A preparation method of chiral R or S 3-methylmorpholine

Abstract

The invention discloses a method for preparing chiral R or S 3-methylmorpholine. The method uses chiral S or R propylene oxide as a raw material, reacts it with Boc ethanolamine under the action of a Lewis acid, and then undergoes a Mitsunobu reaction to close the ring to obtain a chiral morpholine compound. The preparation method of the present invention shortens the steps, improves the total yield, and effectively reduces the unit cost.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing chiral R or S 3-methylmorpholine. Background Art

[0002] Chiral 3-substituted morpholines are an important class of intermediates used to prepare a variety of drug molecules or their key intermediates. Traditional methods for preparing chiral 3-substituted morpholines typically involve first reacting a substituted chiral amino alcohol with chloroacetyl chloride to form an amide. This is followed by a ring-closure reaction with a strong base, such as potassium tert-butoxide, sodium methoxide, or sodium hydride, to form a hexameric lactam. Finally, reduction with a reducing agent, such as lithium aluminum tetrahydride, yields the 3-substituted morpholine.

[0003] For example, the commonly used synthesis method for R-3-methylmorpholine is to react (2R)-2-aminopropanol and chloroacetyl chloride in an equimolar ratio in a solvent mixture of tetrahydrofuran and water at -10°C for 1 hour to obtain the corresponding chiral acyclic amide with a yield of 90%. The crude acyclic chiral amide is then subjected to an intramolecular cyclization reaction with potassium tert-butoxide in isopropanol-dichloromethane at 0°C for 2 hours to obtain the desired morpholinone intermediate. The obtained morpholinone is then reduced with lithium aluminum hydride to obtain (R)-3-methylmorpholine with a yield of 70%. However, this conventional method has disadvantages such as a relatively long number of steps, a relatively low overall yield, and insufficient chiral purity.

[0004] Therefore, it is of great significance to seek a new method for synthesizing chiral 3-methylmorpholine. Summary of the Invention

[0005] The invention provides a preparation method of chiral R or S 3-methylmorpholine. The preparation method shortens the steps, improves the total yield and effectively reduces the unit cost.

[0006] The technical solutions of the present invention are as follows:

[0007] A method for preparing chiral R or S 3-methylmorpholine comprises taking S or R chiral propylene oxide as a raw material, reacting it with N-tert-butyloxycarbonylethanolamine under the action of Lewis acid, and then performing a Mitsunobu reaction to ring-close to obtain a chiral morpholine compound.

[0008] In a preferred embodiment, the Lewis acid is selected from aluminum trichloride or boron trifluoride etherate.

[0009] In a preferred embodiment, the preparation method of the chiral R or S 3-methylmorpholine comprises the following steps:

[0010] (1) S or R propylene oxide reacts with N-tert-butyloxycarbonylethanolamine in the presence of Lewis acid to obtain compound 1;

[0011] (2) reacting compound 1 with hydrogen chloride to obtain compound 2;

[0012] (3) reacting compound 2 with diisopropyl azodicarboxylate to obtain chiral R or S 3-methylmorpholine;

[0013] Wherein, the compound 1 is

[0014]

[0015] The compound 2 is

[0016]

[0017] The reaction of compound 1 with hydrogen chloride can be carried out by passing hydrogen chloride gas into compound 1, preferably until a large amount of solids is formed, which is considered to be a good way to obtain compound 2. A large amount of solids generally refers to a large amount of solids that is clearly observable to the human eye, for example, exceeding 30%, 40%, or 50% of the reaction system.

[0018] As a preferred embodiment of the present invention, step (3) further comprises adding triphenylphosphine as a raw material.

[0019] As a preferred embodiment of the present invention, the reaction molar ratio of the S or R chiral propylene oxide to the N-tert-butyloxycarbonylethanolamine is 1:0.9-1.0; the reaction molar ratio of the S or R chiral propylene oxide to the Lewis acid is 1:15-20.

