine to obtain a compound C; (3) reacting the compound C with a reducing agent to obtain a compound D; (4) reacting the compound D with paratoluensulfonyl chloride to obtain a compound E; (5) reacting the compound E with alkali to obtain a compound F; and (6) carrying out a reaction on the compound F and palladium on carbon to obtain the (S)-oxetane-2-methylamine. According to the preparation method provided by the invention, ring expansion reaction using trimethylsulfoxide iodide in the prior art is avoided, the problem that residual sulfur elements cause poisoning of a palladium-carbon catalyst is solved, meanwhile, sodium azide is also avoided, and the preparation method is safe and reliable in process, high in chiral purity and yield and suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a preparation method of (S)-oxetan-2-methylamine. BACKGROUND

[0002] (S)-Epoxymethylcyclobutane-2-methylamine is a key intermediate of some glucagon-like peptide-1 receptor agonists. At present, the synthesis method of (S)-epoxymethylcyclobutane-2-methylamine mainly includes the following routes:

[0003] Patent application WO2018109607A1 discloses the following route one:

[0004]

[0005] Route one takes (S)-benzyloxymethyl oxirane A1 as a starting material, and expands the ring under alkaline conditions to obtain chiral benzyl epoxy butane A2; further debenzylization to obtain chiral epoxy butane methanol A3; then reacts with methyl sulfonyl chloride to generate methyl sulfonate A4, and then uses sodium azide to generate chiral butane azide A5, and finally hydrogenation to obtain the target compound A0.

[0006] The method is an expansion reaction in the first step, which expands the oxirane to oxetane. In the fourth step, the use of azide compounds has the hazards of instability, easy explosion and high toxicity, resulting in high safety production cost of the method. In addition, the expansion reaction uses trimethyl sulfoxonium iodide, which has a trace amount of sulfur element residue, which poisons the palladium-carbon catalyst, and the hydrogenation reaction is difficult to proceed. In order to remove the residual sulfur, column chromatography purification of the reaction product is necessary, thus seriously restricting the large-scale production.

[0007] Patent CN114728923B discloses the following route two:

[0008]

[0009] Take dibenzylamine as a raw material, and perform ring opening reaction with chiral epichlorohydrin to obtain C2, and then perform ring closure under alkaline conditions to obtain dibenzylamine chiral epoxide C3; similarly, compound C3 is subjected to expansion reaction with trimethyl sulfoxonium iodide under alkaline conditions to obtain dibenzylamine chiral oxetane C4, and finally hydrogenation debenzylization to obtain the target compound A0.

[0010] The route has one less step than route one, although it avoids the use of explosive and highly toxic sodium azide, but the expansion reaction uses trimethyl sulfoxonium iodide, which has a trace amount of sulfur element residue, which poisons the palladium-carbon catalyst, and the hydrogenation reaction is difficult to proceed. In order to remove the residual sulfur, column chromatography purification of the reaction product is necessary, thus seriously restricting the large-scale production.

[0011] Patent application CN115991685A discloses the following route three:

[0012]

[0013] Route 3 uses chiral glycidol B1 as the starting material, and prepares compound B2 by protection with vinyl ethyl ether. Compound B3 is prepared by basic ring expansion with trimethyl sulfoxide. Compound B4 is prepared by deprotection. Compound B4 reacts with p-toluenesulfonyl chloride to generate p-toluenesulfonate B5. Then, it is substituted with potassium phthalimide to generate mixture B6. Finally, deprotection is performed to obtain the target compound A0.

[0014] The biggest change in Route 3 compared to Route 1 is that the benzyl protecting group has been replaced with a vinyl ether protecting group; in addition, the easily explosive reagent sodium azide has been replaced with potassium phthalimide.

[0015] This process still has the following problems: First, chiral glycidol is unstable; the 3-hydroxyl group can undergo a ring-opening reaction with the epoxy of another molecule, thus continuing the polymerization into a high molecular weight compound. Polymerization is slow at room temperature. However, during the formation distillation stage, due to the high temperature, it is prone to explosive polymerization, releasing a large amount of heat and causing an explosion. Therefore, chiral glycidol cannot be produced on a large scale, and raw materials are not easily guaranteed. Furthermore, the final step of the process uses easily explosive hydrazine hydrate for deprotection, posing certain safety risks.

