CN116947777A - Continuous preparation method of chiral 3-substituted morpholine - Google Patents

Abstract

The application discloses a continuous preparation method of chiral 3-substituted morpholine, which comprises three continuous steps, realizes one-pot preparation of 3-substituted morpholine, is simple and convenient to operate, and is suitable for industrialization.

Description

Continuous preparation method of chiral 3-substituted morpholine

Technical Field

The application belongs to the field of organic synthesis, and particularly relates to a continuous preparation method of chiral 3-substituted morpholine.

Background

Chiral 3-substituted morpholines are an important class of intermediates useful in the preparation of a variety of drug molecules or their key intermediates. The traditional method for preparing chiral 3-substituted morpholine is to react substituted chiral amino alcohol with chloroacetyl chloride to obtain amide, then to perform ring closure reaction with strong base such as potassium tert-butoxide, sodium methoxide and sodium hydride to generate hexa-membered lactam, and finally to perform reduction reaction with reducing agent such as lithium aluminum hydride to obtain 3-substituted morpholine.

For example, the route disclosed in WO2014016849, especially the last step, uses lithium aluminum hydride, which releases heat strongly during the reaction, releases heat and generates a large amount of hydrogen during the post-treatment quenching, the reaction is not easy to control and the operators have a certain danger, and in addition, the aluminum salt generated after the quenching is difficult to treat, which is unfavorable for the scale-up production.

Also for example, the route disclosed in CN106749081 a. In the first step of the reaction of chiral aminopropanol and chloroacetyl chloride to produce S-3-methylmorpholine, sodium hydride is used as a strong base. In the second reduction reaction, a mixture of sodium borohydride and zinc chloride is used as a reducing agent, and particularly, the sodium borohydride is used in a large amount, so that more borane is generated, and the reaction is unsafe and is not suitable for amplification.

Therefore, it is of great importance to find a chiral 3-substituted morpholine preparation method which is more suitable for industrial production.

Disclosure of Invention

The application aims to provide a brand new continuous preparation method of chiral 3-substituted morpholine.

The application provides a continuous preparation method of a compound of formula II, which comprises the following steps:

wherein R is a C1-C4 alkyl group or phenyl group;

1) Reacting a compound of formula I with chloroacetaldehyde in an inert solvent, thereby obtaining a first reaction mixture;

2) Mixing the first reaction mixture obtained in the step 1) with a solution of alkali and reacting to obtain a second reaction mixture;

3) Mixing the second reaction mixture obtained in the step 2) with a reducing agent and carrying out a reduction reaction to obtain the compound of the formula II.

In one embodiment, R is methyl, ethyl, n-propyl, isopropyl, or phenyl.

In one embodiment, in step 1), the inert solvent is selected from the group consisting of: dichloromethane, methanol, tetrahydrofuran, and combinations thereof.

In one embodiment, in step 1), the inert solvent is methylene chloride.

In one embodiment, step 1) is: firstly, mixing a compound of a formula I with an inert solvent to obtain a solution containing the compound of the formula I; the chloroacetaldehyde solution is then mixed with a solution containing the compound of formula I and reacted to provide a first reaction mixture.

In one embodiment, in step 1), the molar ratio of the compound of formula I to chloroacetaldehyde is 1:1.

In one embodiment, in step 1), the chloroacetaldehyde is a 40% chloroacetaldehyde solution.

In one embodiment, in step 1), the reaction is carried out at 5-10 degrees.

In one embodiment, in step 1), the reaction is carried out for 1 to 5 hours. Preferably, it is carried out for 1-2 hours.

In an embodiment, in step 2), the base is potassium hydroxide, sodium hydroxide, or a combination thereof.

In one embodiment, in step 2), the base is potassium hydroxide.

In one embodiment, in step 2), the solution of base is a solution of base in an organic solvent. Preferably, the solution of the base is a solution of potassium hydroxide in an organic solvent. Preferably, the organic solvent is methanol, tetrahydrofuran, or a combination thereof. Preferably, the organic solvent is methanol.

In one embodiment, in step 2), the molar ratio of the compound of formula I to base is 1: (1-2).