[0020] As a preferred embodiment of the present invention, the reaction molar concentration of the S or R chiral propylene oxide is 1.5-2.0 M / L; the reaction molar concentration of the N-tert-butyloxycarbonylethanolamine is 1.7-2.5 M / L; and the reaction molar concentration of the Lewis acid is 0.07-0.12 M / L.

[0021] As a preferred embodiment of the present invention, the reaction molar ratio of the compound 2 to the diisopropyl azodicarboxylate is 1:1-1.1, and the reaction molar ratio of the compound 2 to the triphenylphosphine is 1:1-1.1; the reaction molar concentration of the compound 2 is 0.4-1M / L; the reaction molar concentration of the triphenylphosphine is 0.4-1M / L; and the reaction molar concentration of the diisopropyl azodicarboxylate is 0.4-1M / L.

[0022] In one embodiment, in step (1), the reaction solvent may be 1,4-dioxane, in step (2), the reaction solvent may be tetrahydrofuran, and in step (3), the reaction solvent may be dichloromethane. The reaction solvent may be selected by a skilled person based on solubility, and the above is merely an example.

[0023] In one embodiment, in step (1), the reaction temperature is above 30 degrees, more preferably 30-50 degrees, and even more preferably 30-40 degrees.

[0024] In one embodiment, in step (1), the reaction time is 5-10 hours.

[0025] In a preferred embodiment, step (1) comprises: dissolving N-tert-butyloxycarbonylethanolamine in 1,4-dioxane, adding boron trifluoride etherate, heating the mixture to 30-50°C while stirring, adding S-propylene oxide or R-propylene oxide dropwise, and continuing stirring for 5-10 hours after the addition is complete. This order of addition and reaction conditions are suitable for the reaction of the present invention.

[0026] In a preferred embodiment, the step (1) further comprises: adding an alkaline reagent to the reaction system for neutralization, adding methanol dropwise under an ice bath, stirring at room temperature, then filtering, and concentrating to dryness.

[0027] In a preferred embodiment, the step (1) further comprises: adding an organic solvent, washing with water, drying the solid, concentrating to dryness under reduced pressure, and crystallizing with petroleum ether to obtain compound 1.

[0028] In a preferred embodiment, the alkaline reagent in step (1) is powdered potassium carbonate; and the solid drying is drying with magnesium sulfate.

[0029] As a preferred embodiment of the present invention, in step (2), the reaction of compound 1 with hydrogen chloride is carried out by passing hydrogen chloride gas into compound 1 for reaction. More preferably, step (2) comprises, for example, dissolving compound 1 in tetrahydrofuran, passing hydrogen chloride gas into the reaction under an ice bath until a large amount of solid appears, and after thin layer chromatography shows that the raw material disappears, cooling to -5 degrees to 0 degrees, stirring, then filtering, eluting the solid with acetone, and drying to obtain compound 2. The post-processing of the product is a conventional step, and those skilled in the art can also select other treatment methods that can achieve similar effects based on this teaching.

[0030] In a preferred embodiment, step (3) includes:

[0031] The reaction is carried out as follows: Compound 2 is dissolved in a solvent, an alkaline agent is added to adjust the pH value to alkaline, and after stirring at room temperature for several hours, the mixture is filtered, triphenylphosphine is added to the filtrate, and then diisopropyl azodicarboxylate is added dropwise. After the addition is complete, the mixture is stirred at room temperature for more than 10 hours, for example, stirring at room temperature overnight. In one embodiment, the solvent here is dichloromethane. In alternative embodiments, other suitable solvents can also be selected. In a preferred embodiment, the alkaline agent here is powdered potassium carbonate. The room temperature here is the usual meaning, which refers to about 25 degrees Celsius. Preferably, the addition of an alkaline agent to adjust the pH value to alkaline means adjusting the pH value to 8-9. The several hours here can be 2 hours, or other reaction times selected by the technician accordingly.

