A preparation method of oxetane-2-methylamine

Abstract

The invention provides a method for preparing oxetane-2-methylamine, belonging to the technical field of organic synthesis. The present invention uses [2-(1-ethoxyethoxy)methyl] propylene oxide as initial raw material, reacts in the presence of potassium tert-butoxide and trimethylsulfoxide iodide, then the product obtained is reacted with a sulfonyl compound and triethylamine, and then the product obtained is reacted with a phthalamide compound, and finally the product obtained is reacted with an amino-containing compound to obtain oxetane-2-methylamine. The preparation method provided by the present invention is still more than 30% in total yield after amplification production (kilogram level), and the yield is high; moreover, compared with the preparation method of traditional oxetane-2-methylamine, the preparation method provided by the present invention does not need to carry out a palladium-carbon catalytic hydrogenation step, and does not need to use sodium azide dangerous goods, and has high safety and low production cost, simple operation, and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing oxetane-2-methylamine. Background Art

[0002] Oxetane-2-methylamine is an important organic synthesis intermediate compound. U.S. Patent US2019382384A1 discloses a method for preparing oxetane-2-methylamine, and the reaction route is as follows:

[0003] However, the total yield of synthesizing oxetane-2-methylamine by the above preparation method is only 19.3%, which is low. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing oxetane-2-methylamine. The preparation method provided by the present invention has high yield.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for preparing oxetane-2-methylamine, comprising the following steps:

[0007] (1) mixing [2-(1-ethoxyethoxy)methyl]propylene oxide and an acid solution, and performing an acid-catalyzed hydrolysis reaction to obtain (oxetan-2-yl)methanol; the [2-(1-ethoxyethoxy)methyl]propylene oxide includes (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide, (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide, or (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide;

[0008] (2) mixing the (oxetan-2-yl)methanol, a sulfonyl compound, triethylamine and a chloroalkane solvent, and performing an esterification reaction to obtain (oxetan-2-yl)methyl p-toluenesulfonate;

[0009] (3) mixing the (oxetan-2-yl)methyl p-toluenesulfonate, a phthalamide compound and an amide solvent, and performing a first substitution reaction to obtain oxetan-2-ylmethyl-isoindole-1,3-dione;

[0010] (4) Mixing the oxetanemethyl-isoindole-1,3-dione, the amino compound and water, and performing a second substitution reaction to obtain oxetane-2-methylamine.

[0011] Preferably, in step (1), the acid solution preferably comprises one or more of acetic acid solution, formic acid solution, propionic acid solution, butyric acid solution, hydrochloric acid solution and sulfuric acid solution.

[0012] Preferably, in step (1), the molar ratio of the [2-(1-ethoxyethoxy)methyl]propylene oxide to the acid in the acid solution is 1:0.8-2.

[0013] Preferably, in step (1), the mass ratio of the [2-(1-ethoxyethoxy)methyl]propylene oxide to the acid in the acid solution is 17 kg: 3 to 21 kg.

[0014] Preferably, in step (1), the temperature of the acid-catalyzed hydrolysis reaction is 20 to 30° C. and the time is 15 to 20 hours.

[0015] Preferably, in step (1), the acid-catalyzed hydrolysis reaction further includes post-treatment, and the post-treatment includes: adjusting the pH value of the reaction solution obtained by the acid-catalyzed hydrolysis reaction to 11-12, then extracting, and drying the obtained organic phase and concentrating it to constant weight.

[0016] Preferably, in step (2), the molar ratio of (oxetan-2-yl)methanol, sulfonyl compound and triethylamine is 1:1.2-2:1.8-2.5.

[0017] Preferably, in step (2), the esterification reaction is carried out at a temperature of 20 to 30° C. and for a time of 15 to 20 hours.

[0018] Preferably, in step (2), the esterification reaction further includes post-treatment, and the post-treatment includes: adding water to the reaction solution obtained by the esterification reaction to separate the phases, washing the obtained organic phase with hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and water in sequence, and then drying, concentrating and recrystallizing.

[0019] Preferably, in step (3), the molar ratio of the (oxetan-2-yl)methyl p-toluenesulfonate to the phthalamide compound is 1:1 to 1.5.

[0020] Preferably, in step (3), the temperature of the first substitution reaction is 110-120° C., and the time is 3-5 h.

[0021] Preferably, in step (3), the first substitution reaction further includes post-treatment, and the post-treatment includes: cooling the reaction solution obtained by the first substitution reaction to room temperature, adding water and an organic solvent for phase separation to obtain an aqueous phase and an organic phase; subjecting the aqueous phase to organic extraction, and sequentially washing the organic phase obtained by the organic extraction and the organic phase obtained by phase separation with saturated brine, drying, concentrating and recrystallizing.

[0022] Preferably, in step (4), the molar ratio of the oxetanylmethyl-isoindole-1,3-dione to the amino-containing compound is 1:1.5-3.

[0023] Preferably, in step (4), the amino-containing compound comprises one or more of hydrazine hydrate, methylamine and ethylamine.

[0024] Preferably, in step (4), the temperature of the second substitution reaction is 40-50° C. and the time is 35-40 h.

[0025] Preferably, in step (4), the second substitution reaction further includes post-treatment, and the post-treatment includes: cooling the reaction solution obtained by the second substitution reaction and filtering it, adjusting the pH value of the obtained filtrate to 4-5 and then pre-extracting it, adjusting the pH value of the obtained aqueous phase to 13-14 and then extracting it, and drying, concentrating and distilling the obtained organic phase in sequence.

[0026] The present invention provides a method for preparing (S)-oxetane-2-methylamine, comprising the following steps:

[0027] (1) mixing [2-(1-ethoxyethoxy)methyl]propylene oxide and an acid solution, and performing an acid-catalyzed hydrolysis reaction to obtain (oxetan-2-yl)methanol; the [2-(1-ethoxyethoxy)methyl]propylene oxide includes (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide, (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide, or (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide; (2) , sulfonyl compound, triethylamine and chloroalkane solvent are mixed to carry out esterification reaction to obtain (oxetane-2-yl) methyl p-toluenesulfonate; (3) the (oxetane-2-yl) methyl p-toluenesulfonate, phthalamide compound and amide solvent are mixed to carry out first substitution reaction to obtain oxetane methyl-isoindole-1,3-dione; (4) the oxetane methyl-isoindole-1,3-dione, amino compound and water are mixed to carry out second substitution reaction to obtain oxetane-2-methylamine. As shown in the test results of the embodiment, the total yield of laboratory synthesis of (S)-oxetane-2-methylamine is 30.22%, and the total yield of scaled-up production is 30.03%; the total yield of laboratory synthesis of (R)-oxetane-2-methylamine is 32.28%; the total yield of laboratory synthesis of oxetane-2-methylamine is 35.53%. It shows that the preparation method provided by the present invention has high yield and good repeatability.

[0028] Moreover, the preparation method provided by the present invention does not require the palladium-carbon catalytic hydrogenation step, nor does it require the use of dangerous goods such as sodium azide. It has high safety and low production cost, is simple to operate, and is suitable for industrial production. DETAILED DESCRIPTION

[0029] The present invention provides a method for preparing oxetane-2-methylamine, comprising the following steps:

[0030] (1) mixing [2-(1-ethoxyethoxy)methyl]propylene oxide and an acid solution, and performing an acid-catalyzed hydrolysis reaction to obtain (oxetan-2-yl)methanol; the [2-(1-ethoxyethoxy)methyl]propylene oxide includes (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide, (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide, or (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide;

[0031] (2) mixing the (oxetan-2-yl)methanol, a sulfonyl compound, triethylamine and a chloroalkane solvent, and performing an esterification reaction to obtain (oxetan-2-yl)methyl p-toluenesulfonate;

[0032] (3) mixing the (oxetan-2-yl)methyl p-toluenesulfonate, a phthalamide compound and an amide solvent, and performing a first substitution reaction to obtain oxetan-2-ylmethyl-isoindole-1,3-dione;

[0033] (4) Mixing the oxetanemethyl-isoindole-1,3-dione, the amino compound and water, and performing a second substitution reaction to obtain oxetane-2-methylamine.

[0034] The invention mixes [2-(1-ethoxyethoxy)methyl]propylene oxide and an acid solution, and performs an acid-catalyzed hydrolysis reaction to obtain (oxetan-2-yl)methanol; the [2-(1-ethoxyethoxy)methyl]propylene oxide includes (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide, (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide or (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide.

[0035] In the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0036] In the present invention, the preparation method of [2-(1-ethoxyethoxy)methyl]propylene oxide preferably comprises the following steps:

[0037] A glycidyl compound, vinyl ethyl ether and p-toluenesulfonic acid are mixed for addition reaction to obtain 2-[(1-ethoxyethoxy)methyl]ethylene oxide; the glycidyl compound includes (R)-(+)-glycidyl, (S)-glycidyl or glycidyl;

[0038] Potassium tert-butoxide, trimethyl sulfoxide iodide, the 2-[(1-ethoxyethoxy)methyl]ethylene oxide and an alcohol solvent are mixed to carry out a ring expansion reaction to obtain [2-(1-ethoxyethoxy)methyl]propylene oxide.

