Preparation method for chiral r- or s-3-methylmorpholine

Abstract

Disclosed in the present invention is a preparation method for chiral R- or S-3-methylmorpholine. Chiral S- or R-propylene oxide is used as a starting material to react with Boc ethanolamine under the action of a Lewis acid, and then a chiral morpholine compound is obtained by means of a Mitsunobu reaction for ring closing. The preparation method of the present invention has shortened steps and enhanced total yield, thereby efficiently reducing the unit cost.

Description

A method for preparing chiral R or S 3-methylmorpholine Technical Field

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

[0002] Chiral 3-substituted morpholines are an important class of intermediates used in the preparation of various drug molecules or their key intermediates. The traditional method for preparing chiral 3-substituted morpholines typically involves first reacting a substituted chiral amino alcohol with chloroacetyl chloride to obtain an amide, then performing a ring-closure reaction with a strong base such as potassium tert-butoxide, sodium methoxide, or sodium hydride to generate a six-membered lactam, and finally reducing it with a reducing agent such as lithium aluminum hydride to obtain the 3-substituted morpholine.

[0003] For example, the commonly used method for synthesizing R-3-methylmorpholine is as follows: (2R)-2-aminopropanol and chloroacetyl chloride are reacted in an equimolar ratio with a 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-Chemicalbook 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 procedure time, low overall yield, or 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] This invention provides a method for preparing chiral R or S 3-methylmorpholine, which shortens the number of steps, increases the overall yield, and effectively reduces the unit cost.

[0006] The technical solution of the present invention is as follows:

[0007] A method for preparing chiral R or S 3-methylmorpholine involves using S or R chiral propylene oxide as a raw material, reacting it with N-tert-butoxycarbonylethanolamine under the action of a Lewis acid, and then performing a photo-extending reaction to achieve cyclization, thereby obtaining a chiral morpholine compound.

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

[0009] In a preferred embodiment, the method for preparing the chiral R or S 3-methylmorpholine includes the following steps:

[0010] (1) S or R propylene oxide reacts with N-tert-butoxycarbonylethanolamine under the action of Lewis acid to give compound 1;

[0011] (2) Compound 1 was reacted with hydrogen chloride to obtain compound 2;

[0012] (3) Reacting compound 2 with diisopropyl azodicarbonate to give chiral R or S 3-methylmorpholine;

[0013] Wherein, 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 compound 1 through hydrogen chloride gas, preferably until a large amount of solid appears, which is considered a good way to obtain compound 2. A large amount of solid usually refers to a significant amount of solid that can be clearly observed by 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 includes adding the raw material triphenylphosphine.

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

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

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

[0022] In one embodiment, in step (1), the reaction solvent can be 1,4-dioxane; in step (2), the reaction solvent is tetrahydrofuran; and in step (3), the reaction solvent is dichloromethane. The reaction solvent can be selected by a technician based on its solubility; the above are merely illustrative examples.

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

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

[0025] In a preferred embodiment, step (1) includes: dissolving N-tert-butoxycarbonylethanolamine in 1,4-dioxane, then adding boron trifluoride diethyl ether, heating the mixture to 30-50 degrees Celsius with stirring, and then adding S-propylene oxide or R-propylene oxide dropwise. After the addition is complete, stirring continues for 5-10 hours. This order of addition and reaction conditions are suitable for the reaction of this invention.

[0026] In a preferred embodiment, step (1) further includes: 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, step (1) further includes: adding an organic solvent, washing with water, drying the solid, concentrating under reduced pressure to dryness, and crystallizing with petroleum ether to obtain compound 1.

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

[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 through compound 1. More preferably, step (2) includes, for example, dissolving compound 1 in tetrahydrofuran, passing hydrogen chloride gas through it in an ice bath until a large amount of solid appears, and after thin-layer chromatography shows that the raw material has disappeared, cooling to -5°C to 0°C, stirring, then filtering, washing 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 choose other processing methods that can achieve similar effects based on this instruction.

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

[0031] The reaction is carried out as follows: Compound 2 is dissolved in a solvent, and an alkaline reagent is added to adjust the pH to alkaline. After stirring at room temperature for several hours, the mixture is filtered. Triphenylphosphine is added to the filtrate, followed by the dropwise addition of diisopropyl azodicarbonate. After the addition is complete, the mixture is stirred at room temperature for at least 10 hours, for example, overnight at room temperature. In one embodiment, dichloromethane is used as the solvent; in alternative embodiments, other suitable solvents may be used. In a preferred embodiment, powdered potassium carbonate is used as the alkaline reagent. Room temperature here is generally understood to be around 25 degrees Celsius. Preferably, adjusting the pH to alkaline means adjusting the pH to 8-9. The "several hours" here can be 2 hours, or other reaction times chosen by those skilled in the art.