[0032] In a preferred embodiment, the step (3) further comprises:

[0033] Hydrochloric acid is added dropwise to the reaction system until the pH reaches 1-2, the liquid phase is separated, and the organic phase is discarded. The aqueous phase is extracted at least twice with an organic solvent and also discarded. After the aqueous phase is concentrated to half under reduced pressure, the temperature is lowered to 0-10 degrees Celsius, and an alkaline aqueous solution is slowly added dropwise to a pH of 13-14. The reaction mixture is allowed to stand and the liquid phase is separated. This process can remove by-products.

[0034] In a preferred embodiment, the step (3) further comprises:

[0035] After standing and separating the liquids, the upper dark organic layer is dried with solid, filtered, and the filtrate is distilled under reduced pressure to obtain R-3-methylmorpholine or S 3-methylmorpholine.

[0036] In a preferred embodiment, in step (3), the alkaline aqueous solution is a sodium hydroxide aqueous solution, and the solid drying is solid potassium hydroxide drying.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] The preparation method of chiral R or S 3-methylmorpholine provided by the present invention shortens the steps and improves the total yield, thereby effectively reducing the unit cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 It is a reaction process roadmap of a specific embodiment of the present invention;

[0040] Figure 2 It is the reaction process route diagram of process comparative example 1 in the prior art. DETAILED DESCRIPTION

[0041] The invention provides a preparation method of chiral R or S 3-methylmorpholine. The preparation method uses chiral S or R propylene oxide as a raw material, reacts it with Boc ethanolamine under the action of Lewis acid, and then performs Mitsunobu reaction to close the ring to obtain a chiral morpholine compound.

[0042] In a specific embodiment, the Lewis acid is selected from boron trifluoride ether complex, and the corresponding reaction process diagram is shown in FIG. Figure 1 .

[0043] In this document, the term "from a value to another value" is used as a summary to avoid listing all values ​​within the range. Therefore, a description of a specific numerical range encompasses any value within that range and any smaller numerical ranges defined by any value within that range, just as if the values ​​and smaller numerical ranges were explicitly stated in the specification.

[0044] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only intended to illustrate the present invention and are not intended to limit the scope of protection of the present invention. Improvements and adjustments made by those skilled in the art in accordance with the present invention in actual applications still fall within the scope of protection of the present invention.

[0045] Example 1

[0046] The preparation method of chiral R-3-methylmorpholine comprises:

[0047] first step:

[0048] N-tert-Butyloxycarbonylethanolamine (305.30 g, 1.90 mol) was dissolved in 1,4-dioxane (1 L), and boron trifluoride etherate (12.78 g, 0.09 mol) was added. The mixture was heated to 30°C with stirring, and S-propylene oxide (100 g, 1.72 mol) was slowly added dropwise. Stirring continued for 10 hours. Powdered potassium carbonate (712.80 g, 5.16 mol) was added, and 1 L of methanol was slowly added dropwise under an ice bath. Stirring was continued at room temperature for 1 hour and 20 minutes. The mixture was filtered and concentrated to dryness. Dichloromethane (1 L) was added, the mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to dryness. Compound 1 (white solid) (300 g) was crystallized from petroleum ether in a yield of 79.6%. In this example, powdered potassium carbonate was used instead of a conventional potassium carbonate solution. In addition, slowly adding methanol dropwise under an ice bath achieved better dispersion.

[0049] Step 2:

[0050] Compound 1 was dissolved in 1 L of tetrahydrofuran and hydrogen chloride gas was introduced under an ice bath until a large amount of solid appeared. After TLC showed the disappearance of the starting material, the temperature was lowered to 0°C, stirred for 40 minutes, filtered, and the solid was rinsed with 250 ml of acetone and dried to obtain 146.72 g of compound 2 (white powder) with a yield of 90%.