[0039] The invention mixes a glycidol compound, vinyl ethyl ether and p-toluenesulfonic acid for addition reaction to obtain 2-[(1-ethoxyethoxy)methyl]ethylene oxide.

[0040] In the present invention, the glycidyl compound includes (R)-(+)-glycidyl, (S)-(-)-glycidyl or glycidyl; when the glycidyl compound is (R)-(+)-glycidyl, (2S)-2-[(1-ethoxyethoxy)methyl]ethylene oxide is prepared, when the glycidyl compound is (S)-(-)-glycidyl, (2R)-2-[(1-ethoxyethoxy)methyl]ethylene oxide is prepared, and when the glycidyl compound is glycidyl, (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide is prepared. In the present invention, the p-toluenesulfonic acid is preferably used in the form of p-toluenesulfonic acid hydrate. In the present invention, the molar ratio of the glycidol compound, vinyl ethyl ether and p-toluenesulfonic acid is preferably 1:2-5:0.01-0.02, more preferably 1:2.5-4.5:0.012-0.018, and further preferably 1:3-4:0.015-0.016. In the present invention, the mass ratio of the glycidol compound, vinyl ethyl ether and p-toluenesulfonic acid is preferably 10kg:19.5-48.75kg:232-660g, more preferably 10kg:20-40kg:300-500g. The present invention has no special restrictions on the mixing method, and a mixing method well known to those skilled in the art can be used; the mixing order is preferably to pre-mix the glycidol compound and vinyl ethyl ether, cool to 0-10°C, and then add p-toluenesulfonic acid to mix; the present invention has no special restrictions on the cooling method, and a cooling method well known to those skilled in the art can be used; the p-toluenesulfonic acid is preferably added in 3-10 times, more preferably 5-8 times.

[0041] In the present invention, the temperature of the addition reaction is preferably 20 to 30°C, more preferably 22 to 28°C, and further preferably 25 to 26°C; the time of the addition reaction is preferably 3 to 5 hours, more preferably 3.5 to 4.5 hours, and further preferably 4 hours. In the present invention, the reaction occurring during the addition reaction is as shown in Formula (1-1), Formula (1-2) or Formula (1-3):

[0042]

[0043] After the addition reaction, the present invention preferably further comprises post-treatment to obtain 2-[(1-ethoxyethoxy)methyl]ethylene oxide. In the present invention, the post-treatment preferably comprises: washing the reaction solution obtained by the addition reaction with a saturated sodium bicarbonate aqueous solution and then standing for stratification to obtain an aqueous phase and an organic phase; extracting the aqueous phase, combining the obtained organic phases, drying and concentrating. In the present invention, the washing with a saturated sodium bicarbonate aqueous solution is preferably carried out under stirring, the stirring temperature is preferably room temperature, the stirring time is preferably 1 to 2 hours, and more preferably 1.5 hours; the mass ratio of the glycidyl compound to the saturated sodium bicarbonate aqueous solution is preferably 1:1.5 to 5.0, and more preferably 1:2.7. In the present invention, the extraction agent is preferably one or more of methyl tert-butyl ether, isopropyl ether and ethyl acetate. In the present invention, the drying method is preferably drying with a desiccant, and the desiccant preferably includes anhydrous sodium sulfate; after the desiccant is dried, it is preferably filtered to remove the desiccant; the mass ratio of the glycidol compound to the desiccant is preferably 1:0.1-0.5, more preferably 1:0.2-0.3. The present invention does not specifically limit the concentration method, and the concentration method well known to those skilled in the art can be used to concentrate to a constant weight.

[0044] After obtaining 2-[(1-ethoxyethoxy)methyl]ethylene oxide, the present invention mixes potassium tert-butoxide, trimethyl sulfoxide iodide, the 2-[(1-ethoxyethoxy)methyl]ethylene oxide and an alcohol solvent to carry out a ring expansion reaction to obtain [2-(1-ethoxyethoxy)methyl]propylene oxide.

[0045] In the present invention, the molar ratio of 2-[(1-ethoxyethoxy)methyl]oxirane, potassium tert-butoxide and trimethylsulfoxide iodide is 1:2-3:2-3, preferably 1:2.2-2.8:2.2-2.8, and more preferably 1:2.4-2.5:2.4-2.5. In the present invention, the mass ratio of 2-[(1-ethoxyethoxy)methyl]oxirane, potassium tert-butoxide and trimethylsulfoxide iodide is preferably 18kg:27.6-41.4kg:54.2-81.3kg, and more preferably 18kg:30-40kg:60-70kg. In the present invention, the alcohol solvent preferably includes one or more of tert-butyl alcohol, methanol, ethanol, isopropanol and n-butyl alcohol; the ratio of the mass of the 2-[(1-ethoxyethoxy)methyl]oxirane to the volume of the alcohol solvent is preferably 1kg:10-30L, more preferably 1kg:20L. In the present invention, the temperature of mixing the potassium tert-butylate, trimethyl sulfoxide iodide, 2-[(1-ethoxyethoxy)methyl]oxirane and the alcohol solvent is preferably 60-70°C, more preferably 65°C; the order of mixing is preferably premixing the potassium tert-butylate, trimethyl sulfoxide iodide and part of the alcohol solvent to obtain a premixed solution; mixing the 2-[(1-ethoxyethoxy)methyl]oxirane and the remaining alcohol solvent to obtain a 2-[(1-ethoxyethoxy)methyl]oxirane solution; and dropping the 2-[(1-ethoxyethoxy)methyl]oxirane solution into the premixed solution. In the present invention, the volume of the partial alcohol solvent is preferably 2-10% of the total volume of the alcohol solvent, more preferably 5%. In the present invention, the premixing time is preferably 1-2 hours, more preferably 1.5 hours. The present invention has no particular limitation on the speed of the dropwise addition, and it can be added dropwise.

[0046] In the present invention, the temperature of the ring expansion reaction is preferably 60 to 70°C, more preferably 62 to 68°C, and further preferably 64 to 65°C; starting from the completion of the dropwise addition of the 2-[(1-ethoxyethoxy)methyl]oxirane solution, the time of the ring expansion reaction is preferably 15 to 20 hours, more preferably 16 to 19 hours, and further preferably 17 to 18 hours. In the present invention, the reaction occurring during the ring expansion reaction is as shown in Formula (2-1), Formula (2-2) or Formula (2-3):

[0047]

[0048] After the ring-expansion reaction, the present invention preferably further includes post-treatment, and the system of the ring-expansion reaction is post-treated to obtain [2-(1-ethoxyethoxy)methyl]propylene oxide. In the present invention, the post-treatment includes: solid-liquid separation of the reaction solution obtained by the ring-expansion reaction, dilution with water after concentrating the obtained liquid component, extraction, and washing the obtained organic phase with saturated brine, drying and concentrating to constant weight in sequence. The present invention does not specifically limit the method of solid-liquid separation, and a solid-liquid separation method well known to those skilled in the art can be used, such as filtration. The present invention does not specifically limit the method of concentrating the liquid component, and the ratio of the mass of the 2-[(1-ethoxyethoxy)methyl]propylene oxide to the volume of the concentrated solution obtained by concentration is preferably 1kg:1.0~2.0L, more preferably 1kg:1.1~1.2L. In the present invention, the diluent for dilution is preferably water; the ratio of the mass of the 2-[(1-ethoxyethoxy)methyl]propylene oxide to the volume of the dilution water is preferably 1kg:2~5L, more preferably 1kg:2.5L. In the present invention, the extraction agent is preferably one or more of methyl tert-butyl ether, isopropyl ether and ethyl acetate, and the mass ratio of the 2-[(1-ethoxyethoxy)methyl]oxirane to the volume ratio of the extractant is preferably 1kg:1.5~5.0L, more preferably 1kg:2L. In the present invention, the mass ratio of the 2-[(1-ethoxyethoxy)methyl]oxirane to the volume ratio of saturated salt water is preferably 1kg:1.0~5.0L, more preferably 1kg:1.5L. In the present invention, the drying method is preferably drying with a desiccant, and the desiccant preferably includes anhydrous sodium sulfate; after the desiccant is dried, it is preferably filtered to remove the desiccant; the mass ratio of the 2-[(1-ethoxyethoxy)methyl]oxirane to the desiccant is preferably 1:0.1~0.5, more preferably 1:0.2. The present invention does not specifically limit the method for concentrating the filtrate, and it can be concentrated to constant weight using a concentration method well known to those skilled in the art.

[0049] After obtaining [2-(1-ethoxyethoxy)methyl]propylene oxide, the present invention mixes the [2-(1-ethoxyethoxy)methyl]propylene oxide with an acid solution and performs an acid-catalyzed hydrolysis reaction to obtain [oxetan-2-yl]methanol.