[0016] Patent CN 118420569 B reports the fourth synthetic route, with the following reaction formula:

[0017]

[0018] This route is basically the same as route three. Both start with chiral glycidol B1 as the starting material, prepare compound B2 by protection with vinyl ethyl ether, prepare compound B3 by basic ring expansion with trimethyl sulfoxide, prepare compound B4 by deprotection, react compound B4 with methanesulfonyl chloride to generate methanesulfonate (formula IV), then replace it with sodium diformamide to generate compound V, and finally release it to obtain the target compound A0 (formula VI).

[0019] Similarly, this process also suffers from the drawback that chiral glycidol (glycidol) raw materials are not readily available, making industrial-scale production impossible.

[0020] CN 120058644 improved the above route by proceeding through three steps, represented by the following reaction equations:

[0021]

[0022] In the first step, levorotatory epichlorohydrin and bis(tert-butyloxycarbonyl)amine salt undergo a substitution reaction in an organic solvent to generate intermediate 1; in the second step, intermediate 1 and trimethyl sulfoxide undergo a ring-expansion reaction in an organic solvent under the action of a base to generate intermediate 2; in the third step, intermediate 2 is deprotected in an organic solvent under the action of an acid to generate the product.

[0023] The disadvantages of this route are: potassium bis(tert-butyloxycarbonyl)amine is difficult to obtain, and since it is an amide salt, it has low reactivity and the reaction is difficult. During the acidic deprotection reaction of intermediate 2, the oxa-four-membered ring is prone to ring-opening, making product purification difficult and quality hard to guarantee.

[0024] All of the above routes use trimethyl sulfoxide for ring expansion reactions. In all of them, trace amounts of sulfur remain after the reaction, which poisons the palladium on carbon catalyst. This makes it difficult to carry out subsequent hydrogenation reactions, and column chromatography is required to remove the residual sulfur. This results in low production efficiency and seriously restricts large-scale production.

[0025] Patent CN117903088A reports a new route that avoids the use of trimethyl sulfoxide for ring expansion reactions, as follows:

[0026]

[0027] Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate (compound VI) reacts with sodium azide to form ethyl (R)-(+)-4-azido-3-hydroxybutyrate (compound VII), which is then reduced with sodium borohydride to give (R)-(+)-4-azido-1,3-dibutanol (compound II). Further reaction with p-toluenesulfonyl chloride yields (R)-(+)-1-azido-4-p-toluenesulfonyloxy-2-butanol (compound III). Substitution with potassium iodide or sodium iodide gives (R)-(+)-1-azido-4-iodo-2-butanol (compound IV), which undergoes cyclization with a base to form (S)-2-azidomethyloxetane (compound V). Finally, hydrogenation yields the target product (S)-oxetane-2-methylamine A0 (compound I).

[0028] Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate can be easily synthesized from ethyl chloroacetoacetate via enzymatic hydrolysis. Therefore, the raw materials are cheap and readily available, and the process avoids the ring-expansion reaction using trimethyl sulfoxide, thus effectively solving the problem of palladium-carbon catalyst poisoning caused by residual sulfur.

[0029] However, this process still uses sodium azide, which is highly explosive and toxic, posing safety hazards in production. Furthermore, potassium iodide and sodium iodide are very expensive, resulting in high production costs and weak competitiveness. Therefore, this severely restricts the industrial-scale production of this process.

[0030] Therefore, in order to address the shortcomings of the above synthetic routes, there is an urgent need for a safe and low-cost method for preparing (S)-oxetane-2-methylamine. Summary of the Invention

[0031] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing (S)-oxetane-2-methylamine. The preparation method provided by the present invention avoids the ring-expansion reaction using trimethyl sulfoxide in existing processes, solves the problem of palladium-on-carbon catalyst poisoning caused by residual sulfur, and also avoids the use of easily explosive and highly toxic sodium azide. The process is safe and reliable, with inexpensive raw materials, high product quality, high chiral purity, and high yield, making it suitable for industrial-scale production.