[0051] Step 3:

[0052] Compound 2 (146.72 g, 1.23 mol) was dissolved in 2 L of dichloromethane, and powdered potassium carbonate (339.83 g, 2.46 mol) was added. After stirring at room temperature for 2 hours, the mixture was filtered with suction. Triphenylphosphine (322.95 g, 1.23 mol) was added to the filtrate, and then diisopropyl azodicarboxylate (248.98 g, 1.23 mol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight.

[0053] 2N hydrochloric acid is added dropwise to a pH of 1 to salt the product. Byproducts are also dissolved in the reaction system. The liquids are separated and the organic phase is discarded. The aqueous phase is extracted with dichloromethane twice and also discarded. The aqueous phase is concentrated to dryness under reduced pressure, cooled to 0 degrees, and 50% sodium hydroxide aqueous solution is slowly added dropwise to a pH of 14. The above operation can remove byproducts.

[0054] After that, the mixture was allowed to stand for 30 minutes, and the liquid was separated. The upper dark organic layer was dried twice with solid potassium hydroxide, filtered, and the filtrate was distilled under reduced pressure at 80 degrees (20 mmHg) to obtain 99.63 g of R-3-methylmorpholine with a yield of 80% and ee = 96%. The yield of the final product in this example was 57.29%.

[0055] The characterization data of the product R-3-methylmorpholine are as follows:

[0056] 1H NMR (400MHz, CDCl3) δ3.56 (dd, J=10.6, 4.0Hz, 1H), 3.26 (dd, J=10.6, 7.8Hz, 1H), 3.04 (dqd, J=13.0, 6.5, 4.0Hz, 1H), 2.10 (s, 3H), 1.08 (d, J=6.5Hz, 3H).

[0057] Example 2

[0058] The preparation method of chiral R-3-methylmorpholine comprises the following steps:

[0059] first step

[0060] N-tert-Butyloxycarbonylethanolamine (235.95 g, 1.43 mol) was dissolved in 1,4-dioxane (0.85 L), and boron trifluoride etherate (18.60 g, 0.131 mmol) was added. The mixture was stirred and heated to 30°C. S-propylene oxide (85.00 g, 1.46 mol) was slowly added dropwise. Stirring was continued for 10 hours. Powdered potassium carbonate (604.44 g, 4.38 mol) was added, and 0.8 L of methanol was slowly added dropwise under an ice bath. The mixture was stirred at room temperature for 40 minutes, followed by another 10 minutes. The mixture was filtered and concentrated to dryness. Dichloromethane (1 L) was added, the mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to dryness. Compound 1 (white solid) (224 g) was crystallized from petroleum ether to obtain a yield of 70.02%.

[0061] Step 2

[0062] Compound 1 was dissolved in 0.85 L of tetrahydrofuran and hydrogen chloride gas was introduced under an ice bath until a large amount of solid appeared. After TLC showed the disappearance of the starting material, the temperature was lowered to 0°C, stirred for 40 minutes, filtered, and the solid was rinsed with 350 ml of acetone and dried to obtain 137.93 g of compound 2 (white powder) with a yield of 87%.

[0063] Step 3

[0064] Compound 2 (137.93 g, 0.89 mol) was dissolved in 2 L of dichloromethane. Potassium carbonate (245.64 g, 1.78 mol) was added and stirred at room temperature for 2 hours. The mixture was then filtered with suction. Triphenylphosphine (233.18 g, 0.89 mol) was added to the filtrate, followed by the dropwise addition of diisopropyl azodicarboxylate (179.78 g, 0.89 mol). After the addition was complete, the mixture was stirred at room temperature overnight. 2N hydrochloric acid was added dropwise to a pH of 1. The mixture was separated and the organic phase was discarded. The aqueous phase was extracted twice with dichloromethane and similarly discarded. The aqueous phase was concentrated to dryness under reduced pressure, cooled to 0 degrees, and 50% aqueous sodium hydroxide solution was slowly added dropwise to a pH of 14. The mixture was allowed to stand for 30 minutes, and the liquid was separated. The upper dark organic layer was dried twice with solid potassium hydroxide, filtered, and the filtrate was distilled under reduced pressure at 82 degrees (20 mmHg) to obtain 66.51 g of R-3-methylmorpholine with a yield of 74% and ee = 92%. The yield of the final product in this example was 45.01%.