[0050] In the present invention, the acid solution preferably includes one or more of acetic acid solution, formic acid solution, propionic acid solution, butyric acid solution, hydrochloric acid solution and sulfuric acid solution; the concentration of the acid solution is preferably 1.5-3.0 mol / L, more preferably 1.9-2 mol / L; the acid solution is preferably obtained by dissolving an acid in water. In the present invention, the molar ratio of the [2-(1-ethoxyethoxy)methyl]propylene oxide and the acid in the acid solution is preferably 1:0.8-2, more preferably 1:1-1.5. The present invention has no special restrictions on the mixing method, as long as the raw materials can be mixed evenly. In the present invention, the mass ratio of the [2-(1-ethoxyethoxy)methyl]propylene oxide and the acid in the acid solution is preferably 17kg:3-21kg, more preferably 17kg:5-15kg.

[0051] In the present invention, the temperature of the acid-catalyzed hydrolysis reaction is preferably 20 to 30°C, more preferably 22 to 28°C, and further preferably 25 to 26°C; the time of the acid-catalyzed hydrolysis reaction is preferably 15 to 20 hours, more preferably 16 to 19 hours, and further preferably 17 to 18 hours. In the present invention, the reaction occurring during the acid-catalyzed hydrolysis reaction is as shown in Formula (3-1), Formula (3-2) or Formula (3-3):

[0052]

[0053]

[0054] After the acid-catalyzed hydrolysis reaction, the present invention preferably further includes post-treatment to obtain (oxacyclobutane-2-yl) methanol. In the present invention, the post-treatment preferably includes: adjusting the pH value of the reaction solution obtained by the acid-catalyzed hydrolysis reaction to 11-12 and then extracting, drying the obtained organic phase and concentrating it to constant weight. In the present invention, the pH value is preferably adjusted to 11-12 by first adjusting the pH value to 6-7 with bicarbonate and then adjusting the pH to 11-12 with carbonate; the bicarbonate preferably includes sodium bicarbonate and potassium bicarbonate; the bicarbonate is preferably added in 3-10 times; the carbonate preferably includes potassium carbonate and sodium carbonate; the present invention uses the above-mentioned method to adjust the pH value to meet the requirements, while ensuring that the aqueous solution dissolves enough salt to reduce the difficulty of extraction. In the present invention, the extraction agent preferably includes one or more of dichloromethane, ethyl acetate and methyl tert-butyl ether; the present invention does not specifically limit the amount of the extractant, and the amount of the extractant well known to those skilled in the art can be used. In the present invention, the drying method is preferably drying with a desiccant, and the desiccant preferably includes anhydrous sodium sulfate; after the desiccant is dried, it is preferably filtered to remove the desiccant; the mass ratio of [2-(1-ethoxyethoxy)methyl]propylene oxide to the desiccant is preferably 1:0.1-0.5, more preferably 1:0.2. The present invention does not specifically limit the method for concentrating the filtrate, and it can be concentrated to a constant weight using a concentration method well known to those skilled in the art.

[0055] After obtaining (oxetan-2-yl)methanol, the present invention mixes the (oxetan-2-yl)methanol, a sulfonyl compound, triethylamine and a chloroalkane solvent to carry out an esterification reaction to obtain (oxetan-2-yl)methyl p-toluenesulfonate.

[0056] In the present invention, the sulfonyl compound preferably includes one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride, ethylsulfonyl chloride, benzenesulfonyl chloride and 4-nitrobenzenesulfonyl chloride. In the present invention, the molar ratio of (oxetane-2-yl)methanol, sulfonyl compound and triethylamine is preferably 1:1.2-2:1.8-2.5, more preferably 1:1.5-1.8:2-2.2. In the present invention, the mass ratio of (oxetane-2-yl)methanol, sulfonyl compound and triethylamine is preferably 8kg:12-40kg, more preferably 8kg:20-30kg. In the present invention, the chloroalkane solvent preferably includes dichloromethane and / or chloroform; the mass ratio of the (oxetane-2-yl)methanol to the volume of the chloroalkane solvent is preferably 1kg:5-10L, more preferably 1kg:10L. The present invention has no special limitation on the mixing method, as long as the raw materials can be mixed evenly.

[0057] In the present invention, the temperature of the esterification reaction is preferably 20 to 30°C, more preferably 22 to 28°C, and further preferably 25 to 26°C; the time of the esterification reaction is preferably 15 to 20 hours, more preferably 16 to 19 hours, and further preferably 17 to 18 hours. In the present invention, the reaction occurring during the esterification reaction is as shown in Formula (4-1), Formula (4-2) or Formula (4-3):

[0058]

[0059] After the esterification reaction, the present invention preferably further comprises post-treatment to obtain (oxetane-2-yl) methyl p-toluenesulfonate. In the present invention, the post-treatment preferably comprises: adding water to the reaction solution obtained by the esterification reaction for phase separation, washing the obtained organic phase with hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and water in sequence, and then drying, concentrating and recrystallizing. In the present invention, the mass ratio of the (oxetane-2-yl) methanol and the water for phase separation is preferably 1:4-10, more preferably 1:5; the phase separation is preferably stirred and then left to stand, the stirring temperature is preferably room temperature, the stirring time is preferably 15-60min, more preferably 30min; the present invention has no special limitation on the standing time, as long as the aqueous phase and the organic phase can be separated. In the present invention, the concentration of the hydrochloric acid solution is preferably 0.5-1.5mol / L, more preferably 1mol / L; the mass ratio of the (oxetane-2-yl) methanol and the volume ratio of the hydrochloric acid solution is preferably 1kg:3-8L, more preferably 1kg:5L. In the present invention, the mass ratio of the (oxetane-2-yl) methanol to the saturated sodium bicarbonate aqueous solution is preferably 1kg:3-8L, more preferably 1kg:5L. In the present invention, the mass ratio of the (oxetane-2-yl) methanol to the washing water is preferably 1kg:3-8L, more preferably 1kg:5L. In the present invention, the drying method is preferably drying with a desiccant, and the desiccant preferably includes anhydrous sodium sulfate; after the desiccant is dried, it is preferably filtered to remove the desiccant; the mass ratio of the (oxetane-2-yl) methanol to the desiccant is preferably 1:0.2-0.8L, more preferably 1:0.4. The present invention does not specifically limit the concentration method of the filtrate, and it can be concentrated by a concentration method well known to those skilled in the art; the mass ratio of the (oxetane-2-yl) methanol to the volume of the concentrated solution after concentration is preferably 1kg:1.0-2.0L, more preferably 1kg:1.2-1.3L. In the present invention, the organic solvent for recrystallization preferably includes methyl tert-butyl ether, and the ratio of the mass of the (oxetan-2-yl)methanol to the volume of the organic solvent for recrystallization is preferably 1 kg:2.0-5.0 L, more preferably 1 kg:3 L.

[0060] After obtaining (oxetan-2-yl)methyl p-toluenesulfonate, the present invention mixes the (oxetan-2-yl)methyl p-toluenesulfonate, a phthalamide compound and an amide solvent, and performs a first substitution reaction to obtain oxetanylmethyl-isoindole-1,3-dione.

[0061] In the present invention, the phthalamide compound includes one or more of phthalimide and / or phthalimide salt; the phthalimide salt preferably includes potassium phthalimide and / or sodium phthalimide. In the present invention, the molar ratio of the (oxetane-2-yl) methyl p-toluenesulfonate to the phthalamide compound is preferably 1:1-1.5, more preferably 1:1.1-1.4, and further preferably 1:1.2-1.3. In the present invention, the mass ratio of the (oxetane-2-yl) methyl p-toluenesulfonate to the phthalamide compound is preferably 18kg:11-20.7kg, more preferably 18kg:12-15kg. In the present invention, the amide solvent preferably includes N,N-dimethylformamide and / or N,N-dimethylacetamide; the mass ratio of the (oxetan-2-yl)methyl p-toluenesulfonate to the volume of the amide solvent is preferably 1 kg: 5 to 10 L, more preferably 1 kg: 7 L. The present invention has no particular limitation on the mixing method, as long as the raw materials can be mixed uniformly.

