Synthesis method of (S)-oxetane-2-methylamine and intermediate of (S)-oxetane-2-methylamine

Abstract

The invention belongs to the technical field of medicine preparation, and particularly discloses a synthesis method of (S)-oxetane-2-methylamine and an intermediate of (S)-oxetane-2-methylamine, the synthesis method comprises the following steps: step S1, after a compound D and (R)-(-)-epichlorohydrin are subjected to a substitution ring-opening reaction, a ring-closing reaction is carried out in the presence of a first alkaline reagent, and a compound F is obtained; s2, the compound F reacts with trimethyl sulfoxide halide in the presence of a second alkaline reagent, and a compound G is obtained; s3, the compound G is subjected to a hydrogenation debenzylation reaction, and (S)-oxetane-2-methylamine, namely a compound A0, is obtained; wherein R1 is alkyl. The compound A0 prepared by the method provided by the invention is high in yield, high in chiral purity and simple and convenient to operate. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and particularly relates to a synthesis method of (S)-oxetan-2-ylmethanamine and an intermediate thereof. Background Art

[0002] (S)-Oxirane-2-ylmethanamine is a key intermediate for certain glucagon-like peptide-1 receptor agonists.

[0003] Currently, the synthesis methods of (S)-oxirane-2-ylmethanamine mainly include the following routes:

[0004] Patent application WO2018109607A1 discloses the following Route 1:

[0005]

[0006] Route 1 starts with chiral benzyl glycidol A1 as the starting material, expands the ring with trimethylsulfoxonium iodide under alkaline conditions to obtain chiral benzyl oxetane A2; further debenzylates to obtain chiral oxetane methanol A3; then reacts with methanesulfonyl chloride to form a methanesulfonate A4, and then replaces it with sodium azide to form chiral butane azide A5, and finally hydrogenates and reduces to obtain the target compound A0.

[0007] Patent application CN115991685A discloses the following Route 2:

[0008]

[0009] Route 2 starts with chiral glycidol B1 as the starting material, prepares compound B2 through vinyl ethyl ether protection, expands the ring with trimethylsulfoxonium iodide under alkaline conditions to prepare compound B3, removes the protection to prepare compound B4, reacts compound B4 with p-toluenesulfonyl chloride to form p-toluenesulfonate B5, then replaces it with potassium phthalimide to form a mixture B6, and finally removes the protection to obtain the target compound A0.

[0010] The biggest change in Route 2 compared to Route 1 is that the benzyl protecting group is replaced with a vinyl ethyl ether protecting group; in addition, the explosive sodium azide is replaced with potassium phthalimide. Since both Route 2 and Route 1 have a relatively large number of reaction steps, and the last step of Route 2 uses explosive hydrazine hydrate for deprotection, there are certain safety hazards; at the same time, since the deprotection in the last step of Route 2 introduces amino compounds such as hydrazine hydrate, it will also bring more additional purification steps to the low-boiling target product, which is not conducive to large-scale production.

[0011] Patent application CN114728923B discloses the following Route 3:

[0012]

[0013] Route three uses dibenzylamine as a raw material, undergoes a ring-opening reaction with chiral epichlorohydrin to obtain C2, and then undergoes a ring-closing reaction under alkaline conditions to obtain dibenzylamine chiral epoxypropane C3; similarly, compound C3 undergoes a ring-expansion reaction with trimethylsulfoxonium iodide under alkaline conditions to obtain dibenzylamine chiral oxetane C4, and finally undergoes hydrogenation and debenzylation to obtain the target compound A0.

[0014] Obviously, compared with the first two routes, route three has the advantages of a shorter route and cheaper raw materials. However, due to the introduction of highly reactive dibenzylamine, there is a ~2% chiral configuration inversion during the conversion of intermediate C3 to intermediate C4 during the ring-expansion reaction. In addition, since the intermediates C3 and C4 in each step are liquids, it is difficult to carry out crystallization purification. Therefore, the biggest drawback of route three is that it is difficult to obtain a target compound with an optical purity higher than 99%. The specific configuration inversion mechanism is as follows:

[0015]

[0016] Configuration inversion mechanism of compound C3

[0017] Therefore, there is still a large room for improvement in the existing technical routes for synthesizing chiral oxetane methane. It is necessary to provide a new synthetic method for (S)-oxetane-2-methylamine and its intermediates to solve the deficiencies of the existing technology. Summary of the Invention

[0018] Aiming at the deficiencies of the existing technology, based on patent CN114728923B, the present invention further solves the problem of chiral inversion, provides a new synthetic method for (S)-oxetane-2-methylamine, and obtains a target compound with an optical purity higher than 99%.