[0065] The characterization data of the product R-3-methylmorpholine are as follows:

[0066] 1H NMR (400MHz, CDCl3) δ3.61 (dd, J=10.6, 4.0Hz, 1H), 3.24 (dd, J=10.6, 7.8Hz, 1H), 3.09 (dqd, J=13.0, 6.5, 4.0Hz, 1H), 2.10 (s, 3H), 1.07 (d, J=6.5Hz, 3H).

[0067] Example 3

[0068] The preparation method of S-3-methylmorpholine comprises the following steps:

[0069] first step

[0070] N-tert-Butyloxycarbonylethanolamine (664.93 g, 4.13 mmol) was dissolved in 1,4-dioxane (2.1 L), and boron trifluoride etherate (63.9 g, 0.45 mol) was added. The mixture was stirred and heated to 33°C. R-propylene oxide (240 g, 4.13 mol) was slowly added dropwise. Stirring was continued for 10 hours. Powdered potassium carbonate (1139.88 g, 8.26 mol) was added, and 2 L of methanol was slowly added dropwise under an ice bath. Stirring was continued at room temperature for 1 hour and 35 minutes. The mixture was filtered and concentrated to dryness. Dichloromethane (2 L) was added, and the mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to dryness. Compound 1 (743.1 g) was crystallized from petroleum ether to obtain a white solid in an 82% yield.

[0071] Step 2

[0072] Compound 1 was dissolved in 2 L of tetrahydrofuran and hydrogen chloride gas was introduced under an ice bath until a large amount of solid appeared. After TLC showed the disappearance of the starting material, the temperature was lowered to 0°C, stirred for 35 minutes, and filtered. The solid was rinsed with 500 ml of acetone and dried to obtain 478.60 g of compound 2 (white powder) with a yield of 91%.

[0073] Step 3

[0074] Compound 2 (478.6 g, 3.09 mol) was dissolved in 4 L of dichloromethane, potassium carbonate (852.2 g, 6.17 mol) was added, and the mixture was stirred at room temperature for 2 hours, filtered, triphenylphosphine (850.1 g, 3.24 mol) was added to the filtrate, and then diisopropyl azodicarboxylate (655.34 g, 3.24 mol) was added dropwise; after the addition was complete, the mixture was stirred at room temperature overnight; 2N hydrochloric acid was added dropwise until the pH was 1, the liquid was separated, and the organic phase was discarded; the aqueous phase was The chloromethane was extracted twice more and discarded; the aqueous phase was concentrated to dryness under reduced pressure, cooled to 0 degrees, and a 50% aqueous sodium hydroxide solution was slowly added dropwise to a pH of 14. The mixture was allowed to stand for 50 minutes, and the liquids were separated. The upper dark organic layer was dried twice with solid potassium hydroxide, filtered, and the filtrate was distilled under reduced pressure at 78-83 degrees (20 mmHg) to obtain 215.2 g of S-3-methylmorpholine with a yield of 69% and ee = 88%. The yield of the final product in this example was 51.48%.

[0075] The characterization data of the product S-3-methylmorpholine are as follows:

[0076] 1H NMR (400MHz, CDCl3) δ3.59 (dd, J=10.6, 4.0Hz, 1H), 3.22 (dd, J=10.6, 7.8Hz, 1 .05H), 3.01 (dqd, J=13.0, 6.5, 4.0Hz, 1H), 2.12 (s, 3H), 1.04 (d, J=6.5Hz, 3H).

