Synthesis method of (2R, 6S)-4-tertiary butyl-2-methyl-6-(hydroxymethyl) morpholine-2, 4-dicarboxylate

Abstract

The invention discloses a synthesis method of (2R, 6S)-4-tert-butyl-2-methyl6-(hydroxymethyl) morpholine-2, 4-dicarboxylate, which comprises the following steps: by taking a compound (S)-benzyloxymethyl ethylene oxide as a raw material, carrying out a nucleophilic ring-opening reaction of amine and ethylene oxide, a nucleophilic substitution cyclization reaction, a one-pot series deprotection reaction and a protection reaction, thereby obtaining the (2R, 6S)-4-tert-butyl-2-methyl6-(hydroxymethyl) morpholine-2, 4-dicarboxylate. And the (2R, 6S)-4-tertiary butyl 2-methyl 6-(hydroxymethyl) morpholine-2, 4-dicarboxylate is obtained through the three steps of reaction. The synthesis method has the advantages of low cost, mild reaction conditions, simple and efficient operation, simple post-treatment and purification, ideal yield and accurate stereoselectivity control, and provides a potential route for large-scale production of the target compound (2R, 6S)-4-tertiary butyl-2-methyl6-(hydroxymethyl) morpholine-2, 4-dicarboxylate.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester. Background Technology

[0002] Morpholine compounds are an important class of organic compounds with wide applications in life sciences, medicine, and chemistry. For example, 4-tert-butyl-2-ethyl(6S)-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester (CAS No. 1809209-32-2) is used as a key intermediate in the synthesis of 2,6-morpholine derivatives in patent US2017 / 217986. These 2,6-morpholine derivatives can be used to inhibit HIV protease, inhibit HIV replication, prevent HIV infection, and treat HIV. Infection and prevention, treatment and delay of AIDS onset; (2R,6S)-4-(tert-butyloxycarbonyl)-6-(methoxymethyl)morpholine-2-carboxylic acid (CAS No. 1581749-10-1) is used as a key building block in the synthesis of renin inhibitors in patent US2015 / 232459; 4-tert-butyl-2-methyl-2-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester (CAS No. 1312815-10-3) is used as an important building block in the synthesis of MK2 inhibitors in patent WO2011 / 073119, which can be used to treat immune diseases, autoimmune diseases, inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases or proliferative diseases.

[0003] Given the significant economic potential of morpholine compounds, (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester, as one of these compounds, also possesses high economic viability. Currently, no synthetic route for (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester has been reported. Therefore, further research into its synthetic method will not only benefit the development of this compound but also contribute to the development and utilization of morpholine compounds in general. Summary of the Invention

[0004] To address the aforementioned problems in the existing technology, the present invention aims to provide a method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester. The synthesis process is low in cost, has mild reaction conditions, is simple and efficient, has simple post-processing and purification, and achieves ideal yield.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: This invention provides a method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester, and the synthetic route of the method is as follows: Specifically, it includes the following steps: (1) Compound 1, namely (S)-benzyloxymethyl ethylene oxide, was added to the reaction vessel, followed by benzylamine. After the addition was complete, the reaction was carried out at room temperature for 8-20 h. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 2, namely (S)-1-(benzylamino)-3-(benzyloxy)prop-2-ol.

[0006] (2) Compound 2 was added to the reaction vessel, followed by methyl 2-chloroacrylate, and the reaction was carried out at room temperature for 8-20 h. Organic solvent I was then added, and the temperature was lowered to -50 ℃ to -20 ℃. Then, alkali was added. After the addition was complete, the reaction was carried out at -50 ℃ to -20 ℃ for 1-6 h. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 3, namely methyl(2R,6S)-4-benzyl-6-((benzyloxy)methyl)morpholino-2-carboxylic acid ester.

[0007] (3) Compound 3 was added to the reaction vessel, followed by di-tert-butyl dicarbonate, organic solvent II, and palladium hydroxide / carbon. The mixture was stirred at room temperature for 8-20 h under a hydrogen atmosphere. After the reaction was completed, the resulting reaction solution was post-treated to obtain the target compound 4, namely (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester.