[0019] To achieve the above object, the technical solutions adopted by the present invention are specifically described as follows:

[0020] On the one hand, the present invention provides a synthetic method for (S)-oxetane-2-methylamine, which method comprises the following steps:

[0021]

[0022] Step S1: Compound D undergoes a substitution ring-opening reaction with (R)-(-)-epichlorohydrin, and then undergoes a ring-closing reaction in the presence of a first basic reagent to obtain compound F;

[0023] Step S2: Compound F reacts with trimethylsulfoxonium halide in the presence of a second basic reagent to obtain compound G;

[0024] Step S3: Compound G undergoes a hydrogenation debenzylation reaction to obtain (S)-oxetan-2-ylmethanamine, which is Compound A0;

[0025] wherein, R 1 is selected from alkyl,

[0026] Further, the alkyl is selected from methyl and ethyl.

[0027] Further, in Step S1, the solvents used in the ring-opening reaction and the ring-closing reaction are selected from at least one of methanol, ethanol, isopropanol, and water;

[0028] Further, in Step S1, the molar ratio of Compound D to (R)-(-)-epichlorohydrin is 1:1 to 2, preferably 1:1, 1:1.5, or 1:2.

[0029] Further, in Step S1, the ring-opening reaction is carried out at 25°C to 35°C, preferably 25, 30, or 35°C.

[0030] Further, in Step S1, the reaction time of the ring-opening reaction is 40 to 55 hours, preferably 40, 45, 48, 50, or 55 hours.

[0031] Further, the first basic reagent is selected from at least one of sodium hydroxide, potassium hydroxide, cesium carbonate, or potassium carbonate.

[0032] Further, the molar ratio of Compound D to the first basic reagent is 1:1 to 2, preferably 1:1, 1:1.5, 1:1.8, or 1:2.

[0033] Further, the first basic reagent is added dropwise. After the addition is complete, the temperature is controlled at 20 to 30°C and the reaction is carried out for 1 to 5 hours, preferably at 20, 25, or 30°C.

[0034] Further, after the ring-closing reaction in Step S1 is completed, an ether reagent is used for extraction and separation to obtain the Compound F of formula F. Preferably, the ether reagent is methyl tert-butyl ether.

[0036] Further, in Step S2, the second basic reagent is selected from at least one of potassium tert-butoxide and sodium tert-butoxide.

[0037] Further, the molar ratio of Compound F, trimethylsulfoxonium halide, and the second basic reagent is 1:1 to 2:1.5 to 2.5, preferably 1:1:1.5, 1:1.5:2, 1:1.8:2, or 1:2:2.5.

[0038] Further, the trimethylsulfoxonium halide is selected from at least one of trimethylsulfoxonium bromide and trimethylsulfoxonium iodide.

[0039] Further, the solvent used in the reaction in step S2 is selected from at least one of dioxane, dimethyl sulfoxide, ethanol, isopropanol, and tert-butanol.

[0040] Further, in step S2, under the protection of an inert gas, the solution containing compound F is added dropwise to the trimethylsulfoxonium halide solution containing the second basic reagent.

[0041] Further, the reaction in step S2 is carried out under the protection of an inert gas at 80 - 85°C for 5 - 6 hours, preferably at 80, 81, 82, 83, 84 or 85°C, and preferably for 5, 5.5 or 6 hours.

[0042] Further, in step S2, the inert gas includes at least one of argon and nitrogen.

[0043] Further, in step S2, the solution containing compound F is prepared by dissolving compound F in the solvent used in the reaction in step S2.

[0044] Further, in step S2, after the reaction, water is added for quenching, the solvent is removed, and the organic phase obtained by extraction with methyl tert-butyl ether is post-treated to obtain compound G.