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

[0033] Add hydrochloric acid dropwise to the reaction system until the pH reaches 1-2, separate the liquid and discard the organic phase; extract the aqueous phase at least twice with an organic solvent, and discard the organic phase as well; concentrate the aqueous phase under reduced pressure to half, cool it to 0-10 degrees Celsius, slowly add an alkaline aqueous solution dropwise until the pH reaches 13-14, let it stand, and separate the liquid and extract the liquid. The above process can remove byproducts.

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

[0035] After standing and separation, the upper dark organic layer is dried with a 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 an aqueous sodium hydroxide solution, and the solid drying is solid potassium hydroxide drying.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] The method for preparing chiral R or S 3-methylmorpholine provided by this invention shortens the steps and increases the overall yield, thereby effectively reducing the unit cost. Attached Figure Description

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

[0040] Figure 2 is a reaction process route diagram of Comparative Example 1 in the prior art. Detailed Implementation

[0041] This invention provides 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 Lewis acid, and then performs a photo-extending reaction to obtain a chiral morpholine compound.

[0042] In one specific embodiment, the Lewis acid is selected as a boron trifluoride diethyl ether complex, and the corresponding reaction process route is shown in Figure 1.

[0043] In this document, the range expressed as "from one value to another" is a concise way of representing a range to avoid listing all the values ​​in that range in the specification. Therefore, the description of a particular range of values ​​covers any value within that range as well as the smaller range of values ​​defined by that value, just as if the arbitrary value and the smaller range of values ​​were explicitly stated in the specification.

[0044] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Improvements and adjustments made by those skilled in the art based on the present invention in practical applications still fall within the scope of protection of the present invention.

[0045] Example 1

[0046] The preparation methods of chiral R-3-methylmorpholine include:

[0047] first step:

[0048] N-tert-Butoxycarbonylethanolamine (305.30 g, 1.90 mol) was dissolved in 1,4-dioxane (1 L), followed by the addition of boron trifluoride diethyl ether (12.78 g, 0.09 mol). The mixture was heated to 30°C with stirring, and S-propylene oxide (100 g, 1.72 mol) was slowly added dropwise. After the addition was complete, stirring was 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. The mixture was stirred at room temperature for 1 hour, followed by another 20 minutes of stirring. The mixture was filtered, concentrated to dryness, and then dichloromethane (1 L) was added. The mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to dryness. The product was then crystallized from petroleum ether to obtain 300 g of compound 1 (white solid), with a yield of 79.6%. In this example, powdered potassium carbonate was specifically chosen for this step instead of the conventional potassium carbonate solution. In addition, the slow addition of methanol under an ice bath achieved better dispersion.

[0049] Step Two:

[0050] Compound 1 was dissolved in 1 L of tetrahydrofuran. Hydrogen chloride gas was passed through the mixture in an ice bath until a large amount of solid appeared. After the TLC showed that the starting material had disappeared, the mixture was cooled to 0 degrees Celsius, stirred for 40 minutes, filtered, and the solid was washed 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. Triphenylphosphine (322.95 g, 1.23 mol) was added to the filtrate, followed by the dropwise addition of diisopropyl azodicarbonate (248.98 g, 1.23 mol). After the addition was complete, the mixture was stirred at room temperature overnight.

[0053] Add 2N hydrochloric acid dropwise until the pH reaches 1, causing the product to form a salt. Simultaneously, the byproducts dissolve within the reaction system. Separate the liquid and discard the organic phase. Extract the aqueous phase twice more with dichloromethane, discarding the organic phase as well. Concentrate the aqueous phase to dryness under reduced pressure, cool to 0°C, and slowly add a 50% sodium hydroxide aqueous solution until the pH reaches 14. These steps remove the byproducts.

[0054] After standing for 30 minutes, 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 includes the following steps:

[0059] first step

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

[0061] Step 2

[0062] Compound 1 was dissolved in 0.85 L of tetrahydrofuran. Hydrogen chloride gas was introduced under ice bath until a large amount of solid appeared. After the TLC showed that the starting material disappeared, the mixture was cooled to 0 degrees Celsius, stirred for 40 minutes, filtered, and the solid was washed 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, and potassium carbonate (245.64 g, 1.78 mol) was added. After stirring at room temperature for 2 hours, the mixture was filtered. Triphenylphosphine (233.18 g, 0.89 mol) was added to the filtrate, followed by the dropwise addition of diisopropyl azodicarbonate (179.78 g, 0.89 mol). After the addition was complete, the mixture was stirred overnight at room temperature. 2N hydrochloric acid was added dropwise until the pH reached 1. The mixture was separated, and the organic phase was discarded. The aqueous phase was extracted twice more with dichloromethane, and the extracts were discarded as well. The aqueous phase was concentrated to dryness under reduced pressure, cooled to 0 degrees Celsius, and a 50% sodium hydroxide aqueous solution was slowly added dropwise until the pH reached 14. After standing for 30 minutes, the mixture 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 Celsius (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 includes the following steps:

[0069] first step

[0070] N-tert-Butoxycarbonylethanolamine (664.93 g, 4.13 mmol) was dissolved in 1,4-dioxane (2.1 L), followed by the addition of boron trifluoride diethyl ether (63.9 g, 0.45 mol). The mixture was heated to 33°C with stirring, and R-propylene oxide (240 g, 4.13 mol) was slowly added dropwise. After the addition was complete, 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 ice bath conditions. The mixture was stirred at room temperature for 1 hour, followed by another 35 minutes of stirring. The mixture was filtered, concentrated to dryness, and then washed with water and dried over magnesium sulfate. The solution was then concentrated to dryness under reduced pressure and crystallized from petroleum ether to give compound 1 (white solid) 743.1 g, yield 82%.

[0071] Step 2

[0072] Compound 1 was dissolved in 2 L of tetrahydrofuran. Hydrogen chloride gas was passed through the mixture in an ice bath until a large amount of solid appeared. After the TLC showed that the starting material had disappeared, the mixture was cooled to 0 degrees Celsius, stirred for 35 minutes, filtered, and the solid was washed 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, and potassium carbonate (852.2 g, 6.17 mol) was added. After stirring at room temperature for 2 hours, the mixture was filtered. Triphenylphosphine (850.1 g, 3.24 mol) was added to the filtrate, followed by the dropwise addition of diisopropyl azodicarbonate (655.34 g, 3.24 mol). After the addition was complete, the mixture was stirred at room temperature overnight. 2N hydrochloric acid was added dropwise until the pH reached 1. The mixture 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 Celsius, and 50% sodium hydroxide aqueous solution was slowly added dropwise until the pH reached 14. The mixture was allowed to stand for 50 minutes, separated, and the upper dark organic layer was dried twice with solid potassium hydroxide. The mixture was filtered, and the filtrate was distilled under reduced pressure at 78-83 degrees Celsius (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] Please refer to Figure 2 for the process route of Comparative Example 1.

[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 mixture was cooled to -10°C. Chloroacetyl chloride (165.40 g, 1.46 mol) was added dropwise. After the addition was complete, the mixture was kept at this temperature for 1 hour. The reaction was observed on TLC. After the reaction was complete, the reaction solution became clear. EA was added to separate the layers. The mixture was extracted twice with EA and once with DCM. The solution was dried and concentrated to obtain 161 g of a pale yellow liquid of compound 1, 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) solid was slowly added in portions. After the addition was complete, the mixture was brought to room temperature and reacted for 1 hour. The reaction was observed to be complete by TLC. The pH was adjusted to 7 with 2N HCl solution, and the mixture was extracted three times with dichloromethane. The solution was dried over magnesium sulfate, concentrated under reduced pressure, and then slurried and filtered to obtain 61.26 g of compound 2 solid, with a yield of 50%.

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

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

[0084] The overall 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 overall yields of Examples 1-3 and Comparative Example 1, it can be seen that the overall yield of the method for preparing chiral R and S 3-methylmorpholine provided by the present invention is significantly increased by several times.

[0088] The method for preparing chiral R and S-type 3-methylmorpholine provided by this invention significantly reduces the number of reaction steps and processes compared to existing technologies, resulting in a simpler overall process, higher total yield, and substantial reduction in production costs, making it suitable for industrial production. Furthermore, by selecting a Lewis acid as the boron trifluoride diethyl ether complex, this invention can further improve the overall yield of the reaction.

[0089] This invention illustrates a preparation route for chiral R or S 3-methylmorpholine through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of raw materials, additions of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention. Under the teachings of this invention and the above embodiments, those skilled in the art can readily foresee that all raw materials or their equivalent substitutions, processing methods or their equivalent substitutions listed or exemplified in this invention can achieve this invention.

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

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

[0092] Under the guidance of the present invention and the above embodiments, those skilled in the art will readily foresee that all the raw materials or their equivalents, processing methods or their equivalents listed or exemplified in the present invention can achieve the present invention, and that the upper and lower limits and range values ​​of the parameters of each raw material and processing method can also achieve the present invention. Examples 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 a raw material, it reacts with N-tert-butoxycarbonylethanolamine under the action of Lewis acid, and then undergoes photo-extending reaction to cyclize, yielding a chiral morpholine compound.