[0008] Preferably, in step (1), the molar ratio of compound 1 to benzylamine is 1:1.5~6.

[0009] Preferably, in step (1), the post-processing procedure includes: After the reaction was completed, the reaction solution was purified to obtain compound 2, namely (S)-1-(benzylamino)-3-(benzyloxy)prop-2-ol.

[0010] Preferably, in step (1), the purification method is selected from one or more of column chromatography, distillation, pulping or recrystallization.

[0011] Preferably, in step (2), the alkali is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, potassium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, and lithium bis(trimethylsilyl)amino.

[0012] Preferably, in step (2), the organic solvent I is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, and n-hexane.

[0013] Preferably, in step (2), the molar ratio of compound 2 and methyl 2-chloroacrylate is 1:1.0~3.0.

[0014] Preferably, in step (2), the molar ratio of compound 2 to the base is 1:1.0~2.0.

[0015] Preferably, in step (2), the mass-to-volume ratio of compound 2 to organic solvent I is 1:5~40 g / mL.

[0016] Preferably, in step (2), the post-processing procedure includes: After the reaction was complete, an alkaline aqueous solution was added, and the mixture was extracted with organic solvent III. The organic phases were combined, dried, and concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain compound 3, namely methyl(2R,6S)-4-benzyl-6-((benzyloxy)methyl)morpholino-2-carboxylic acid ester.

[0017] Preferably, in step (2), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0018] Preferably, in step (2), the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, and potassium carbonate solution.

[0019] Preferably, in step (2), the purification method is selected from one or more of column chromatography, distillation, pulping or recrystallization.

[0020] Preferably, in step (3), the molar ratio of compound 3 and ditert-butyl dicarbonate is 1:1.0~1.3.

[0021] Preferably, in step (3), the mass ratio of compound 3 to palladium hydroxide / carbon is 1:0.03~0.2.

[0022] Preferably, in step (3), the mass-to-volume ratio of compound 3 to organic solvent II is 1:5~40 g / mL.

[0023] Preferably, in step (3), the post-processing procedure includes: After the reaction was complete, the mixture was filtered, the filtrate was collected, and the solution was evaporated to dryness to obtain the target compound 4, namely (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester. Using (S)-benzyloxymethyl ethylene oxide as a starting material, the method involves a three-step reaction: nucleophilic ring-opening reaction of an ethylene oxide derivative with an amine, intramolecular nucleophilic substitution cyclization reaction, and a one-pot tandem deprotection and protection reaction to obtain (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester. This synthetic method offers significant advantages, including low cost, mild reaction conditions, simple and efficient operation, easy post-processing and purification, ideal yield, and precise stereoselectivity control. It provides a potential route for the process production of the target compound 2,6-bis(2-pyridyl)-4(1H)-pyridone. Attached Figure Description

[0025] Figure 1 The image shows the 1H NMR spectrum of compound 4 from Example 1. Detailed Implementation

[0026] To more fully understand and demonstrate the technical solutions, objectives, and advantages of the present invention, the technical effects produced by the present invention will be further described in detail and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. It should be noted that other embodiments obtained by those skilled in the art without departing from the concept of the present invention are all within the protection scope of the present invention.

[0027] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0028] Example 1 This embodiment provides a method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester. The synthetic route is as follows:

[0029] The specific steps are as follows: (1) Compound 1, namely (S)-benzyloxymethyl ethylene oxide (500.00 g, 3.04 mol, 1.00 eq), was added to a 3L three-necked flask, followed by benzylamine (1.50 kg, 14.01 mol, 4.60 eq). After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was complete, the mixture was directly distilled. The benzylamine was discharged at an internal temperature of 110 °C, and the product was discharged at 185 °C to obtain compound 2, namely (S)-1-(benzylamino)-3-(benzyloxy)prop-2-ol (826.00 g, 97% purity, 97% yield).