[0032] To achieve this objective, the present invention adopts the following technical solution:

[0033] This invention provides a method for preparing (S)-oxetane-2-methylamine, the method comprising the following steps:

[0034]

[0035] (1) (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester (compound A) was cyclized under alkaline conditions to give (R)-(+)-3,4-epoxybutyrate ethyl ester;

[0036] (2) (R)-(+)-3,4-epoxybutyrate ethyl ester (compound B) was reacted with dibenzylamine to obtain (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester;

[0037] (3) (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester (compound C) was reacted with a reducing agent to obtain (R)-(+)-4-dibenzylamino-1,3-dibutanol;

[0038] (4) Reaction of (R)-(+)-4-dibenzylamino-1,3-dibutanol (compound D) with p-toluenesulfonyl chloride yields (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol;

[0039] (5) Reaction of (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol (compound E) with a base yields (S)-oxetane-2-dibenzylaminomethyl;

[0040] (6) Reaction of (S)-oxetane-2-dibenzylamine methyl (compound F) with palladium on carbon yields (S)-oxetane-2-methylamine (compound A0).

[0041] The above preparation method avoids the ring expansion reaction of trimethyl sulfoxide used in existing processes by adopting a specific preparation route, solves the problem of palladium on carbon catalyst poisoning caused by residual sulfur, and also avoids the use of easily explosive and highly toxic sodium azide. The process is safe and reliable, and the raw materials are inexpensive, the product quality is good, the chiral purity is high, and it is suitable for industrial-scale production.

[0042] Preferably, the alkali used in the alkaline conditions described in step (1) includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium carbonate.

[0043] Preferably, the molar ratio of (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester to the base is (0.8-1.5):1, for example, 0.8:1, 0.9:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0044] Preferably, the temperature of the ring-closing reaction in step (1) is 0-50℃, such as 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃ or 50℃, but not limited to the values ​​listed above. Other values ​​not listed in the above range are also applicable, preferably 10-25℃.

[0045] Preferably, the molar ratio of (R)-(+)-3,4-epoxybutyrate ethyl ester to dibenzylamine in step (2) is 1:(1-2), such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 1:(1-1.2).

[0046] Preferably, the reaction temperature in step (2) is 0-70℃, such as 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃ or 70℃, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 40-55℃.

[0047] Preferably, the reducing agent in step (3) includes sodium borohydride and / or potassium borohydride;

[0048] Preferably, the molar ratio of (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester to reducing agent in step (3) is 1:(0.3-2), such as 1:0.3, 1:0.6, 1:0.9, 1:1.2, 1:1.5, 1:1.8 or 1:2, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 1:(0.6-1.5).

[0049] Preferably, the reaction temperature in step (3) is 0-75℃, such as 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃ or 75℃, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, with 30-45℃ being the preferred temperature.

[0050] Preferably, the molar ratio of (R)-(+)-4-dibenzylamino-1,3-dibutanol to p-toluenesulfonyl chloride in step (4) is 1:(1-2), such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 1:(1-1.5).

[0051] Preferably, the reaction in step (4) is carried out under alkaline conditions, wherein the base used in the alkaline conditions includes any one or a combination of at least two of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or pyridine.

[0052] Preferably, the reaction temperature in step (4) is -10 to 15°C, such as -10°C, -5°C, 0°C, 5°C, 10°C or 15°C, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0053] Preferably, the alkali in step (5) includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or sodium hydride.

[0054] Preferably, the molar ratio of (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol to the base in step (5) is 1:(1-5), such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 1:(1.5-3).

[0055] Preferably, the reaction temperature in step (5) is 0-100℃, such as 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ or 100℃, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 50-90℃.

[0056] Preferably, the solvent for the reaction in step (6) includes any one or a combination of at least two of methanol, ethanol, isopropanol or ethyl acetate;

[0057] Preferably, the pressure of the reaction in step (6) is 0.1-3 MPa, such as 0.1 MPa, 0.5 MPa, 1 MPa, 1.5 MPa, 2 MPa, 2.5 MPa or 3 MPa, but not limited to the values ​​listed above. Other values ​​not listed in the above range are also applicable, preferably 0.5-1.5 MPa.