[0062] In the present invention, the temperature of the first substitution reaction is preferably 110-120°C, more preferably 112-118°C, and further preferably 115-116°C; the time of the first substitution reaction is preferably 3-5h, more preferably 3.5-4.5h, and further preferably 4h. In the present invention, the reaction occurring during the first substitution reaction is as shown in Formula (5-1), Formula (5-2) or Formula (5-3):

[0063]

[0064] After the first substitution reaction, the present invention preferably further comprises post-treatment to obtain oxetanylmethyl-isoindole-1,3-dione. In the present invention, the post-treatment preferably comprises: cooling the reaction solution obtained by the first substitution reaction to room temperature, adding water and an organic solvent for phase separation, and obtaining an aqueous phase and an organic phase; subjecting the aqueous phase to organic extraction, and sequentially washing the organic phase obtained by the organic extraction and the organic phase obtained by phase separation with saturated brine, drying, concentrating and recrystallizing. The present invention does not specifically limit the cooling method, and a cooling method well known to those skilled in the art may be used. In the present invention, the ratio of the mass of the (oxetane-2-yl) methyl p-toluenesulfonate to the volume of water for phase separation is preferably 1kg:5-10L, more preferably 1kg:7L; the organic solvent for phase separation preferably includes one or more of ethyl acetate, methyl tert-butyl ether and dichloromethane; the ratio of the mass of the (oxetane-2-yl) methyl p-toluenesulfonate to the volume of the organic solvent for phase separation is preferably 1kg:3-8L, more preferably 1kg:5L; the phase separation is preferably left standing after stirring, the stirring temperature is preferably room temperature, and the stirring time is preferably 15-60min, more preferably 30min; the present invention has no special limitation on the standing time, as long as it can achieve phase separation of the aqueous phase and the organic phase. In the present invention, the extractant for extraction preferably includes one or more of ethyl acetate, isopropyl acetate and methyl tert-butyl ether; the number of extractions is preferably 2 to 3 times; the ratio of the mass of the (oxetan-2-yl) methyl p-toluenesulfonate to the volume of the extractant for a single extraction is preferably 1kg:2.0 to 5.0L, more preferably 1kg:2.5L. In the present invention, the ratio of the mass of the (oxetan-2-yl) methyl p-toluenesulfonate to the volume of saturated brine is preferably 1kg:3 to 8L, more preferably 1kg:5L. In the present invention, the drying method is preferably drying with a desiccant, and the desiccant preferably includes anhydrous sodium sulfate; after the desiccant is dried, it is preferably further filtered to remove the desiccant; the mass ratio of the (oxetan-2-yl) methanol to the desiccant is preferably 1:0.1 to 0.5L, more preferably 1:0.2. The present invention has no special limitation on the concentration method of the filtrate, and the filtrate can be concentrated by a concentration method well known to those skilled in the art; the ratio of the mass of the (oxetane-2-yl) methyl p-toluenesulfonate to the volume of the concentrated solution after concentration is preferably 1kg: 1.0-2.0L, more preferably 1kg: 1.2-1.3L. In the present invention, the organic solvent for recrystallization preferably includes petroleum ether and n-heptane; the ratio of the mass of the (oxetane-2-yl) methyl p-toluenesulfonate to the volume of the organic solvent for recrystallization is preferably 1kg: 4-8L, more preferably 1kg: 5L; the organic solvent for recrystallization is preferably added dropwise, and the present invention has no special limitation on the speed of the dropwise addition, and it can be added dropwise.

[0065] After obtaining oxetanylmethyl-isoindole-1,3-dione, the present invention mixes the oxetanylmethyl-isoindole-1,3-dione, an amino compound and water to carry out a second substitution reaction to obtain oxetane-2-methylamine.

[0066] In the present invention, the amino-containing compound includes one or more of hydrazine hydrate, methylamine and ethylamine; the amino-containing compound is preferably used in the form of an amino-containing compound solution, and the concentration of the amino-containing compound solution is preferably 30-100wt%, more preferably 50-80wt%; the solvent in the amino-containing compound solution preferably includes water and / or an alcohol solvent, and the alcohol solvent preferably includes methanol and / or ethanol. In the present invention, the molar ratio of the oxetanylmethyl-isoindole-1,3-dione to the amino-containing compound is preferably 1:1.5-3, more preferably 1:2-2.5. In the present invention, the mass ratio of the oxetanylmethyl-isoindole-1,3-dione to the amino-containing compound is preferably 10kg:1.5-12kg, more preferably 10kg:3-10kg. In the present invention, the mass ratio of the oxetanylmethyl-isoindole-1,3-dione to water is preferably 1:3-8, more preferably 1:5. The present invention has no special limitation on the mixing method, as long as the raw materials can be mixed evenly; the mixing order is preferably to mix oxetanylmethyl-isoindole-1,3-dione and water and then add the amino compound; the amino compound is preferably added dropwise, and the present invention has no special limitation on the dropping speed, and it can be added dropwise.

[0067] In the present invention, the temperature of the second substitution reaction is preferably 40 to 50°C, more preferably 42 to 48°C, and further preferably 45 to 46°C; the time of the second substitution reaction is preferably 35 to 40h, more preferably 36 to 39h, and further preferably 37 to 38h. In the present invention, the reaction occurring during the second substitution reaction is as shown in Formula (6-1), Formula (6-2) or Formula (6-3):

[0068]

[0069] After the second substitution reaction, the present invention preferably further comprises post-treatment to obtain (S)-oxetane-2-methylamine. In the present invention, the post-treatment preferably comprises: cooling the reaction solution obtained by the second substitution reaction and filtering, adjusting the pH value of the obtained filtrate to 4-5 and then pre-extracting, adjusting the pH value of the obtained aqueous phase to 13-14 and then extracting, and drying, concentrating and distilling the obtained organic phase in sequence. The present invention has no special limitation on the cooling method, and cooling to 0-10°C is sufficient. In the present invention, the acid solution used to adjust the pH value to 4-5 preferably comprises hydrochloric acid solution and / or sulfuric acid solution; the concentration of the acid solution is preferably 3-5 mol / L, more preferably 4 mol / L. In the present invention, the extractants for pre-extraction and extraction independently preferably comprise dichloromethane and / or chloroform; the mass of the oxetane methyl-isoindole-1,3-dione and the volume of the extractant for pre-extraction are preferably 1kg:1.5-3.0L, more preferably 1kg:2L. In the present invention, the alkaline solution used to adjust the pH value to 13-14 preferably includes sodium hydroxide and / or potassium hydroxide; the concentration of the alkaline solution is preferably 3-5 mol / L, more preferably 4 mol / L. In the present invention, the number of extractions is preferably 5-7 times, more preferably 6 times, and the mass of the oxetanylmethyl-isoindole-1,3-dione and the volume of the extractant for a single extraction are preferably 1 kg: 1.5-3.0 L, more preferably 1 kg: 2-2.5 L. In the present invention, the drying method is preferably drying with a desiccant, and the desiccant preferably includes anhydrous sodium sulfate; after the desiccant is dried, it is preferably further filtered to remove the desiccant; the mass ratio of the (oxetan-2-yl)methanol to the desiccant is preferably 1: 0.1-0.5 L, more preferably 1: 0.2-0.3. The present invention has no special limitation on the concentration method of the filtrate, and the concentration method well known to those skilled in the art can be used; the ratio of the mass of the oxetanylmethyl-isoindole-1,3-dione to the volume of the concentrated solution after concentration is preferably 1 kg: 1 to 4 L, more preferably 1 kg: 2 to 3 L. In the present invention, the distillation temperature is preferably 20 to 60° C., more preferably 30 to 50° C.; the distillation time is preferably 10 to 30 hours, more preferably 15 to 20 hours.

[0070] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0071] Example 1

[0072]

[0073] Laboratory preparation

[0074] (1) Add 100.0 g (1.35 mol, 1.00 equ.) of (R)-(+)-glycidol and 194.7 g (2.70 mol, 2.00 equ.) of ethyl vinyl ether to a reaction flask, cool to 5°C, add 2.6 g (0.01 mol, 0.01 equ.) of p-toluenesulfonic acid hydrate three times, react at 25°C for 4 h, add 270.0 g of saturated sodium bicarbonate aqueous solution and stir for 1 h, let stand and separate, dry the obtained organic phase with 20.0 g of anhydrous sodium sulfate and filter, and concentrate the obtained filtrate to constant weight to obtain (2S)-2-[(1-ethoxyethoxy)methyl]oxirane (179.0 g, yield 90%).

[0075] NMR data of (2S)-2-[(1-ethoxyethoxy)methyl]oxirane: 1 HNMR (300MHz, CDCl3): δ4.70(1H,m), δ3.60(2H,m), δ3.40(2H,m), δ3.08(1H,m), δ2.74(1H,t ,J=4.8Hz), δ2.56(1H,dd,J=2.4,5.1Hz), δ1.26(3H,d,J=2.4,5.1Hz), 1.15(3H,t,J=7.2Hz).

[0076] (2) 1900.0 mL of tert-butanol, 153.5 g (1.37 mol, 2.00 equ.) of potassium tert-butoxide and 301.5 g (1.37 mol, 2.00 equ.) of trimethylsulfoxide iodide were added to a reaction flask, and the mixture was heated to 65° C. and stirred for 1 h. 100.0 g (0.68 mol, 1.00 equ.) of (2S)-2-[(1-ethoxyethoxy)methyl]oxirane was dissolved in 100.0 mL of tert-butanol to obtain a (2S)-2-[(1-ethoxyethoxy)methyl]oxirane solution. At 65°C, add (2S)-2-[(1-ethoxyethoxy)methyl]ethylene oxide solution dropwise, and then continue the ring expansion reaction at 65°C for 15 hours. Filter, concentrate the filtrate to 100 mL, add 250.0 mL of water, extract with 200.0 mL of methyl tert-butyl ether, wash the organic phase with 150.0 mL of saturated brine, then dry with 20.0 g of anhydrous sodium sulfate, filter, and concentrate to constant weight to obtain (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide (102.6 g, yield is 94%).