[0030] (2) Compound 2 (800.00 g, 2.95 mol, 1.00 eq) was added to a 20 L three-necked flask, followed by methyl 2-chloroacrylate (373.11 g, 3.10 mol, 1.05 eq), and the mixture was reacted at room temperature for 12 h. Then, tetrahydrofuran (5.0 L) was added, the temperature was lowered to -30 ℃, and potassium tert-butoxide solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF) was added. After the addition was complete, the mixture was kept at -30 ℃ and reacted for 2 h. After the reaction was complete, saturated sodium bicarbonate solution (2.0 L) was added, and the mixture was extracted twice with ethyl acetate (2.0 L × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 3, namely methyl(2R,6S)-4-benzyl-6-((benzyloxy)methyl)morpholino-2-carboxylic acid ester (weight 1.04 kg, purity 97%, yield 96%).

[0031] (3) Compound 3 (900.00 g, 2.53 mol, 1.00 eq) was added to a 20 L three-necked flask, followed by di-tert-butyl dicarbonate (580.26 g, 2.66 mol, 1.05 eq), methanol (8.0 L), and palladium hydroxide / carbon (72 g). The mixture was purged with hydrogen three times and stirred at room temperature for 12 h. After the reaction was complete, palladium hydroxide was filtered through diatomaceous earth, the filtrate was collected, and the solution was evaporated to dryness to obtain the target compound 4, namely (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester (CAS No.: 1951425-25-4, off-white solid, weight 689.00 g, purity 98%, yield 97%).

[0032] The 1H NMR spectrum of (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester is shown below. Figure 1 As shown, the obtained characterization data are as follows: .

[0033] Example 2 The reaction was carried out according to step (1), which was basically the same as in Example 1, except that 12h in step (1) was replaced with 8h, and the yield of compound 2 was 93%.

[0034] Example 3 The reaction was carried out according to step (1), which was basically the same as in Example 1, except that 12h in step (1) was replaced with 20h, and the yield of compound 2 was 97%.

[0035] Example 4 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that methyl 2-chloroacrylate (373.11 g, 3.10 mol, 1.05 eq) in step (2) was replaced with methyl 2-chloroacrylate (355.34 g, 2.95 mol, 1.00 eq), and the yield of compound 3 was 94%.

[0036] Example 5 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that methyl 2-chloroacrylate (373.11 g, 3.10 mol, 1.05 eq) in step (2) was replaced with methyl 2-chloroacrylate (533.01 g, 4.42 mol, 1.50 eq), and the yield of compound 3 was 96%.

[0037] Example 6 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that methyl 2-chloroacrylate (373.11 g, 3.10 mol, 1.05 eq) in step (2) was replaced with methyl 2-chloroacrylate (888.35 g, 7.37 mol, 2.50 eq), and the yield of compound 3 was 95%.

[0038] Example 7 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the potassium tert-butoxide solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF) in step (2) was replaced with sodium tert-butoxide solution (1.77 kmL, 3.54 mol, 1.20 eq, 2.00 M in THF). The yield of compound 3 was 95%.

[0039] Example 8 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the potassium tert-butoxide solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF) in step (2) was replaced with bis(trimethylsilyl)amino potassium solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF). The yield of compound 3 was 93%.

[0040] Example 9 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the potassium tert-butoxide solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF) in step (2) was replaced with potassium tert-butoxide solution (2.95 kmL, 2.95 mol, 1.00 eq, 1.00 M in THF). The yield of compound 3 was 92%.

[0041] Example 10 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the potassium tert-butoxide solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF) in step (2) was replaced with potassium tert-butoxide solution (3.83 kmL, 3.83 mol, 1.30 eq, 1.00 M in THF). The yield of compound 3 was 96%.

[0042] Example 11 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that the potassium tert-butoxide solution (3.24 kmL, 3.24 mol, 1.10 eq, 1.00 M in THF) in step (2) was replaced with potassium tert-butoxide solution (5.90 kmL, 5.90 mol, 2.00 eq, 1.00 M in THF). The yield of compound 3 was 95%.

[0043] Example 12 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that 5.0 L of tetrahydrofuran in step (2) was replaced with 5.0 L of 2-methyltetrahydrofuran, and the yield of compound 3 was 96%.

[0044] Example 13 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that 5.0 L of tetrahydrofuran in step (2) was replaced with 5.0 L of methyl tert-butyl ether, and the yield of compound 3 was 93%.

[0045] Example 14 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that -30 ℃ in step (2) was replaced with -50 ℃, and the yield of compound 3 was 90%.