[0077] Comparative Example 1

[0078] For the process route of comparative example 1, please refer to Figure 2 .

[0079] Preparation method of R-3-methylmorpholine:

[0080] Aminopropanol (100 g, 1.33 mol) was dissolved in a solution of 9 L THF and 9 L water. Potassium carbonate (551 g, 3.99 mol) was added and the temperature was lowered to -10 degrees. Chloroacetyl chloride (165.40 g, 1.46 mol) was added dropwise. After the addition was complete, the mixture was kept warm for 1 hour. The reaction was complete as shown by TLC. The reaction solution was clear. EA was added and the mixture was separated. The mixture was extracted twice with EA and once with DCM. The mixture was dried and concentrated to obtain 161 g of compound 1 as a light yellow liquid with a yield of 80%.

[0081] Compound 1 (161 g, 1.06 mol) was dissolved in 10 L of dichloromethane and 10 L of isopropanol. The solution was cooled to 0°C and potassium tert-butoxide (358.23 g, 3.19 mol) was slowly added in batches as a solid. The temperature was raised to room temperature and the reaction was allowed to react for 1 hour. The reaction was complete by TLC. The pH was adjusted to 7 with 2N HCl solution, and the solution was extracted three times with dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure. A small amount of EA was added to slurry and filtered to obtain 61.26 g of compound 2 as a solid with a yield of 50%.

[0082] Compound 2 (61.26 g, 0.53 mol) was dissolved in 10% tetrahydrofuran, cooled to 0°C, and lithium aluminum hydride (60.66 g, 1.59 mol) was added in batches. After the addition, the temperature was raised to room temperature and the reaction was allowed to react for 1 hour. The reaction was complete on TLC. The solution was cooled to 0°C, 121.32 g of water was added dropwise, and 121.32 g of 10% sodium hydroxide solution was added dropwise. The solution was filtered and the tetrahydrofuran was concentrated under normal pressure to obtain 21.2 g of the product with a yield of 39.40% and an ee of 80%. The yield of the final product in this example was 15.82%.

[0083] In this comparative example, compound 1 and compound 2 specifically refer to Figure 2 Compound 1 and Compound 2 are shown.

[0084] The total yields of the preparation methods provided in Examples 1-3 and Comparative Example 1 were calculated, and the results are shown in Table 1 below.

[0085] Table 1

[0086]

[0087] Comparing the total yields of Examples 1-3 and Comparative Example 1, it can be seen that the total yield of the method for preparing chiral R and S 3-methylmorpholine provided by the present invention is significantly increased by several times.

[0088] Compared to existing technologies, the method for preparing chiral R and S 3-methylmorpholine provided by the present invention significantly reduces the number of reaction steps and processes, simplifies the overall process, and achieves a higher total yield, significantly reducing production costs and making it suitable for industrial production. Furthermore, by selecting a Lewis acid as a boron trifluoride etherate complex, the present invention can further improve the total yield of the reaction.

[0089] The present invention illustrates the preparation route of a chiral R or S 3-methylmorpholine of the present invention by the above-described embodiments, but the present invention is not limited to the above-described embodiments, that is, it does not mean that the present invention must rely on the above-described embodiments to implement. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention and the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope of the present invention and the disclosure range. Under the teaching of the present invention and the above-described embodiments, those skilled in the art can easily foresee that each raw material or its equivalent replacement, each processing method or its equivalent replacement that the present invention enumerates or exemplifies can realize the present invention.

[0090] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0091] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0092] Under the guidance of the present invention and the above-mentioned embodiments, it is easy for those skilled in the art to foresee that the raw materials or their equivalent substitutes, the processing methods or their equivalent substitutes listed or exemplified in the present invention can realize the present invention, and the upper and lower limit values ​​and interval values ​​of the parameters of the raw materials and processing methods can realize the present invention. The embodiments are not listed one by one here.