[0045] Further, in step S2, the post-treatment process is as follows: the organic phase obtained by extraction with methyl tert-butyl ether is washed, dried, and concentrated, and then the residue is added to an alcohol solvent. The temperature is raised to 60 - 70°C to make the solution clear, and then cooled to 0 - 5°C for crystallization. After crystallization is completed, it is filtered and dried to obtain compound G. Preferably, the temperature is raised to 60, 65 or 70°C; preferably, it is cooled to 0, 1, 2, 3, 4 or 5°C.

[0046] Further, in step S2, the alcohol solvent is selected from at least one of methanol, ethanol, n-propanol, and isopropanol.

[0047] Further, step S3 includes: mixing compound G, acetic acid, and palladium-carbon, and then heating and reacting under a hydrogen atmosphere to obtain compound A0.

[0048] Further, the specific reaction process in step S3 is as follows:

[0049] Mix compound G, acetic acid, and palladium-carbon, and react at 45 - 55°C for 8 - 24 hours under a hydrogen pressure of 0.5 - 1.2 MPa; preferably, the hydrogen pressure is 0.5, 0.8, 1 or 1.2 MPa; preferably, the reaction temperature is 45, 50 or 55°C; preferably, the reaction time is 10 hours;

[0050] Further, in the reaction of step S3, the molar ratio of compound G to acetic acid is 1:1 to 1.5, preferably 1:1, and the mass ratio of palladium-carbon to compound G is 1:5 to 10, preferably 1:5, 1:8 or 1:10.

[0051] Further, in the reaction of step S3, the mass ratio of palladium-carbon to compound G is 1:5 to 10, preferably 1:8 or 1:10.

[0052] On the one hand, the present invention provides a compound F, which is

[0053] On the one hand, the present invention provides a compound F, which is selected from or a mixture of both.

[0054] On the one hand, the present invention provides a compound G, which is

[0055] On the one hand, the present invention provides a compound G, which is selected from or a mixture of both.

[0056] On the other hand, the present invention provides a preparation method of p-toluenesulfonate of (S)-oxetan-2-ylmethanamine, comprising: reacting compound A0 prepared by the synthesis method of the present invention with p-toluenesulfonic acid or its hydrate in a solvent to obtain p-toluenesulfonate of (S)-oxetan-2-ylmethanamine.

[0057] Further, the solvent is selected from at least one of water, tetrahydrofuran, and alcohol solvents; preferably, the alcohol solvent is selected from methanol or ethanol.

[0058] Further, the reaction temperature of the reaction is 10°C - 60°C, preferably 10, 20, 30, 40, 50, 55 or 60°C; more preferably, the reaction is carried out at 50 - 60°C for 0.5 - 2 hours, preferably 0.5, 1, 1.5 or 2 hours, and then cooled to 10 - 20°C for 0.5 - 2 hours, preferably the reaction time is 0.5, 1, 1.5 or 2 hours, and preferably cooled to 10, 15 or 20°C.

[0059] Further, a post-treatment step is also included after the reaction ends.

[0060] Further, the post-treatment step includes: filtration, washing, and drying.

[0061] Further, the washing is carried out with tetrahydrofuran.

[0062] Beneficial effects

[0063] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0064] 1: The present invention provides a method for efficiently and safely synthesizing (S)-oxetan-2-ylmethanamine. This method adopts special substrate and intermediate structures, effectively improving the chiral purity of the product on the premise of ensuring a sufficiently high yield, solving the problem of configuration inversion in the prior art, and having important economic significance.

[0065] 2: The present invention uses N-benzyl-1-phenylethylamine with a larger steric hindrance, making it difficult to form an intramolecular quaternary ammonium salt of a four-membered ring under the conditions of ring expansion, thereby reducing and avoiding the possibility of configuration inversion.

[0066] 3: Compared with the prior art, the chiral purity of the present invention is greatly improved, as shown below: ① Comparing the yields of compound C4 in the prior art CN114728923B are 38% and 40% respectively, with ee 96%; the yield of compound G prepared in this application is 52% or 54%, and ee is 99.6%; ② Comparing the ee value of compound A0 in the prior art CN 114728923 B is not shown. The inventors of this application repeated the experiment and obtained ee of 94.4%; the ee of compound A0 prepared in this application is 99.6%.