[0046] Example 15 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that -30 ℃ in step (2) was replaced with -40 ℃, and the yield of compound 3 was 93%.

[0047] Example 16 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that -30 ℃ in step (2) was replaced with -20 ℃, and the yield of compound 3 was 94%.

[0048] Example 17 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that 2 h in step (2) was replaced with 6 h, and the yield of compound 3 was 96%.

[0049] Example 18 Using compound 3, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (3). The reaction steps were basically the same as in Example 1, except that methanol in step (3) was replaced with isopropanol, and the yield of compound 4 was 95%.

[0050] Example 19 Using compound 3, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (3). The reaction steps were basically the same as in Example 1, except that methanol in step (3) was replaced with tetrahydrofuran, and the yield of compound 4 was 96%.

[0051] Example 20 Using compound 3, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (3). The reaction steps were basically the same as in Example 1, except that Pd(OH)2 / C (72 g) in step (3) was replaced with Pd(OH)2 / C (27 g), and the yield of compound 4 was 88%.

[0052] Example 21 Using compound 3, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (3). The reaction steps were basically the same as in Example 1, except that Pd(OH)2 / C (72 g) in step (3) was replaced with Pd(OH)2 / C (45 g), and the yield of compound 4 was 92%.

[0053] Example 22 Using compound 3, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (3). The reaction steps were basically the same as in Example 1, except that Pd(OH)2 / C (72 g) in step (3) was replaced with Pd(OH)2 / C (90 g), and the yield of compound 4 was 97%.

[0054] Example 23 Using compound 3, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (3). The reaction steps were basically the same as in Example 1, except that Pd(OH)2 / C (72 g) in step (3) was replaced with Pd(OH)2 / C (180 g), and the yield of compound 4 was 96%.

[0055] Comparative Example 1 Using compound 2, which was prepared in the same manner as in Example 1, as a raw material, the reaction was carried out according to step (2). The reaction steps were basically the same as in Example 1, except that -30 °C in step (2) was replaced with 0 °C, and the yield of compound 3 was 71%.

[0056] As can be seen from Examples 1-3, in step (1), the reaction effect is basically optimal when the reaction time is 12 h.

[0057] As can be seen from Examples 1 and 4-6, in step (2), when the molar ratio of compound 2 to methyl 2-chloroacrylate is 1.0:(1.0~2.5), the yield of compound 3 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 2 to methyl 2-chloroacrylate is 1.0:1.05 and 1.0:1.50, and the reaction effect is better.

[0058] As can be seen from Examples 1 and 7-8, in step (2), potassium tert-butoxide (t-BuOK), sodium tert-butoxide (t-BuONa), and potassium bis(trimethylsilyl)amino (KHMDS) were used as bases for the reaction, and the reaction proceeded smoothly. The yield of compound 3 was high and not less than 90%. Among them, the reaction yield was the highest when t-BuOK was used as the base.

[0059] As can be seen from Examples 1 and 9-11, in step (2), when the molar ratio of compound 2 to potassium tert-butoxide is 1.0:(1.0~2.0), the yield of compound 3 is relatively high. Among them, the product yields are basically the same when the molar ratio of compound 2 to potassium tert-butoxide is 1.0:1.1 and 1.0:1.3, and the reaction effect is better.

[0060] As can be seen from Examples 1 and 12-13, in step (2), tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 3 was high in all cases. Among them, the reaction yield was highest when tetrahydrofuran and 2-methyltetrahydrofuran were used as solvents.

[0061] Based on Examples 1, 14-16, and Comparative Example 1, it can be seen that in step (2), when the temperature is lowered to the range of -50 ℃ to -20 ℃, the yield of compound 3 is relatively high, not less than 90%, and the reaction yield first increases and then decreases with the increase of temperature. The reaction yield is relatively high at -30 ℃. However, when the temperature of Comparative Example 1 is lowered to 0 ℃, the reaction effect is not good, and the yield of compound 3 is low, only 71%.

[0062] Based on Examples 1 and 17, it can be seen that in step (2), the reaction effect is basically optimal when the final reaction time is 2 hours.