[0077] NMR data of (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide: 1HNMR (300MHz, CDCl3): δ5.00(1H,m), δ4.86(1H,m), δ4.72(1H,m), δ4.62(1H,m), δ3.74(3H,m), δ3.56(1H,m), δ1.40(3H,m), δ1.26(1H,t,J=7.2Hz).

[0078] (3) 270.0 mL of water, 31.1 g (0.52 mol, 0.83 equ.) of acetic acid and 100.0 g (0.62 mol, 1.00 equ.) of (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide were added to the reaction flask, and the acid-catalyzed hydrolysis reaction was carried out at 25° C. for 15 h. 45.0 g of sodium bicarbonate was added three times to adjust the pH value to 7, and then 150.0 g of potassium carbonate was added to adjust the pH value to 12. The mixture was extracted with dichloromethane, and the obtained organic phase was dried over 20.0 g of anhydrous sodium sulfate and filtered. The obtained filtrate was concentrated to constant weight to obtain [(2S)-oxetan-2-yl]methanol (49.2 g, yield 90%).

[0079] NMR data of [(2S)-oxetan-2-yl]methanol: 1 HNMR (300MHz, CDCl3): δ4.91(1H,m), δ4.68(1H,m), δ4.51(1H,m), δ3.70(1H,m), δ3.61(1H,m), δ3.08(1H,m), δ2.60(2H,m).

[0080] (4) Add 1000.0 mL of dichloromethane, 100.0 g (1.13 mol, 1.00 equ.) of [(2S)-oxetan-2-yl]methanol, 205.8 g (2.03 mol, 1.80 equ.) of triethylamine and 258.5 g (1.36 mol, 1.20 equ.) of p-toluenesulfonyl chloride to a reaction flask, mix well, and then esterify at 25° C. for 15 h. Add 500.0 mL of water and stir for 30 min. Let stand. The phases were separated, and the obtained organic phase was washed with 500.0 mL of 1 mol / L aqueous hydrochloric acid solution, 500.0 mL of saturated sodium bicarbonate solution and 500.0 mL of water in sequence. The obtained organic phase was dried over 20.0 g of anhydrous sodium sulfate and then filtered, concentrated to 100.0 mL, and recrystallized from 300.0 mL of methyl tert-butyl ether to obtain [(2S)-oxetan-2-yl]methyl p-toluenesulfonate (221.8 g, yield was 81%).

[0081] NMR data of [(2S)-oxetan-2-yl]methyl p-toluenesulfonate: 1HNMR (300MHz, CDCl3): δ7.76 (2H, d, J = 8.1Hz), δ7.30 (2H, d, J = 8.1Hz), δ4.86 (1H, m), δ4.52(1H,m), δ4.43(1H,m), δ4.10(2H,m), δ2.64(1H,m), δ2.49(1H,m), δ2.39(3H,s).

[0082] (5) Add 700.0 mL of N,N-dimethylformamide, 100.0 g (0.41 mol, 1.00 equ.) of [(2S)-oxetan-2-yl]methyl p-toluenesulfonate and 76.4 g (0.41 mol, 1.00 equ.) of potassium phthalimide to a reaction flask and mix well. Heat to 115° C. and perform the first substitution reaction for 3 h. Cool to room temperature, add 700.0 mL of water and 500.0 mL of ethyl acetate and stir. Stir for 30 min, let stand for phase separation, and obtain an organic phase and an aqueous phase. The obtained aqueous phase is extracted twice with 250.0 mL of ethyl acetate, respectively. The organic phases are combined and washed with 500.0 mL of saturated brine, dried over 20.0 g of anhydrous sodium sulfate, filtered, and the obtained filtrate is concentrated to 200.0 mL, and then 500.0 mL of petroleum ether is added dropwise for recrystallization to obtain (2S)-oxetanylmethyl-isoindole-1,3-dione (62.3 g, yield is 70%).

[0083] NMR data of (2S)-oxetanylmethyl-isoindole-1,3-dione: 1 H NMR (300MHz, CDCl3): δ7.86(2H,m), δ7.73(2H,m), δ5.07(1H,m), δ4.64(2H,m), δ4.04(1 H,dd,J=6.3Hz,14.1Hz), δ3.92(1H,dd,J=5.4Hz,14.1Hz), δ2.73(1H,m), δ2.54(1H,m).

[0084] (6) Add 500.0 mL of water and 100.0 g (0.46 mol, 1.00 equ.) of (2S)-oxetanylmethyl-isoindole-1,3-dione to the reaction flask and mix well. Then, add 45.0 g (0.72 mol, 1.50 equ.) of 80 wt% hydrazine hydrate aqueous solution dropwise. Perform the second substitution reaction at 45° C. for 35 h. After cooling to 5° C., filter the solution. The solution was adjusted to pH 4 and extracted with 200.0 mL of dichloromethane. The pH value of the aqueous phase was adjusted to 14 with a 4 mol / L sodium hydroxide aqueous solution and extracted 5 times with 200.0 mL of dichloromethane. The organic phases were combined and dried over 30.0 g of anhydrous sodium sulfate and filtered. The filtrate was concentrated to 200 mL and then distilled at 40° C. for 5 h to obtain (S)-oxetane-2-methylamine (28.0 g, yield 70%).

[0085] NMR data of (S)-oxetane-2-methylamine: 1 H NMR (300MHz, CDCl3): δ4.78(1H,m), δ4.66(1H,m), δ4.47(1H,m), δ2.86(2H,d,J=5.1Hz), δ2.59(1H,m), δ2.43(1H,m), δ1.62(2H,brs). MS(ESI + , m / z)=88.2.

[0086] Example 2

[0087] Scale-up

[0088] (1) Add 10.0 kg (134.99 mol, 1.00 equ.) of (R)-(+)-glycidol and 19.5 kg (269.98 mol, 2.00 equ.) of ethyl vinyl ether to a reaction flask, cool to 5° C., add 256.8 g (1.35 mol, 0.01 equ.) of p-toluenesulfonic acid hydrate in batches, and react at 25° C. for 4 h. Add 27.0 kg of saturated aqueous sodium bicarbonate solution and stir for 1 h. Allow to stand and separate the liquids. Dry the obtained organic phase with 2.0 kg of anhydrous sodium sulfate and filter. Concentrate the obtained filtrate to constant weight to obtain 18.0 kg of (2S)-2-[(1-ethoxyethoxy)methyl]ethylene oxide. Yield: 91%.

[0089] NMR data of (2S)-2-[(1-ethoxyethoxy)methyl]oxirane: 1HNMR (300MHz, CDCl3): δ4.70(1H,m), δ3.60(2H,m), δ3.40(2H,m), δ3.08(1H,m), δ2.74(1H,t ,J=4.8Hz), δ2.56(1H,dd,J=2.4,5.1Hz), δ1.26(3H,d,J=2.4,5.1Hz), 1.15(3H,t,J=7.2Hz).

[0090] (2) 342.0 L of tert-butanol, 27.6 kg (246.28 mol, 2.00 equ.) of potassium tert-butoxide and 54.2 kg (246.28 mol, 2.00 equ.) of trimethylsulfoxide iodide were added to a reaction flask, and the temperature was raised to 65° C. and stirred for 1 h; 18.0 kg (123.14 mol, 1.00 equ.) of (2S)-2-[(1-ethoxyethoxy)methyl]oxirane was dissolved in 18 L of tert-butanol to obtain (2S)-2-[(1-ethoxyethoxy)methyl]oxirane. ] ethylene oxide solution; at 65°C, add (2S)-2-[(1-ethoxyethoxy)methyl]ethylene oxide solution dropwise and heat for ring expansion reaction for 15 hours, filter, concentrate the filtrate to 20L, add 45.0L of water, extract with 18.0L of methyl tert-butyl ether, wash the organic phase with 27.0L of saturated brine, dry with 3.6kg of anhydrous sodium sulfate, filter, and concentrate to constant weight to obtain (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide (17.8kg, yield is 90%).

[0091] NMR data of (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide: 1 HNMR (300MHz, CDCl3): δ5.00(1H,m), δ4.86(1H,m), δ4.72(1H,m), δ4.62(1H,m), δ3.74(3H,m), δ3.56(1H,m), δ1.40(3H,m), δ1.26(1H,t,J=7.2Hz).