In one embodiment, in step 2), the reaction is carried out at 15-20 degrees.

In one embodiment, in step 2), the reaction is carried out for 10 to 20 hours. Preferably, this is done for 15-16 hours.

In one embodiment, step 3) is: mixing the second reaction mixture obtained in the step 2) with a reducing agent and carrying out reduction reaction so as to obtain a crude product containing the compound of the formula II; the crude product is rectified to give the compound of formula II.

In one embodiment, in step 3), the molar ratio of the compound of formula I to the reducing agent is 1: (0.375-0.5).

In one embodiment, in step 3), the reduction reaction is carried out at 15-20 degrees.

In one embodiment, in step 3), the reduction reaction is carried out for 10 to 20 hours. Preferably, this is done for 15-16 hours.

In one embodiment, in step 3), after the reduction reaction is completed, separating solids and liquids in the reaction system, and collecting and concentrating the liquids; or mixing the reaction system with water, collecting and concentrating the organic phase; the residue obtained is a crude product containing a compound of formula II.

In an embodiment, in step 3), the conditions of the rectification are selected from one or more of the following group:

a) A glass filler rectifying column with the diameter of 40mm and the height of 300-500 mm is adopted;

b) Vacuum degree 50 mmHg;

c) 60-90 degrees.

In one embodiment, in step 3), the reducing agent is sodium borohydride.

The method of the application is a brand new synthetic route and belongs to a one-pot method. The method comprises three steps, the post-treatment is not needed between each two steps, the reaction system of the previous step can be directly used for the next step, continuous feeding can be realized, the operation steps are greatly simplified, the operation is simpler, and the method is suitable for industrial application.

The second step of the application uses milder and safer alkali with lower price to carry out the ring closing reaction, and the third step is easier to reduce compared with the traditional amide, uses milder sodium borohydride as a reducing agent, does not need to be matched with zinc chloride to use, and the dosage of the sodium borohydride only needs 0.375-0.5 equivalent of imine, thereby saving the cost.

The total yield of the three steps of the method can also reach more than 20%, the GC purity of the product exceeds 95%, the chiral purity in the whole process is kept stable, and the EE value of the product can reach 99%.

The method of the application is applicable to the preparation of various chiral 3-substituted morpholines, and the preparation process of various chiral 3-substituted morpholines has very good effect.

The inventors repeatedly screened various reaction conditions such as reaction temperature, reaction solvent, etc. in the course of developing the preparation method of the present application. On the premise of screening a large number of experimental results, the following unexpected findings are: if the reaction temperature is too high or an improper reaction solvent is selected, the reaction product may become contaminated, and the product properties may be deteriorated. For example, methanol was used as the reaction solvent in the first step, and as a result, it was found that even if the reaction time was prolonged, the reaction could not be completed, eventually leading to a decrease in the yield of the reaction product.

It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 shows the EE value of the S-3-methylmorpholine prepared in example 1, which is required to be derivatized, followed by benzyloxycarbonyl and then detected, since the S-3-methylmorpholine has a very weak UV absorption and does not respond to liquid chromatography.

Detailed Description

As used herein, mixing of two materials may be by adding (including dropping) one material to the other, or in reverse order.

The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, the starting materials are commercially available.

Example 1

In a first step, a 5 liter glass reaction flask was charged with 1.5 liters of methylene chloride, 300 g of L-alaninol (4 moles) was added, cooled to 5℃with ice water, 784 g of chloroacetaldehyde hydrate (40%, 4 moles) was added dropwise, and the temperature was controlled at 5 to 10 ℃. The reaction was completed for about 1 hour at 5-10℃for 1 hour. The reaction solution is directly put into the next step.

In the second step 300 g (5.4 moles) of potassium hydroxide was added to 1.5 liters of methanol in portions with stirring and the solution was stirred for further use. Gradually dripping the alkali liquor into the reaction liquid in the first step, controlling the temperature to be 10-15 ℃ and finishing dripping in about one hour. After completion of the dropwise addition, the reaction was carried out at 15-20℃for 16 hours, and the starting material of the TLC plate (DCM: meOH=20:1, one drop of ammonia water was added) was completed, and the reaction solution was directly fed to the next step.