[0067] 4: Compared with the prior art, the purification process of this application is simpler and more convenient, as shown below: Comparing compound C4 in the prior art CN114728923B is a liquid, which is purified by column chromatography with a chemical purity of 88%; compound G prepared in this application is a white solid, which can be purified by recrystallization with a chemical purity higher than 98%, facilitating large-scale industrial production.

[0068] 5: Compared with the prior art, the preparation process of this application is simpler and more convenient: in the process of preparing compound A0 from compound G, this application only needs to add palladium-carbon once to complete, with simple operation; while in the process of preparing compound A0 from compound C4 in the prior art CN 114728923 B, palladium-carbon needs to be added 5 times, and the resulting product after the reaction is an ethanol solution, without showing chiral purity, etc., which has certain limitations for subsequent reactions and is not conducive to large-scale industrial production.

[0069] Term Explanation

[0070] Unless otherwise specified, the following terms and phrases as used herein are intended to have the following meanings:

[0071] In the present invention, expressions such as "compound A0", "compound of formula A0" and "compound represented by formula A0" refer to the same compound.

[0072] The term "and / or" should be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.

[0073] The terms "optional", "optionally" or "optionally" mean that the subsequently described event or situation may but does not necessarily occur.

[0074] In the present invention, "room temperature" refers to the ambient temperature, which can be 20°C - 30°C; in some embodiments, it is 22°C - 28°C; in some embodiments, it is 24°C - 26°C; in some embodiments, it is 25°C.

[0075] The term "wt%" represents mass percentage.

[0076] The terms "w / w" both represent mass fraction. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 is the HNMR spectrum of compound F1 1 HNMR spectrum;

[0078] Figure 2 is the HNMR spectrum of compound G1 1 HNMR spectrum;

[0079] Figure 3 is the HNMR spectrum of compound A0 1 HNMR spectrum;

[0080] Figure 4 is the HNMR spectrum of compound A1 1 HNMR spectrum;

[0081] Figure 5 is the chiral spectrum of the racemate of compound A0;

[0082] Figure 6 is the chiral spectrum of compound A0;

[0083] Figure 7 is the chiral spectrum of the racemate of compound A1;

[0084] Figure 8 is the chiral spectrum of compound A1. DETAILED DESCRIPTION OF THE INVENTION

[0085] The technical solutions of the present invention will be illustrated by way of examples below. The scope claimed by the present invention includes but is not limited to the following embodiments.

[0086] Example 1: Repeat the method B of Patent CN114728923B to prepare compound C3

[0087]

[0088] Add dibenzylamine (152 g) and isopropanol (121 g) to a 2000 mL three-necked flask and stir the mixture at 10 - 20 °C. Dropwise add (R)-(-)-epichlorohydrin (105 g), and stir the mixture at 15 °C until the reaction reaches <1% remaining (R)-(-)-epichlorohydrin. Slowly add 20% w / w sodium hydroxide solution (183 g), and stir the mixture at 25 °C. Add another portion of 20% w / w sodium hydroxide solution (20 g) in water, and stir the mixture at 25 °C until <0.5% remaining intermediate. Separate the layers and concentrate the organic layer under reduced pressure to a remaining volume of approximately 200 mL. Add 688 g of ethyl acetate, concentrate the mixture again under reduced pressure to a remaining volume of approximately 200 mL, then add 683 g of ethyl acetate and 460 g of water. Stir, let stand, and separate the aqueous layer. Add 461 g of water to the organic layer, stir, let stand, and separate the aqueous layer. Add 451 g of water to the organic phase, stir, let stand, and separate the aqueous layer. Concentrate the organic layer under reduced pressure to a remaining volume of approximately 130 mL to obtain 191 g of the target compound, with a yield of 98% and an ee value of 99.8% and a chemical purity of 98.2%.

[0089] Example 2: Repeat the method A of patent CN114728923B to prepare compound C4

[0090]

[0091] Add trimethylsulfoxonium iodide (66.5 g) and potassium tert-butoxide (45.7 g) to a 2000 mL three-necked flask, 500 mL of tert-butanol. Heat to 85 °C under nitrogen protection and keep the temperature. Dropwise add the tert-butanol solution of compound C3 (50 g of compound C3 dissolved in 250 mL of tert-butanol) over 2 - 3 hours, and then keep the reaction for 5 hours. Cool to 30 - 35 °C, filter, and wash the filter cake with n-heptane. Concentrate the combined filtrate to obtain the crude product. Dissolve the crude product in 500 mL of n-heptane, wash with 200 mL of water, let stand for liquid separation, separate the aqueous layer, and extract with n-heptane once more. Wash the combined organic layer with saturated sodium chloride, dry over anhydrous sodium sulfate, and then perform column chromatography to obtain 22.6 g of compound C4, with a yield of 43%. A pale yellow oil, with a chemical purity of 88% and an ee value of 94.4%.