[0058] Preferably, the temperature of the reaction in step (6) is 0-100℃, such as 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ or 100℃, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable, preferably 30-80℃.

[0059] Compared with the prior art, the present invention has the following beneficial effects:

[0060] This invention provides a method for preparing (S)-oxetane-2-methylamine. By adopting a specific preparation route, it avoids the ring expansion reaction of trimethyl sulfoxide used in existing processes, effectively solves the problem of palladium-on-carbon catalyst poisoning caused by residual sulfur, and also avoids the use of easily explosive and highly toxic sodium azide. The process is safe and reliable, and the raw materials are inexpensive, the product quality is good, the chiral purity is high, and it is suitable for industrial-scale production. Attached Figure Description

[0061] Figure 1 This is the 1H NMR spectrum of (S)-oxetane-2-methylamine obtained in Example 1. Detailed Implementation

[0062] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0063] Example 1

[0064] This embodiment provides a method for preparing (S)-oxetane-2-methylamine, the specific steps of which are as follows:

[0065]

[0066] Step 1: Prepare compound B. Add 400g of dichloromethane and 166.6g of (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester (compound A, 1.0 mol) to a 1000mL reaction flask, stir, and cool to 5-10°C. Add 40g of sodium hydroxide (1.0 mol) in four batches, 10g each time. Control the amount and rate of addition to ensure the reaction solution temperature does not exceed 15°C. After addition, maintain the reaction at 10-15°C for 1 hour. Sample and monitor the conversion of raw material A until it is completely reacted. Filter to remove the generated inorganic salts. Do not purify the reaction solution; directly add it to the next reaction step.

[0067] The second step involves preparing compound C. The reaction solution from the previous step was heated to 35-40°C, and 217 g (1.1 mol) of dibenzylamine was added dropwise. The addition was completed in approximately one hour. The reaction was maintained at this temperature for 2 hours, and a sample was taken to confirm complete conversion of raw material B to C. The reaction was stopped, and the solvent dichloromethane was recovered by atmospheric distillation. Excess dibenzylamine was removed by vacuum distillation, yielding 290.3 g of a pale yellow oil. The combined yields of the two steps were 88.7%.

[0068] Step 3: Preparation of compound D. 290.3 g (0.89 mol) of compound C from the previous step was added to 2000 mL of methanol and stirred until dissolved. The mixture was cooled to -5 to 0 °C, and 45.4 g (1.2 mol) of sodium borohydride and 11 g (0.1 mol) of calcium chloride were added in portions. The mixture was then slowly heated to 35-45 °C. The reaction was maintained at this temperature for 2 hours. HPLC analysis showed that the reactant C had reacted completely. The mixture was cooled to room temperature, and 1000 mL of water was added. Methanol was recovered by vacuum distillation. The mixture was extracted three times with 500 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the dichloromethane solvent was recovered by atmospheric distillation to dryness. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give 236.6 g (0.83 mol, yield 93.6%) of a white solid powder.

[0069] Step 4: Preparation of Compound E. 236.6 g (0.83 mol) of compound D was dissolved in 1000 mL of dichloromethane. 151.5 g (1.5 mol) of triethylamine was added, and the mixture was cooled to between -5 and 0°C. A mixture of 171.5 g (0.9 mol) of p-toluenesulfonyl chloride and 300 mL of dichloromethane was added dropwise. The addition was completed over approximately 2.5 hours. The temperature was maintained between 0 and 5°C, and the mixture was stirred for 1 hour. The freezer was then turned off, and the mixture was allowed to warm naturally to room temperature. After stirring for 2 hours, a sample was taken for HPLC analysis, and no starting material D remained. The mixture was washed with 800 g of 0.5N dilute hydrochloric acid aqueous solution, and the aqueous phase was discarded. The organic phase was washed with 1000 g of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 342.5 g (0.78 mol) of compound E as a pale yellow oil, with a yield of 94%.