[0092] (3) 45.9 L of water, 5.3 kg (88.07 mol, 0.83 equ.) of acetic acid and 17.0 kg (106.11 mol, 1.00 equ.) of (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide were added to a reaction flask, and the reaction was carried out at 25° C. for 15 h with acid-catalyzed hydrolysis. 7.6 kg of sodium bicarbonate was added in 5 portions to adjust the pH value to 7, and then 25.5 kg of potassium carbonate was added to adjust the pH value to 12. The mixture was extracted with dichloromethane, and the obtained organic phase was dried over 3.4 kg of anhydrous sodium sulfate and filtered. The obtained filtrate was concentrated to constant weight to obtain [(2S)-oxetan-2-yl]methanol (8.3 kg, yield: 89%).

[0093] NMR data of [(2S)-oxetan-2-yl]methanol: 1 HNMR (300MHz, CDCl3): δ4.91(1H,m), δ4.68(1H,m), δ4.51(1H,m), δ3.70(1H,m), δ3.61(1H,m), δ3.08(1H,m), δ2.60(2H,m).

[0094] (4) Add 80.0 L of dichloromethane, 8.0 kg (90.80 mol, 1.00 equ.) of [(2S)-oxetan-2-yl]methanol, 16.5 kg (163.44 mol, 1.80 equ.) of triethylamine and 20.8 kg (108.96 mol, 1.20 equ.) of p-toluenesulfonyl chloride to the reaction flask, mix well, and then esterify for 15 h at 25 °C. Then add 40.0 L of water and stir. The reaction mixture was stirred for 30 minutes, and the phases were separated by standing. The organic phase was washed with 40.0 L of 1 mol / L hydrochloric acid aqueous solution, 40.0 L of saturated sodium bicarbonate aqueous solution and 40.0 L of water in sequence, dried over 3.2 kg of anhydrous sodium sulfate, filtered, concentrated to 10.0 L, and recrystallized from 24.0 L of methyl tert-butyl ether to obtain [(2S)-oxetan-2-yl]methyl p-toluenesulfonate (18.0 kg, yield 82%).

[0095] NMR data of [(2S)-oxetan-2-yl]methyl p-toluenesulfonate: 1 HNMR (300MHz, CDCl3): δ7.76 (2H, d, J = 8.1Hz), δ7.30 (2H, d, J = 8.1Hz), δ4.86 (1H, m), δ4.52(1H,m), δ4.43(1H,m), δ4.10(2H,m), δ2.64(1H,m), δ2.49(1H,m), δ2.39(3H,s).

[0096] (5) Add 126.0 L of N,N-dimethylformamide, 18.0 kg (74.38 mol, 1.00 equ.) of [(2S)-oxetan-2-yl]methyl p-toluenesulfonate and 13.8 kg (74.38 mol, 1.00 equ.) of potassium phthalimide to the reaction flask and mix well. Heat to 115° C. and perform the first substitution reaction for 3 h. Cool to room temperature and add 126.0 L of water and 90.0 L of acetic acid. The ethyl ester was stirred for 30 min, and allowed to stand for phase separation to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with 45.0 L of ethyl acetate, respectively. The organic phases were combined and washed with 90.0 L of saturated brine, dried over 3.6 kg of anhydrous sodium sulfate, and filtered. The filtrate was concentrated to 40.0 L, and then 90.0 L of petroleum ether was added dropwise for recrystallization to obtain (2S)-oxetanylmethyl-isoindole-1,3-dione (10.8 kg, yield was 67%).

[0097] NMR data of (2S)-oxetanylmethyl-isoindole-1,3-dione: 1 H NMR (300MHz, CDCl3): δ7.86(2H,m), δ7.73(2H,m), δ5.07(1H,m), δ4.64(2H,m), δ4.04(1 H,dd,J=6.3Hz,14.1Hz), δ3.92(1H,dd,J=5.4Hz,14.1Hz), δ2.73(1H,m), δ2.54(1H,m).

[0098] (6) 50.0 L of water and 10.0 kg (46.08 mol, 1.00 equ.) of (2S)-oxetanylmethyl-isoindole-1,3-dione were added to the reaction flask and mixed evenly. Then, 4.5 kg (69.12 mol, 1.50 equ.) of 80 wt% hydrazine hydrate aqueous solution was added dropwise. The second substitution reaction was carried out at 45° C. for 35 h. The mixture was cooled to 5° C. and filtered. The pH value of the obtained filtrate was adjusted to 4 with 35 wt.% hydrochloric acid aqueous solution and extracted with 20.0 L of dichloromethane. The obtained aqueous phase was adjusted to pH 14 with 4 mol / L sodium hydroxide aqueous solution and extracted with 20.0 L of dichloromethane for 6 times. The organic phases were combined and dried with 3.0 kg of anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated to 20 L. Then, it was distilled at 40° C. for 15 h to obtain the product (S)-oxetane-2-methylamine (3.0 kg, yield 75%).

[0099] NMR data of (S)-oxetane-2-methylamine: 1H NMR (300MHz, CDCl3): δ4.78(1H,m), δ4.66(1H,m), δ4.47(1H,m), δ2.86(2H,d,J=5.1Hz), δ2.59(1H,m), δ2.43(1H,m), δ1.62(2H,brs). MS(ESI + , m / z)=88.2.

[0100] Example 3

[0101]

[0102] Laboratory preparation

[0103] (1) Add 60.0 g (0.68 mol, 1.00 equ.) of (S)-(-)-glycidol and 98.1 g (1.36 mol, 2.00 equ.) of ethyl vinyl ether to a reaction flask, cool to 5°C, add 1.29 g (0.0068 mol, 0.01 equ.) of p-toluenesulfonic acid hydrate three times, and react at 25°C for 4 h. Add 162.0 g of saturated aqueous sodium bicarbonate solution and stir for 1 h. Let stand and separate the liquids. Dry the obtained organic phase with 12.0 g of anhydrous sodium sulfate and filter. Concentrate the obtained filtrate to constant weight to obtain (2R)-2-[(1-ethoxyethoxy)methyl]ethylene oxide (84.5 g, yield 85%).

[0104] NMR data of (2R)-2-[(1-ethoxyethoxy)methyl]oxirane: 1 HNMR (300MHz, CDCl3): δ4.77(1H,m), δ3.73(2H,m), δ3.51(2H,m), δ3.16(1H,m), δ2.81(1H,t ,J=4.8Hz), δ2.65(1H,dd,J=2.4,5.1Hz), δ1.29(3H,d,J=2.4,5.1Hz), 1.21(3H,t,J=7.2Hz).

[0105] (2) Add 950.0 mL of tert-butanol, 76.8 g (0.68 mol, 2.00 equ.) of potassium tert-butoxide and 150.8 g (0.68 mol, 2.00 equ.) of trimethylsulfoxide iodide to a reaction flask, and heat to 65° C. and stir for 1 h; dissolve 50.0 g (0.34 mol, 1.00 equ.) of (2R)-2-[(1-ethoxyethoxy)methyl]oxirane in 50.0 mL of tert-butanol to obtain a (2R)-2-[(1-ethoxyethoxy)methyl]oxirane solution; At 65°C, add (2R)-2-[(1-ethoxyethoxy)methyl]ethylene oxide solution dropwise, and then continue the ring expansion reaction at 65°C for 15 hours. Filter, concentrate the filtrate to 50 mL, add 125.0 mL of water, extract with 100.0 mL of methyl tert-butyl ether, wash the organic phase with 75.0 mL of saturated brine, then dry with 10.0 g of anhydrous sodium sulfate, filter, and concentrate to constant weight to obtain (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide (50.6 g, yield is 93%).

[0106] NMR data of (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide: 1 HNMR (300MHz, CDCl3): δ4.93(1H,m), δ4.80(1H,m), δ4.65(1H,m), δ4.56(1H,m), δ3.67(3H,m), δ3.49(1H,m), δ1.35(3H,m), δ1.21(1H,t,J=7.2Hz).

[0107] (3) 135.0 mL of water, 15.6 g (0.26 mol, 0.83 equ.) of acetic acid and 50.0 g (0.31 mol, 1.00 equ.) of (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide were added to the reaction flask, and the acid-catalyzed hydrolysis reaction was carried out at 25° C. for 15 h. 22.5 g of sodium bicarbonate was added three times to adjust the pH value to 7, and then 75.0 g of potassium carbonate was added to adjust the pH value to 12. The mixture was extracted with dichloromethane, and the obtained organic phase was dried over 10.0 g of anhydrous sodium sulfate and filtered. The obtained filtrate was concentrated to constant weight to obtain [(2R)-oxetan-2-yl]methanol (24.7 g, yield 90%).

[0108] NMR data of [(2R)-oxetan-2-yl]methanol: 1 HNMR (300MHz, CDCl3): δ4.96(1H,m), δ4.71(1H,m), δ4.50(1H,m), δ3.73(1H,m), δ3.65(1H,m), δ3.10(1H,m), δ2.65(2H,m).