[0092] Example 3: Repeat the method B of patent CN114728923B to prepare compound A0 hydrochloride

[0093]

[0094] In a 1000 mL hydrogenation kettle, add compound C4 (46 g), ethanol (460 mL), add 31 mL of 5M hydrochloric acid aqueous solution, and add 5% palladium on carbon (22.5 g, 60% water content). Evacuate, fill with nitrogen, repeat three times, then evacuate, fill with hydrogen, repeat three times, then pressurize to 40 psig and heat to 40 °C for reaction for 20 hours. After the reaction is completed, filter the palladium on carbon, concentrate and evaporate the solvent, cool to room temperature, slurry with ethyl acetate, filter, and dry to obtain 17.2 g of compound A0 hydrochloride, with a yield of 82%. ee value: 94.4%.

[0095] Example 4: Preparation of Compound F1

[0096]

[0097] Add compound D1 (100 g, 1.0 eq.), (R)-(-)-epichlorohydrin (65.67 g, 1.5 eq.) and 100 mL of isopropanol to a 1000 mL three-necked flask, control the temperature at 30 °C for reaction for 48 hours, and control the raw material D1 by HPLC to be less than 1%. Dropwise add 30% sodium hydroxide solution (113.57 g, 1.8 eq.). After the addition is complete, control the temperature at 25 °C for reaction for 3 hours, and control the reaction of E1 by HPLC. Add 500 mL of methyl tert-butyl ether, let it stand for liquid separation, and extract the aqueous phase once with 300 mL of methyl tert-butyl ether. Combine the organic phases, wash with 300 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate to remove the solvent to obtain compound F1, a pale yellow oily liquid of 124.0 g. Yield 98%, ee value: 99.8%. LCMS, [M+1]=268; 1 HNMR(CDCl 3 )δ7.48-7.27(m,10H),4.1(q,1H),3.86(d,1H),3.58(d,1H),3.01(m,1H),2.74-2.57(m,3H),2.40(dd,1H),1.50(d,3H).

[0098] Example 5: Preparation of Compound G1

[0099]

[0100] Method 1:

[0101] In a 2000 mL three-necked flask, add 1000 mL of tert-butanol, trimethylsulfoxonium bromide (116.5 g, 1.8 eq.), and potassium tert-butoxide (83.9 g, 2.0 eq.). Under nitrogen protection, heat up to 80 °C, and add a tert-butanol solution (300 mL) of compound F1 (100 g, 1.0 eq.) dropwise at a rate of 5 seconds per drop. After the addition is complete, keep the temperature at 80 °C and react for 5 hours. Cool to room temperature, add 1000 mL of water, concentrate to remove tert-butanol, and extract the residue with methyl tert-butyl ether (500 mL × 2). Combine the organic phases, wash with 300 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate to remove the solvent, add methanol (300 mL) to the residue, heat up to 65 °C to dissolve it clearly, cool to 0 °C to crystallize, filter, and dry to obtain 56.8 g of white solid of compound G1, with a yield of 54%, ee value: 99.6%, chemical purity 99.0%, and melting point 61 °C. LCMS, [M+1] = 282; 1 HNMR(CDCl 3 )δ7.49-7.28(m,10H),4.94(m,1H),4.65(m,1H),4.50(m,1H),4.05(q,1H),3.75(d,1H),3.66(d,1H),2.85(dd,1H),2.82(dd,1H),2.54(m,1H),2.40(m,1H),1.50(d,3H).