Claims

1. A method for preparing chiral R or S 3-methylmorpholine, characterized in that: Using S or R chiral propylene oxide as raw material, it is reacted with N-tert-butyloxycarbonylethanolamine under the action of Lewis acid, and then undergoes Mitsunobu reaction to close the ring to obtain a chiral morpholine compound; wherein, The Lewis acid is selected from aluminum trichloride or boron trifluoride ether complex; The preparation method of the chiral R or S 3-methylmorpholine comprises the following steps: (1) S or R propylene oxide reacts with N-tert-butyloxycarbonylethanolamine in the presence of Lewis acid to give compound 1; (2) reacting compound 1 with hydrogen chloride to obtain compound 2; (3) Compound 2 is reacted with diisopropyl azodicarboxylate to obtain chiral R or S 3-methylmorpholine; Wherein, the compound 1 is ， The compound 2 is ； Furthermore, the step (3) further comprises adding triphenylphosphine as a raw material.

2. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein The reaction molar ratio of the S or R chiral propylene oxide to the N-tert-butyloxycarbonylethanolamine is 1:0.9-1.0; the reaction molar ratio of the S or R chiral propylene oxide to the Lewis acid is 1:15-20.

3. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein The reaction molar concentration of the S or R chiral propylene oxide is 1.5-2.0 M / L; the reaction molar concentration of the N-tert-butyloxycarbonylethanolamine is 1.7-2.5 M / L; and the reaction molar concentration of the Lewis acid is 0.07-0.12 M / L.

4. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein The reaction molar ratio of the compound 2 to the diisopropyl azodicarboxylate is 1:1-1.1, and the reaction molar ratio of the compound 2 to the triphenylphosphine is 1:1-1.1; the reaction molar concentration of the compound 2 is 0.4-1M / L; the reaction molar concentration of the triphenylphosphine is 0.4-1M / L; and the reaction molar concentration of the diisopropyl azodicarboxylate is 0.4-1M / L.

5. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein In the step (2), the reaction of compound 1 with hydrogen chloride is carried out by passing hydrogen chloride gas into compound 1 until a solid is formed.

6. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein In step (1), the reaction temperature is 30-50 degrees, and the reaction time is more than 5-10 hours; In the step (3), the reaction temperature is room temperature and the reaction time is more than 10 hours.

7. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein The step (1) comprises: dissolving N-tert-butyloxycarbonylethanolamine in a solvent, adding boron trifluoride etherate, heating the mixture to 30-50 degrees while stirring, adding S-propylene oxide or R-propylene oxide dropwise, and continuing stirring for 5-10 hours after the addition is complete.

8. The method for preparing chiral R or S 3-methylmorpholine according to claim 7, wherein: The step (1) further comprises: adding an alkaline reagent to the reaction system for neutralization, adding methanol dropwise under an ice bath, stirring at room temperature, and then filtering.

9. The method for preparing chiral R or S 3-methylmorpholine according to claim 8, wherein The alkaline reagent is powdered potassium carbonate.

10. The method for preparing chiral R or S 3-methylmorpholine according to claim 1, wherein The step (3) comprises: dissolving compound 2 in a solvent, adding an alkaline reagent to make the pH value alkaline, stirring at room temperature for several hours, filtering, adding triphenylphosphine to the filtrate, and then adding diisopropyl azodicarboxylate dropwise; after the addition is complete, stirring at room temperature for more than 10 hours.

11. The method for preparing chiral R or S 3-methylmorpholine according to claim 10, wherein: The step (3) further includes: Hydrochloric acid is added dropwise to the reaction system until the pH reaches 1-2, the liquids are separated, and the organic phase is discarded; the aqueous phase is extracted with an organic solvent at least twice again and also discarded; after the aqueous phase is concentrated to half under reduced pressure, the temperature is lowered to 0-10 degrees, and an alkaline aqueous solution is slowly added dropwise to a pH of 13-14, the solution is allowed to stand, and the liquids are separated.

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