[0109] (4) Add 500.0 mL of dichloromethane, 50.0 g (0.56 mol, 1.00 equ.) of [(2R)-oxetan-2-yl]methanol, 102.9 g (1.02 mol, 1.80 equ.) of triethylamine and 129.2 g (0.68 mol, 1.20 equ.) of p-toluenesulfonyl chloride to the reaction flask, mix well, and then esterify at 25°C for 15 h. Add 250.0 mL of water and stir for 30 min. The phases were separated, and the obtained organic phase was washed with 250.0 mL of 1 mol / L aqueous hydrochloric acid solution, 250.0 mL of saturated sodium bicarbonate aqueous solution and 250.0 mL of water in sequence. The obtained organic phase was dried over 10.0 g of anhydrous sodium sulfate and then filtered, concentrated to 50.0 mL, and recrystallized from 150.0 mL of methyl tert-butyl ether to obtain [(2R)-oxetan-2-yl]methyl p-toluenesulfonate (113.8 g, yield 84%).

[0110] NMR data of [(2R)-oxetan-2-yl]methyl p-toluenesulfonate: 1 HNMR (300MHz, CDCl3): δ7.83 (2H, d, J = 8.1Hz), δ7.36 (2H, d, J = 8.1Hz), δ4.93 (1H, m), δ4.60(1H,m), δ4.49(1H,m), δ4.16(2H,m), δ2.73(1H,m), δ2.57(1H,m), δ2.39(3H,s).

[0111] (5) Add 350.0 mL of N,N-dimethylformamide, 50.0 g (0.20 mol, 1.00 equ.) of [(2R)-oxetan-2-yl]methyl p-toluenesulfonate and 38.2 g (0.20 mol, 1.00 equ.) of potassium phthalimide to the reaction flask and mix well. Heat to 115° C. and carry out the first substitution reaction for 3 h. Cool to room temperature, add 350.0 mL of water and 250.0 mL of ethyl acetate and stir. The mixture was stirred for 30 min, and allowed to stand for phase separation to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with 125.0 mL of ethyl acetate, respectively. The organic phases were combined and washed with 250.0 mL of saturated brine, dried over 10.0 g of anhydrous sodium sulfate, and filtered. The filtrate was concentrated to 100.0 mL, and then 5250.0 mL of petroleum ether was added dropwise for recrystallization to obtain (2R)-oxetanylmethyl-isoindole-1,3-dione (31.7 g, yield was 73%).

[0112] NMR data of (2R)-oxetanylmethyl-isoindole-1,3-dione: 1H NMR (300MHz, CDCl3): δ7.86(2H,m), δ7.73(2H,m), δ5.07(1H,m), δ4.61(2H,m), δ4.07(1 H,dd,J=6.3Hz,14.1Hz), δ3.91(1H,dd,J=5.4Hz,14.1Hz), δ2.70(1H,m), δ2.57(1H,m).

[0113] (6) Add 250.0 mL of water and 50.0 g (0.23 mol, 1.00 equ.) of (2R)-oxetanylmethyl-isoindole-1,3-dione to the reaction flask and mix well. Then, add 22.5 g (0.36 mol, 1.50 equ.) of 80 wt% hydrazine hydrate aqueous solution dropwise. The second substitution reaction is carried out at 45° C. for 35 h, with intermediate control. After cooling to 5° C., filter the reaction mixture and purify the filtrate with 35 wt.% hydrochloric acid. The aqueous solution was adjusted to pH 4 and extracted with 100.0 mL of dichloromethane. The pH value of the aqueous phase was adjusted to 14 with a 4 mol / L sodium hydroxide aqueous solution and extracted 5 times with 100.0 mL of dichloromethane. The organic phases were combined and dried over 15.0 g of anhydrous sodium sulfate and filtered. The filtrate was concentrated to 100 mL and then distilled at 40° C. for 5 h to obtain (R)-oxetane-2-methylamine (14.8 g, yield was 74%).

[0114] NMR data of (R)-oxetane-2-methylamine: 1 H NMR (300MHz, CDCl3): δ4.61(1H,m), δ4.49(1H,m), δ4.36(1H,m), δ2.67(2H,d,J=5.1Hz), δ2.51(1H,m), δ2.41(1H,m), δ1.62(2H,brs). MS(ESI + , m / z)=88.2.

[0115] Example 4

[0116]

[0117] Laboratory preparation

[0118] (1) Add 60.0 g (0.68 mol, 1.00 equ.) of glycidol and 98.1 g (1.36 mol, 2.00 equ.) of ethyl vinyl ether to a reaction flask, cool to 5°C, add 1.3 g (0.0068 mol, 0.01 equ.) of p-toluenesulfonic acid hydrate three times, and react at 25°C for 4 h. Add 162.0 g of saturated aqueous sodium bicarbonate solution and stir for 1 h. Let stand and separate the liquids. Dry the obtained organic phase with 12.0 g of anhydrous sodium sulfate and filter. Concentrate the obtained filtrate to constant weight to obtain [2-(1-ethoxyethoxy)methyl]ethylene oxide (82.5 g, yield 83%).

[0119] NMR data of [2-(1-ethoxyethoxy)methyl]ethylene oxide: 1 H NMR (300MHz, CDCl3): δ4.70~4.77(1H,m), δ3.60~3.73(2H,m), δ3.40~3.51(2H,m), δ3.09~3.16(1H,m), δ2.74~2.81( 1H,t,J=4.8Hz), δ2.56~2.65(1H,dd,J=2.4,5.1Hz), δ1.26~1.29(3H,d,J=2.4,5.1Hz), 1.15~1.21(3H,t,J=7.2Hz).

[0120] (2) Add 950.0 mL of tert-butanol, 76.8 g (0.68 mol, 2.00 equ.) of potassium tert-butoxide and 150.8 g (0.68 mol, 2.00 equ.) of trimethylsulfoxide iodide to a reaction flask, and heat to 65° C. and stir for 1 h; dissolve 50.0 g (0.34 mol, 1.00 equ.) of [2-(1-ethoxyethoxy)methyl]oxirane in 50.0 mL of tert-butanol to obtain a [2-(1-ethoxyethoxy)methyl]oxirane solution; Add [2-(1-ethoxyethoxy)methyl]ethylene oxide solution dropwise at 5°C, and then continue the ring-expansion reaction at 65°C for 15 hours. Filter, concentrate the filtrate to 50.0 mL, add 125.0 mL of water, extract with 100.0 mL of methyl tert-butyl ether, wash the organic phase with 75.0 mL of saturated brine, then dry with 10.0 g of anhydrous sodium sulfate, filter, and concentrate to constant weight to obtain [2-(1-ethoxyethoxy)methyl]propylene oxide (51.2 g, yield is 94%).

[0121] NMR data of [2-(1-ethoxyethoxy)methyl]propylene oxide: 1H NMR (300MHz, CDCl3): δ4.93~5.00(1H,m), δ4.80~4.86(1H,m), δ4.65~4.72(1H,m), δ4.56~4.62(1 H,m), δ3.67~3.74(3H,m), δ3.49~3.56(1H,m), δ1.35~1.40(3H,m), δ1.21~1.26(1H,t,J=7.2Hz).

[0122] (3) 135.0 mL of water, 15.6 g (0.26 mol, 0.83 equ.) of acetic acid and 50.0 g (0.31 mol, 1.00 equ.) of [2-(1-ethoxyethoxy)methyl]propylene oxide were added to the reaction flask, and the acid-catalyzed hydrolysis reaction was carried out at 25° C. for 15 h. 22.5 g of sodium bicarbonate was added three times to adjust the pH value to 7, and then 75.0 g of potassium carbonate was added to adjust the pH value to 12. The mixture was extracted with dichloromethane, and the obtained organic phase was dried with 10.0 g of anhydrous sodium sulfate and filtered. The obtained filtrate was concentrated to constant weight to obtain (oxetan-2-yl)methanol (25.7 g, yield 94%).

[0123] NMR data of (oxetane-2-yl)methanol: 1 H NMR (300MHz, CDCl3): δ4.91~4.96(1H,m), δ4.68~4.71(1H,m), δ4.50~4.51(1H,m) , δ3.70~3.73(1H,m), δ3.61~3.65(1H,m), δ3.08~3.10(1H,m), δ2.60~2.65(2H,m).

[0124] (4) Add 500.0 mL of dichloromethane, 50.0 g (0.56 mol, 1.00 equ.) of (oxetan-2-yl)methanol, 102.9 g (1.02 mol, 1.80 equ.) of triethylamine and 129.2 g (0.68 mol, 1.20 equ.) of p-toluenesulfonyl chloride to the reaction flask, mix well, and then esterify for 15 h at 25 °C. Add 250.0 mL of water and stir for 30 min. The phases were separated, and the obtained organic phase was washed with 250.0 mL of 1 mol / L aqueous hydrochloric acid solution, 250.0 mL of saturated sodium bicarbonate solution and 250.0 mL of water in sequence. The obtained organic phase was dried over 10.0 g of anhydrous sodium sulfate and then filtered, concentrated to 50.0 mL, and recrystallized from 150.0 mL of methyl tert-butyl ether to obtain (oxetan-2-yl) methyl p-toluenesulfonate (115.3 g, yield 85%).