[0102] Method 2:

[0103] In a 1000 mL three-necked flask, add 500 mL of tert-butanol, trimethylsulfoxonium iodide (79.1 g, 1.8 eq.), and potassium tert-butoxide (41.9 g, 2.0 eq.). Under nitrogen protection, heat up to 80 °C, and add a tert-butanol solution (150 mL) of compound F1 (50 g, 1.0 eq.) dropwise. After the addition is complete, keep the temperature at 80 °C and react for 5 hours. Cool to room temperature, add 500 mL of water, concentrate to remove tert-butanol, and extract the residue with methyl tert-butyl ether (250 mL × 2). Combine the organic phases, wash with 150 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate to remove the solvent, add methanol (150 mL) to the residue, heat up to 65 °C to dissolve it clearly, cool to 0 °C to crystallize, filter, and dry to obtain compound G1, 27.3 g of white solid, with a yield of 52%, ee value: 99.6%, and chemical purity 98.5%.

[0104] Example 6: Preparation of Compound A0

[0105]

[0106] In a 500 mL hydrogenation autoclave, add 200 mL of methanol, compound G1 (40 g, 1.0 eq.), acetic acid (8.5 g, 1.0 eq.) and 10% palladium on carbon (4 g). Evacuate the autoclave and replace the gas with nitrogen three times. Then fill it with hydrogen to 1 MPa and heat up to 45 - 55 °C for reaction for 5 hours. Cool down to room temperature, add 10% palladium on carbon (4 g), replace the gas with nitrogen three times, then fill it with hydrogen to 1 MPa and heat up to 45 - 55 °C for reaction for 10 hours. Cool down to room temperature, filter to remove the palladium on carbon, and wash the palladium on carbon with 50 mL of methanol. Concentrate the filtrate to dryness, add 100 mL of water, adjust the pH to 10 with sodium hydroxide solution, extract with dichloromethane (150 mL × 4), combine the organic phases, dry over anhydrous magnesium sulfate, then concentrate the dichloromethane under reduced pressure and further rectify to obtain 9.67 g of the target compound A0, with a yield of 78% and an ee value of 99.6%. LCMS, [M + 1] = 88; 1 HNMR(CDCl 3 )δ4.77(m,1H),4.64(m,1H),4.46(m,1H),2.87(d,2H),2.58(m,1H),2.42(m,1H).

[0107] Example 7: Preparation of Compound A1

[0108]

[0109] In a 500 mL hydrogenation autoclave, add 200 mL of methanol, compound G1 (40 g, 1.0 eq.), acetic acid (8.5 g, 1.0 eq.) and 10% palladium on carbon (4 g). Evacuate the autoclave and replace the gas with nitrogen three times. Then fill it with hydrogen to 1 MPa and heat up to 45 - 55 °C for reaction for 5 hours. Cool down to room temperature, add 10% palladium on carbon (4 g), replace the gas with nitrogen three times, then fill it with hydrogen to 1 MPa and heat up to 45 - 55 °C for reaction for 10 hours,. Cool down to room temperature, filter to remove the palladium on carbon, and wash the palladium on carbon with 50 mL of methanol. Concentrate the filtrate to dryness, add 200 mL of tetrahydrofuran, 20 mL of water, p-toluenesulfonic acid monohydrate (27.0 g, 1.0 eq.), heat up to 55 °C and stir for 1 hour, cool down to 10 °C and stir for 1 hour. Filter, wash the filter cake with 50 mL of tetrahydrofuran, and dry in vacuo at 50 °C to obtain 31.4 g of the target compound A1, with a yield of 85% and an ee value of 99.7%. 1 HNMR(CDCl 3 )δ7.95(br,3H),7.51(d,2H),7.14(d,2H),4.88(m,1H),4.57 - 4.44(m,2H),3.11(d,1H),3.04(d,1H),2.65(m,1H),2.46(m,1H),2.30(s,3H).

[0110] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing (S)-oxetane-2-methylamine, characterized in that: The method comprises the following steps: Step S1: Compound D undergoes a substitution ring-opening reaction with (R)-(-)-epichlorohydrin, and then undergoes a ring-closing reaction in the presence of a first alkaline reagent to obtain Compound F; Step S2: Compound F reacts with trimethylsulfoxide halide in the presence of a second alkaline reagent to obtain compound G; Step S3: Compound G is subjected to a hydrogenation debenzylation reaction to obtain (S)-oxetane-2-methylamine, i.e., Compound A0; Among them, R 1 Methyl or ethyl is selected.