[0070] Step 5: Preparation of compound F. 1000 g of methanol and 342.5 g of compound E (0.78 mol) were added to a reaction flask and stirred to dissolve. 360 g (2.0 mol) of 30% sodium methoxide solution was added, and the mixture was heated to 75–80 °C and refluxed for 8 hours. HPLC analysis showed no residue of starting material E. The methanol solvent was distilled off under reduced pressure to dryness, cooled to room temperature, and 500 g of water was added. The pH was adjusted to 7–8 with 1N dilute hydrochloric acid. 500 mL of dichloromethane was added, and the mixture was stirred for 5 minutes. After separation, the aqueous phase was separated again by adding another 500 mL of dichloromethane and stirring for 5 minutes. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 178.2 g (0.67 mol) of compound F as a pale yellow oil, with a yield of 85.6%.

[0071] Step 6: Preparation of compound A0. 1000 g of methanol, 178.2 g of compound F (0.67 mol), and 15 g of 10% palladium on carbon catalyst were sequentially added to a high-pressure hydrogenation reactor. Hydrogen gas was introduced, and the mixture was heated to 65-75°C and pressurized to 1.2 MPa. The reaction was maintained at this temperature and pressure for 20 hours. HPLC analysis was performed until the starting material F completely disappeared. The catalyst was removed by filtration, and methanol was removed by atmospheric distillation to dryness. The product was then distilled under reduced pressure to obtain 54.7 g (0.63 mol) of a colorless oily liquid, with a yield of 94%.

[0072] The overall yield of the six steps was 63% (calculated based on the starting material (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester).

[0073] Characterization data are as follows (see NMR images) Figure 1 ):

[0074] 1 H-NMR (CDCl3; 400MHz): δ4.76-4.82(m,1H),4.64-4.69(m,1H),4.47-4.52(m ,1H),4.87-4.89(m,2H),2.58-2.66(m,1H),2.39-2.47(m,1H),1.67(r,2H).

[0075] Example 2

[0076] This embodiment provides a method for preparing (S)-oxetane-2-methylamine, the specific steps of which are as follows:

[0077]

[0078] Step 1: Prepare compound B. Add 400g of dichloroethane and 1.0 mol of (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester (compound A) to a 1000mL reaction flask. Stir and cool to 5-10°C. Add 62g of potassium hydroxide (1.1 mol) in four batches, 15.5g each time. Control the amount and rate of addition to ensure the reaction solution temperature does not exceed 15°C. After addition, maintain the reaction at 15-20°C for 1 hour. Sample and monitor the conversion of raw material A until it is completely reacted. Filter to remove the generated inorganic salts. Do not purify the reaction solution; directly add it to the next reaction step.

[0079] The second step is the preparation of compound C. The reaction solution from the previous step was stirred at room temperature, and 197.5 g (1.0 mol) of dibenzylamine was added dropwise over approximately one hour. The mixture was then heated to 45-50°C and maintained at this temperature for 2 hours. A sample was taken to confirm complete conversion of raw material B to C. The reaction was stopped, and the solvent dichloromethane was recovered by atmospheric distillation. Excess dibenzylamine was removed by vacuum distillation, yielding 273.6 g of a pale yellow oil. The combined yields of the two steps were 84%.

[0080] Step 3: Preparation of compound D. 273.6 g (0.84 mol) of compound C from the previous step was added to 2000 mL of methanol and stirred until dissolved. The mixture was cooled to -5 to 0 °C, and 1.0 mol of potassium borohydride and 4.3 g (0.1 mol) of lithium chloride were added in portions. The mixture was then slowly heated to 40-45 °C. The reaction was maintained at this temperature for 2 hours. HPLC analysis showed that the reactant C had reacted completely. The mixture was cooled to room temperature, and 800 mL of water was added. Methanol was recovered by vacuum distillation. The remaining aqueous solution was extracted three times with 400 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the dichloromethane solvent was recovered by atmospheric distillation to dryness. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give 239.8 g (0.76 mol, 91%) of a white solid powder.