2. The method for preparing chiral R or S 3-methylmorpholine as described in claim 1, characterized in that, The Lewis acid is selected from aluminum trichloride or boron trifluoride diethyl ether complexes.

3. The method for preparing chiral R or S 3-methylmorpholine as described in claim 1, characterized in that, The preparation method of the chiral R or S 3-methylmorpholine includes the following steps: (1) S or R propylene oxide reacts with N-tert-butoxycarbonylethanolamine under the action of Lewis acid to give compound 1; (2) Compound 1 was reacted with hydrogen chloride to obtain compound 2; (3) Reacting compound 2 with diisopropyl azodicarbonate to give chiral R or S 3-methylmorpholine; Wherein, compound 1 is ; The compound 2 is 。 4. The method for preparing chiral R or S 3-methylmorpholine as described in claim 3, characterized in that, Step (3) also includes adding the raw material triphenylphosphine.

5. The method for preparing chiral R or S 3-methylmorpholine as described in claim 1 or 3, characterized in that, The molar ratio of the chiral propylene oxide of S or R to the N-tert-butoxycarbonylethanolamine is 1:0.9-1.0; the molar ratio of the chiral propylene oxide of S or R to the Lewis acid is 1:15-20.

6. The method for preparing chiral R or S 3-methylmorpholine as described in claim 1 or 3, characterized in that, The reaction molar concentration of the chiral propylene oxide of S or R is 1.5-2.0 M / L; the reaction molar concentration of the N-tert-butoxycarbonylethanolamine is 1.7-2.5 M / L; and the reaction molar concentration of the Lewis acid is 0.07-0.12 M / L.

7. The method for preparing chiral R or S 3-methylmorpholine as described in claim 4, characterized in that, The molar ratio of compound 2 to diisopropyl azodicarbonate is 1:1-1.1, and the molar ratio of compound 2 to triphenylphosphine is 1:1-1.1; the molar concentration of compound 2 is 0.4-1 M / L; the molar concentration of triphenylphosphine is 0.4-1 M / L; and the molar concentration of diisopropyl azodicarbonate is 0.4-1 M / L.

8. The method for preparing chiral R or S 3-methylmorpholine as described in claim 3, characterized in that, In step (2), reacting compound 1 with hydrogen chloride involves passing compound 1 through hydrogen chloride gas until a solid appears.

9. The method for preparing chiral R or S 3-methylmorpholine as described in claim 3, characterized in that, In step (1), the reaction temperature is 30-50 degrees Celsius, and the reaction time is 5-10 hours or more; In step (3), the reaction temperature is room temperature and the reaction time is more than 10 hours.

10. The method for preparing chiral R or S 3-methylmorpholine as described in claim 3, characterized in that, Step (1) includes: dissolving N-tert-butoxycarbonylethanolamine in a solvent, then adding boron trifluoride diethyl ether, heating the mixture to 30-50 degrees Celsius while stirring, and adding S-propylene oxide or R-propylene oxide dropwise. After the addition is complete, continue stirring for 5-10 hours.

11. The method for preparing chiral R or S 3-methylmorpholine as described in claim 10, characterized in that, Step (1) further includes: adding an alkaline reagent to the reaction system for neutralization, adding methanol dropwise under an ice bath, stirring at room temperature, and then filtering.

12. The method for preparing chiral R or S 3-methylmorpholine as described in claim 11, characterized in that, The alkaline reagent is powdered potassium carbonate.

13. The method for preparing chiral R or S 3-methylmorpholine as described in claim 3, characterized in that, Step (3) includes: dissolving compound 2 in a solvent, adding an alkaline reagent to make the pH alkaline, stirring at room temperature for several hours, filtering, adding triphenylphosphine to the filtrate, and then adding diisopropyl azodicarbonate dropwise; after the addition is complete, stirring at room temperature for more than 10 hours.

14. The method for preparing chiral R or S 3-methylmorpholine as described in claim 13, characterized in that, Step (3) further includes: adding hydrochloric acid dropwise to the reaction system until the pH is 1-2, separating the liquid and discarding the organic phase; extracting the aqueous phase at least twice with an organic solvent and discarding it again; concentrating the aqueous phase under reduced pressure to half, cooling it to 0-10 degrees Celsius, slowly adding alkaline aqueous solution dropwise until the pH is 13-14, letting it stand, and separating the liquid.

Images