2. The synthesis method according to claim 1, characterized in that: In step S1, the solvent used in the ring-opening reaction and the ring-closing reaction is selected from at least one of methanol, ethanol, isopropanol and water; and / or In step S1, the molar ratio of compound D to (R)-(-)-epichlorohydrin is 1:1-2, preferably 1:1.5; and / or In step S1, the ring-opening reaction is carried out at 25°C to 35°C; and / or In step S1, the reaction time of the ring-opening reaction is 40 to 55 hours, preferably 48 hours; and / or The first alkaline agent is selected from at least one of sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate; and / or The molar ratio of the compound D to the first alkaline agent is 1:1-2, preferably 1:1.8; and / or The first alkaline reagent is added dropwise, and after the addition is completed, the temperature is controlled at 20-30° C. to react for 1-5 hours, preferably 3 hours; and / or in step S1, after the ring-closing reaction is completed, an ether reagent is used for extraction and separation to obtain the compound of formula F, preferably, the ether reagent is methyl tert-butyl ether; and / or R 1 C 1～6 alkyl.

3. The synthesis method according to claim 1, characterized in that: In step S2, the second alkaline reagent is selected from at least one of potassium tert-butoxide and sodium tert-butoxide; and / or The molar ratio of the compound F, trimethyl sulfoxide halide and the second alkaline agent is 1:1-2:1.5-2.5, preferably 1:1.8:2; and / or The trimethyl sulfoxide halide is selected from at least one of trimethyl sulfoxide bromide and trimethyl sulfoxide iodide; and / or The solvent used in the reaction in step S2 is selected from at least one of dioxane, dimethyl sulfoxide, ethanol, isopropanol and tert-butanol; and / or In step S2, under the protection of an inert gas, the solution containing compound F is added dropwise to the trimethyl sulfoxide halide solution containing the second alkaline agent, and / or The reaction in step S2 is carried out under inert gas protection at 80-85° C. for 5-6 hours; and / or The inert gas includes at least one of argon and nitrogen; and / or The solution containing compound F is prepared by dissolving compound F in the solvent used in the reaction in step S2; and / or In step S2, after the reaction is completed, water is added to quench, the solvent is removed, and the organic phase obtained by extraction with methyl tert-butyl ether is post-treated to obtain compound G; and / or In step S2, the post-treatment process is: adding an alcohol solvent to the residue after washing, drying and concentrating the organic phase obtained by extraction with methyl tert-butyl ether, heating the solution to 60-70° C. to clarify the solution, cooling the solution to 0-5° C. for crystallization, filtering and drying after the crystallization is completed to obtain compound G; and / or The alcohol solvent is selected from at least one of methanol, ethanol, n-propanol and isopropanol.

4. The synthesis method according to claim 1, characterized in that: Step S3 comprises: mixing compound G, acetic acid and palladium carbon, and then heating the mixture under a hydrogen atmosphere to react to obtain compound A0; and / or The reaction process in step S3 is specifically as follows: Compound G, acetic acid and palladium carbon are mixed and reacted at 45-55° C. for 8-24 hours under a hydrogen pressure of 0.5-1.2 MPa.

5. Compound F, characterized in that for 6. Compound F, characterized in that Selected from Or a mixture of both.

7. Compound G, characterized in that for 8. Compound G, characterized in that Selected from Or a mixture of both.

9. A method for preparing p-toluenesulfonate of (S)-oxetane-2-methylamine, characterized in that: include: The compound A0 prepared by the synthesis method according to any one of claims 1 to 4 is reacted with p-toluenesulfonic acid or its hydrate in a solvent to obtain p-toluenesulfonate of (S)-oxetane-2-methylamine.

10. The preparation method according to claim 9, characterized in that: The solvent is selected from at least one of water, tetrahydrofuran and alcohol solvents; preferably, the alcohol solvent is selected from methanol or ethanol; The reaction temperature of the reaction is 10°C-60°C; further preferably, the reaction is carried out at 50-60°C for 0.5-2 hours, preferably 1 hour, and then the temperature is lowered to 10-20°C for 0.5-2 hours, preferably 1 hour; Optionally, after the reaction is completed, a post-treatment step is further included; Optionally, the post-processing steps include: filtering, washing and drying; Optionally, the washing is performed using tetrahydrofuran.

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