[0081] Step 4: Preparation of Compound E. 239.8 g (0.76 mol) of compound D was dissolved in 1000 mL of dichloromethane. 129 g (1.0 mol) of diisopropylethylamine was added, and the mixture was cooled to between -5 and 0 °C. A mixture of 1.0 mol of p-toluenesulfonyl chloride and 300 mL of dichloromethane was added dropwise. The addition was completed over approximately 2.5 hours. The temperature was maintained between 0 and 5 °C, and the mixture was stirred for 1 hour. The freezer was then turned off, and the mixture was allowed to warm naturally to room temperature. After stirring for 2 hours, a sample was taken for HPLC analysis, and no starting material D remained. The mixture was washed with 800 g of 0.5 N dilute hydrochloric acid aqueous solution, and the aqueous phase was discarded. The organic phase was washed with 1000 g of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 293.8 g (0.67 mol) of compound E as a pale yellow oil, with a yield of 88.2%.

[0082] Step 5: Preparation of compound F. 1000 g of methanol and 293.8 g of compound E (0.67 mol) were added to a reaction flask and stirred to dissolve. 173 g of sodium tert-butoxide (1.8 mol) was added, and the reaction was maintained at 70-75°C for 12 hours. HPLC analysis showed no residual starting material E. The mixture was filtered, and the methanol solvent was distilled under reduced pressure to dryness. After returning to room temperature, 800 g of water was added, and the pH was adjusted to 7-8 with 1N dilute hydrochloric acid. 500 mL of dichloromethane was added, and the mixture was stirred for 5 minutes. After separation, another 500 mL of dichloromethane was added to the aqueous phase, and the mixture was stirred for 5 minutes. After separation, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 162.2 g (0.61 mol) of compound F as a pale yellow oil, with a yield of 91%.

[0083] Step 6: Preparation of compound A0. 1000 g of methanol, 162.6 g of compound F (0.61 mol), and 12 g of 10% palladium on carbon catalyst were sequentially added to a high-pressure hydrogenation reactor. Hydrogen gas was introduced, and the mixture was heated to 70-80°C and pressurized to 0.15 MPa. The reaction was maintained at this temperature and pressure for 20 hours. HPLC analysis was performed until the starting material F completely disappeared. The catalyst was removed by filtration, and methanol was removed by atmospheric distillation to dryness. The product was then distilled under reduced pressure to obtain 49.6 g (0.57 mol) of a colorless oily liquid, with a yield of 93%.

[0084] The overall yield of the six steps was 57% (calculated based on the starting material (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester).

[0085] Example 3

[0086] This embodiment provides a method for preparing (S)-oxetane-2-methylamine, the specific steps of which are as follows:

[0087]

[0088] Step 1: Prepare compound B. Add 400g of dichloromethane and 1.0 mol of (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester (compound A) to a 1000mL reaction flask. Stir and cool to 5-10°C. Add 48g of sodium hydroxide (1.2 mol) in four batches, 12g each time. Control the amount and rate of addition to ensure the reaction solution temperature does not exceed 15°C. After addition, maintain the reaction at 15-20°C for 1 hour. Sample and test the conversion of raw material A until it is completely reacted. Filter to remove the generated inorganic salts. Do not purify the reaction solution; directly add it to the next reaction step.

[0089] The second step involves preparing compound C. The reaction solution from the previous step was cooled to 0-5°C, and 236 g (1.2 mol) of dibenzylamine was added dropwise. The addition was completed in approximately one hour. The mixture was then slowly heated to 40-45°C and maintained at this temperature for another 2 hours. A sample was taken to confirm complete conversion of raw material B to C. The reaction was then stopped, and the solvent dichloromethane was recovered by atmospheric distillation. Excess dibenzylamine was removed by vacuum distillation, yielding 285.7 g of a pale yellow oil. The combined yield of the two steps was 87.3%.

[0090] Step 3: Preparation of compound D. 285.7 g (0.87 mol) of compound C from the previous step was added to 2000 mL of methanol and stirred until dissolved. The mixture was cooled to -5 to 0 °C, and 1.2 mol of sodium borohydride and 3.5 g (0.08 mol) of lithium chloride were added in portions. The mixture was then slowly heated to 35-40 °C. The reaction was maintained at this temperature for 2 hours, and HPLC analysis showed that the reactant C had reacted completely. The mixture was cooled to room temperature, and 800 mL of water was added. Methanol was recovered by vacuum distillation. The mixture was extracted three times with 400 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the dichloromethane solvent was recovered by atmospheric distillation to dryness. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give 233.7 g (0.82 mol, yield 94.1%) of a white solid powder.