[0063] As can be seen from Examples 1 and 18-19, in step (3), methanol, isopropanol and tetrahydrofuran were used as solvents for the reaction, and the reaction proceeded smoothly. The yield of compound 4 was high in all cases. Among them, the reaction yield was the highest when methanol was used as the solvent.

[0064] As can be seen from Examples 1 and 20-23, in step (3), when the mass ratio of compound 3:Pd(OH)2 / C is 1:0.03~0.2, the yield of compound 4 is relatively high. Among them, the product yields when the mass ratio of compound 3:Pd(OH)2 / C is 1:0.08 and 1:0.1 are basically the same, and the reaction effect is better.

[0065] The above are merely preferred embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester, characterized in that, The synthetic route of the synthetic method is as follows: 。 2. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 1, characterized in that, Includes the following steps: (1) Compound 1, namely (S)-benzyloxymethyl ethylene oxide, was added to the reaction vessel, followed by benzylamine. After the addition was complete, the reaction was carried out at room temperature for 8-20 h. After the reaction was completed, the resulting reaction solution was post-treated to obtain compound 2, namely (S)-1-(benzylamino)-3-(benzyloxy)prop-2-ol. (2) Add compound 2 to the reaction vessel, then add methyl 2-chloroacrylate, and react at room temperature for 8~20 h; then add organic solvent I, cool to -50 ℃~-20 ℃, then add alkali, and after the addition is complete, maintain the temperature at -50 ℃~-20 ℃ and react for 1~6 h; after the reaction is completed, the resulting reaction solution is post-treated to obtain compound 3, namely methyl(2R,6S)-4-benzyl-6-((benzyloxy)methyl)morpholino-2-carboxylic acid ester; (3) Add compound 3 to the reaction vessel, then add ditert-butyl dicarbonate, add organic solvent II, then add palladium hydroxide / carbon, and stir at room temperature for 8-20 h under hydrogen atmosphere; after the reaction is completed, the resulting reaction solution is post-treated to obtain target compound 4, namely (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester.

3. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 2, characterized in that, In step (1), The molar ratio of compound 1 to benzylamine is 1:1.5~6.

4. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 2, characterized in that, In step (1), The post-processing process includes: After the reaction was completed, the reaction solution was purified to obtain compound 2, namely (S)-1-(benzylamino)-3-(benzyloxy)prop-2-ol.

5. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 4, characterized in that, In step (1), The purification method is selected from one or more of column chromatography, distillation, pulping, or recrystallization.

6. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 2, characterized in that, In step (2), The base is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, potassium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, and lithium bis(trimethylsilyl)amino. The organic solvent I is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethyl ether, and n-hexane; The molar ratio of compound 2 and methyl 2-chloroacrylate is 1:1.0~3.0; The molar ratio of compound 2 to the base is 1:1.0~2.0; The mass-to-volume ratio of compound 2 to organic solvent I is 1:5~40 g / mL.

7. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 2, characterized in that, In step (2), The post-processing includes: after the reaction is complete, adding an alkaline aqueous solution, extracting with organic solvent III, combining the organic phases, drying the organic phases, concentrating under reduced pressure to obtain a crude product; purifying the crude product to obtain compound 3, namely methyl(2R,6S)-4-benzyl-6-((benzyloxy)methyl)morpholino-2-carboxylic acid ester.

8. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 7, characterized in that, In step (2), The organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane; The alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, and potassium carbonate solution; The purification method is selected from one or more of column chromatography, distillation, pulping, or recrystallization.

9. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 2, characterized in that, In step (3), The molar ratio of compound 3 to ditert-butyl dicarbonate is 1:1.0~1.3; The mass ratio of compound 3 to palladium hydroxide / carbon is 1:0.03~0.2; The mass-to-volume ratio of compound 3 to organic solvent II is 1:5~40 g / mL.

10. The method for synthesizing (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester according to claim 2, characterized in that, In step (3), The post-processing procedure includes: after the reaction is completed, filtering, collecting the filtrate, evaporating to dryness, and obtaining target compound 4, namely (2R,6S)-4-tert-butyl-2-methyl-6-(hydroxymethyl)morpholine-2,4-dicarboxylic acid ester.

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