[0125] NMR data of (oxetane-2-yl)methyl p-toluenesulfonate:1 H NMR (300MHz, CDCl3): δ7.76~7.83 (2H,d,J=8.1Hz), δ7.30~7.36 (2H,d,J=8.1Hz), δ4.86~4.93 (1H,m), δ4.52~ 4.60(1H,m), δ4.43~4.49(1H,m), δ4.10~4.16(2H,m), δ2.64~2.73(1H,m), δ2.49~2.57(1H,m), δ2.39(3H,s).

[0126] (5) Add 350.0 mL of N,N-dimethylformamide, 50.0 g (0.20 mol, 1.00 equ.) of (oxetan-2-yl)methyl p-toluenesulfonate and 38.2 g (0.20 mol, 1.00 equ.) of potassium phthalimide to the reaction flask and mix well. Heat to 115°C and carry out the first substitution reaction for 3 h. Cool to room temperature, add 350.0 mL of water and 250.0 mL of ethyl acetate and stir. Stir for 30 min, let stand for phase separation, and obtain an organic phase and an aqueous phase. The obtained aqueous phase was extracted twice with 125.0 mL of ethyl acetate, respectively. The organic phases were combined and washed with 250.0 mL of saturated brine, dried over 10.0 g of anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated to 100.0 mL, and then 5250.0 mL of petroleum ether was added dropwise for recrystallization to obtain oxetanylmethyl-isoindole-1,3-dione (32.6 g, yield was 75%).

[0127] NMR data of oxetanylmethyl-isoindole-1,3-dione: 1 H NMR (300MHz, CDCl3): δ7.86(2H,m), δ7.73(2H,m), δ5.07(1H,m), δ4.61~4.64(2H,m), δ4.04~4.07(1H, dd,J=6.3Hz,14.1Hz), δ3.91~3.92(1H,dd,J=5.4Hz,14.1Hz), δ2.70~2.73(1H,m), δ2.54~2.57(1H,m).

[0128] (6) Add 250.0 mL of water and 50.0 g (0.23 mol, 1.00 equ.) of oxetanemethyl-isoindole-1,3-dione to the reaction flask and mix well. Then, add 22.5 g (0.36 mol, 1.50 equ.) of 80 wt% hydrazine hydrate aqueous solution dropwise. The second substitution reaction is carried out at 45° C. for 35 h, and then cooled to 5° C. and filtered. The filtrate is adjusted to pH 4 with 35 wt.% hydrochloric acid aqueous solution, extracted with 100.0 mL of dichloromethane, and the aqueous phase is adjusted to pH 14 with 4 mol / L sodium hydroxide aqueous solution, extracted 5 times with 100.0 mL of dichloromethane, and the organic phases are combined and dried with 15.0 g of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to 100 mL, and then distilled at 40° C. for 5 h to obtain oxetane-2-methylamine (15.2 g, yield 76%).

[0129] NMR data of oxetane-2-methylamine: 1 H NMR (300MHz, CDCl3): δ4.61~4.78(1H,m), δ4.49~4.66(1H,m), δ4.36~4.47(1H,m), δ2 .67~2.86(2H,d,J=5.1Hz), δ2.51~2.59(1H,m), δ2.41~2.43(1H,m), δ1.62(2H,brs). MS(ESI + , m / z)=88.2.

[0130] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing oxetane-2-methylamine, characterized in that: The following steps are involved: (1) mixing [2-(1-ethoxyethoxy)methyl]propylene oxide and an acid solution, and performing an acid-catalyzed hydrolysis reaction to obtain (oxetan-2-yl)methanol; the [2-(1-ethoxyethoxy)methyl]propylene oxide is selected from (2S)-[2-(1-ethoxyethoxy)methyl]propylene oxide, (2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide or (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide; the molar ratio of the [2-(1-ethoxyethoxy)methyl]propylene oxide to the acid in the acid solution is 1:0.8-2; the temperature of the acid-catalyzed hydrolysis reaction is 20-30° C., and the time is 15-20 hours; The glycidyl compound and vinyl ethyl ether are pre-mixed and then cooled to 0-10° C., and then p-toluenesulfonic acid is added and mixed, and an addition reaction is carried out at 20-30° C. to obtain 2-[(1-ethoxyethoxy)methyl]ethylene oxide; the glycidyl compound is selected from (R)-(+)-glycidyl, (S)-(-)-glycidyl or glycidyl; when the glycidyl compound is (R)-(+)-glycidyl, (2S)-2-[(1-ethoxyethoxy)methyl]ethylene oxide is prepared. Ethane, when the glycidyl compound is (S)-(-)-glycidyl, (2R)-2-[(1-ethoxyethoxy)methyl]ethylene oxide is prepared, when the glycidyl compound is glycidyl, (2S,2R)-[2-(1-ethoxyethoxy)methyl]propylene oxide is prepared, the p-toluenesulfonic acid is used in the form of p-toluenesulfonic acid hydrate, and the molar ratio of the glycidyl compound, vinyl ethyl ether and p-toluenesulfonic acid is 1:2-5:0.01-0.02; Premixing potassium tert-butoxide, trimethyl sulfoxide iodide and part of alcohol solvent to obtain a premixed solution; mixing 2-[(1-ethoxyethoxy)methyl]ethylene oxide and the remaining alcohol solvent to obtain a 2-[(1-ethoxyethoxy)methyl]ethylene oxide solution; dropping the 2-[(1-ethoxyethoxy)methyl]ethylene oxide solution into the premixed solution, and performing a ring expansion reaction at 60-70° C. to obtain [2-(1-ethoxyethoxy)methyl]propylene oxide; the volume of the part of alcohol solvent is 2-10% of the total volume of the alcohol solvent, and the molar ratio of the 2-[(1-ethoxyethoxy)methyl]ethylene oxide, potassium tert-butoxide and trimethyl sulfoxide iodide is 1:2-3:2-3; (2) mixing the (oxetane-2-yl)methanol, p-toluenesulfonyl chloride, triethylamine and chloroalkane solvent, and performing an esterification reaction to obtain (oxetane-2-yl)methyl p-toluenesulfonate; the molar ratio of the (oxetane-2-yl)methanol, p-toluenesulfonyl chloride and triethylamine is 1:1.2-2:1.8-2.5; the temperature of the esterification reaction is 20-30°C, and the time is 15-20 hours; (3) mixing the (oxetane-2-yl) methyl p-toluenesulfonate, a phthalamide compound and an amide solvent, and performing a first substitution reaction to obtain oxetane methyl-isoindole-1,3-dione; the phthalamide compound is selected from one or more of phthalimide and / or phthalimide salt; the molar ratio of the (oxetane-2-yl) methyl p-toluenesulfonate to the phthalamide compound is 1:1 to 1.5; the temperature of the first substitution reaction is 110 to 120°C, and the time is 3 to 5 hours; (4) mixing the oxetane methyl-isoindole-1,3-dione, hydrazine hydrate and water to carry out a second substitution reaction to obtain oxetane-2-methylamine; the molar ratio of the oxetane methyl-isoindole-1,3-dione to hydrazine hydrate is 1:1.5-3; the temperature of the second substitution reaction is 40-50°C and the time is 35-40h; In step (1), the acid-catalyzed hydrolysis reaction further includes post-treatment, wherein the post-treatment includes: adjusting the pH value of the reaction solution obtained by the acid-catalyzed hydrolysis reaction to 11 to 12, extracting, and drying and concentrating the obtained organic phase to constant weight; In step (2), the esterification reaction further includes post-treatment, and the post-treatment includes: adding water to the reaction solution obtained by the esterification reaction to separate the phases, washing the obtained organic phase with hydrochloric acid solution, saturated sodium bicarbonate aqueous solution and water in sequence, and then drying, concentrating and recrystallizing; In step (3), the first substitution reaction further includes post-treatment, wherein the post-treatment includes: cooling the reaction solution obtained by the first substitution reaction to room temperature, adding water and an organic solvent to separate phases to obtain an aqueous phase and an organic phase; subjecting the aqueous phase to organic extraction, and sequentially washing the organic phase obtained by the organic extraction and the organic phase obtained by the phase separation with saturated brine, drying, concentrating and recrystallizing; In step (4), the second substitution reaction also includes post-treatment, and the post-treatment includes: cooling the reaction solution obtained by the second substitution reaction and filtering it, adjusting the pH value of the obtained filtrate to 4-5 and then pre-extracting it, adjusting the pH value of the obtained aqueous phase to 13-14 and then extracting it, and drying, concentrating and distilling the obtained organic phase in sequence.

2. The preparation method according to claim 1, characterized in that: In step (1), the acid solution is selected from one or more of acetic acid solution, formic acid solution, propionic acid solution, butyric acid solution, hydrochloric acid solution and sulfuric acid solution.

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