[0091] Step 4: Preparation of Compound E. 233.7 g (0.82 mol) of compound D was dissolved in 1000 mL of dichloromethane. 101 g (1.0 mol) of triethylamine and 12.5 g (0.1 mol) of 4-dimethylaminopyridine were added. The mixture was cooled to -5 to 0 °C, and a mixture of 1.0 mol of p-toluenesulfonyl chloride and 300 mL of dichloromethane was added dropwise. The addition was completed over approximately 2.5 hours. The temperature was maintained between 0 and 5 °C, and the mixture was stirred for 1 hour. The freezer was then turned off, and the mixture was allowed to warm naturally to room temperature. After stirring for 2 hours, a sample was taken for HPLC analysis, and no starting material D remained. The mixture was washed with 1000 g of 0.5 N dilute hydrochloric acid aqueous solution, and the aqueous phase was discarded. The organic phase was washed with 1000 g of water. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 316.7 g (0.72 mol) of compound E as a pale yellow oil, with a yield of 88%.

[0092] Step 5: Preparation of compound F. 1000 g of tert-butanol and 316.7 g of compound E (0.72 mol) were added to a reaction flask and stirred to dissolve. 246 g of potassium tert-butoxide (2.2 mol) was added, and the mixture was refluxed at 85-90°C for 6 hours. HPLC analysis showed no residual starting material E. The mixture was filtered, and the filtrate was distilled off under reduced pressure to dryness. After cooling to room temperature, 800 g of water was added, and the pH was adjusted to 7-8 with 1N dilute hydrochloric acid. 500 mL of dichloromethane was added, and the mixture was stirred for 5 minutes. After separation, another 500 mL of dichloromethane was added to the aqueous phase, and the mixture was stirred for 5 minutes. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 173.2 g (0.65 mol) of compound F as a pale yellow oil, with a yield of 90%.

[0093] Step 6: Preparation of compound A0. 1000 g of methanol, 173.2 g of compound F (0.65 mol), and 15 g of 10% palladium on carbon catalyst were sequentially added to a high-pressure hydrogenation reactor. Hydrogen gas was introduced, and the temperature was controlled between 50-60°C. The pressure was increased to 1.2 MPa, and the reaction was maintained at this temperature and pressure for 20 hours. HPLC analysis was performed until the starting material F was completely eliminated. The catalyst was removed by filtration, and methanol was removed by atmospheric distillation to dryness. The product was then distilled under reduced pressure to obtain 52.3 g (0.6 mol) of a colorless oily liquid, with a yield of 92%.

[0094] The overall yield of the six steps was 60% (calculated based on the starting material (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester).

[0095] Example 4

[0096] This embodiment provides a method for preparing (S)-oxetane-2-methylamine. The specific steps are the same as in Example 1, except that in the first step, the molar ratio of (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester to alkali:sodium hydroxide is 1:1.5.

[0097] The second step yielded 236.7 g (0.73 mol) of compound C as a pale yellow oil, with a combined yield of 73%.

[0098] Example 5

[0099] This embodiment provides a method for preparing (S)-oxetane-2-methylamine. Except for the fifth step, where the reaction temperature is between 95-100°C, the specific steps are the same as in Example 1.

[0100] In the fifth step, compound F was obtained as a pale yellow oil, weighing 148.5 g (0.56 mol), with a yield of 71.3%.

[0101] Example 6

[0102] This embodiment provides a method for preparing (S)-oxetane-2-methylamine. Except for the fifth step, where the reaction temperature is between 15-20°C, the specific steps are the same as in Example 1.

[0103] In the fifth step, compound F was obtained as a pale yellow oil, weighing 109 g (0.41 mol), with a yield of 52%.

[0104] Example 7

[0105] This embodiment provides a method for preparing (S)-oxetane-2-methylamine. Except for the addition of 153 g (0.85 mol) of 30% sodium methoxide solution in step 5, the specific steps are the same as in Example 1.

[0106] In the fifth step, compound F was obtained as a pale yellow oil, weighing 127.7 g (0.48 mol), with a yield of 61.6%.

[0107] As can be seen from the above, the method provided by the present invention avoids the ring expansion reaction of trimethyl sulfoxide in the existing process, effectively solves the problem of palladium carbon catalyst poisoning caused by residual sulfur, and also avoids the use of easily explosive and highly toxic sodium azide. The process is safe and reliable, and the raw materials are inexpensive, the product quality is good, and the chiral purity is high. Comparing Examples 1-7, it can be seen that the present invention can further improve the product yield by controlling relevant parameters.

[0108] The applicant declares that the present invention illustrates the preparation method of (S)-oxetane-2-methylamine through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0109] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0110] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing (S)-oxetane-2-methylamine, characterized in that, The preparation method of the (S)-oxetane-2-methylamine includes the following steps: (1) (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester was cyclized under alkaline conditions to obtain (R)-(+)-3,4-epoxybutyrate ethyl ester; (2) (R)-(+)-3,4-epoxybutyrate ethyl ester was reacted with dibenzylamine to obtain (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester; (3) (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester was reacted with a reducing agent to obtain (R)-(+)-4-dibenzylamino-1,3-dibutanol; (4) Reaction of (R)-(+)-4-dibenzylamino-1,3-dibutanol with p-toluenesulfonyl chloride yields (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol; (5) Reaction of (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol with a base yields (S)-oxetane-2-dibenzylaminomethyl; (6) Reaction of (S)-oxetane-2-dibenzylamine methyl with palladium on carbon yields the (S)-oxetane-2-methylamine.

2. The method for preparing (S)-oxetane-2-methylamine according to claim 1, characterized in that, The alkali used in the alkaline conditions described in step (1) includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, potassium carbonate, or sodium carbonate. Preferably, the molar ratio of (R)-(+)-4-chloro-3-hydroxybutyrate ethyl ester to the base is (0.8-1.5):

1.

3. The method for preparing (S)-oxetane-2-methylamine according to claim 1 or 2, characterized in that, The temperature of the ring-closing reaction in step (1) is 0-50℃, preferably 10-25℃.

4. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-3, characterized in that, The molar ratio of (R)-(+)-3,4-epoxybutyrate ethyl ester to dibenzylamine in step (2) is 1:(1-2), preferably 1:(1-1.2).

5. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-4, characterized in that, The reaction temperature in step (2) is 0-70℃, preferably 40-55℃.

6. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-5, characterized in that, The reducing agent in step (3) includes sodium borohydride and / or potassium borohydride; Preferably, the molar ratio of (R)-(+)-4-dibenzylamino-3-hydroxybutyrate ethyl ester to the reducing agent in step (3) is 1:(0.3-2), more preferably 1:(0.6-1.5); Preferably, the temperature of the reaction in step (3) is 0-75°C, more preferably 30-45°C.

7. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-6, characterized in that, The molar ratio of (R)-(+)-4-dibenzylamino-1,3-dibutanol to p-toluenesulfonyl chloride in step (4) is 1:(1-2), preferably 1:(1-1.5); Preferably, the reaction in step (4) is carried out under alkaline conditions, wherein the base used for the alkaline conditions includes any one or a combination of at least two of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or pyridine; Preferably, the temperature of the reaction in step (4) is -10 to 15°C.

8. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-7, characterized in that, The alkali mentioned in step (5) includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or sodium hydride.

9. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-8, characterized in that, In step (5), the molar ratio of (R)-(+)-1-dibenzylamino-4-p-toluenesulfonyloxy-2-butanol to the base is 1:(1-5), preferably 1:(1.5-3; Preferably, the temperature of the reaction in step (5) is 0-100℃, more preferably 50-90℃.

10. The method for preparing (S)-oxetane-2-methylamine according to any one of claims 1-9, characterized in that, The solvent for the reaction in step (6) includes any one or a combination of at least two of methanol, ethanol, isopropanol or ethyl acetate; Preferably, the pressure of the reaction in step (6) is 0.1-3 MPa, more preferably 0.5-1.5 MPa; Preferably, the temperature of the reaction in step (6) is 0-100℃, more preferably 30-80℃.

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