The third step, controlling the temperature to be less than 15-20 degrees, adds 57 g sodium borohydride (1.5 mol) in batches of 10 g each, 1 hour apart. The reaction was completed at 15-20℃for 20 hours, and TLC (DCM: meOH=20:1) was used to monitor the completion of the reaction of the starting materials. The solids in the system were removed by suction filtration and the solids were washed with 500 ml of dichloromethane. The filtrates were combined and rotary distilled under reduced pressure until no significant liquid had evaporated, the residue remaining at about 500 ml.

Rectifying and purifying, namely distilling the product S-3-methylmorpholine by using a glass packing rectifying column with the diameter of 40mm and the height of 500 mm and the vacuum degree of 50 mm Hg and 62 degrees, wherein LCMS (ESI): 102 (M+H), 120 g of a colorless liquid. The total yield of the three steps is 29.7%, the GC98% and EE > 99.5% (EE value is tested after the S-3-methylmorpholine reacts with benzyl chloroformate), and the chiral purity of the process is well maintained as shown by the detection result.

¹ HNMR(400MHz,CDCl ₃ )3.72-3.79(m,2H)，3.43-3.49(m,1H),3.05-3.10(m,1H),2.83-3.01(m,3H)，0.95(d,3H,J＝6.4)。

Into a 50 ml three-necked flask, 1 g (0.01 mol) of S-3-methylmorpholine was added, 20 ml of methylene chloride was added, 1.5 g (0.15 mol) of triethylamine was further added, the mixture was cooled to 0℃and 2.04 g (0.012 mol) of benzyl chloroformate was added dropwise, the temperature was controlled at 0 to 5℃and the reaction was allowed to proceed for 1 hour at the end of the dropwise addition of 20 ml of water. Separating, extracting the water phase twice with 20 ml of dichloromethane, combining the dichloromethane phases, washing with saturated saline, drying with anhydrous sodium sulfate, spin-drying, passing through a column, 200-300 mesh silica gel, and ethyl acetate: petroleum ether = 1:10 rinse. Compound 1 ((S) -3-methylmorpholine-4-carboxylic acid benzyl ester) was obtained as a colorless oil, 1.98 g, 84% yield. For EE value detection. The results are shown in FIG. 1 and Table 1.

TABLE 1

	Peak to peak	Retention time (min)	Area percent	Height
					1	(R) -3-methylmorpholine-4-carboxylic acid benzyl ester	6.712
2	(S) -3-methylmorpholine-4-carboxylic acid benzyl ester	7.199	100	227750

Example 2

In a first step, a 5 liter glass reaction flask was charged with 1.5 liters of methanol, 300 g of L-alaninol (4 moles) was added, cooled to 5℃with ice water, 784 g of chloroacetaldehyde hydrate (40%, 4 moles) was added dropwise, and the temperature was controlled at 5 to 10 ℃. After about 1 hour of completion, the reaction was continued for 1 hour at 5-10 degrees, and as a result, the TLC plate (DCM: meOH=20:1, one drop of ammonia was added) found that the starting material was not reacted, and the reaction was continued for 5 hours. The reaction solution is directly put into the next step.

In the second step 300 g of potassium hydroxide (5.4 moles) were added to 1.2 liters of methanol in portions with stirring and the solution was stirred for further use. Gradually dripping the alkali liquor into the reaction liquid in the first step, controlling the temperature to be 10-15 ℃ and finishing dripping in about one hour. After completion of the dropwise addition, the reaction was carried out at 15-20℃for 10 hours, and the starting material of the TLC plate (DCM: meOH=20:1, one drop of ammonia water was added) was completed, and the reaction solution was directly fed to the next step.

The third step, controlling the temperature to be less than 5-10 degrees, adds 57 g sodium borohydride (1.5 mol) in batches of 10 g each, 1 hour apart. The reaction was completed at 5-10℃for 10 hours, and TLC (DCM: meOH=20:1, one drop of ammonia water) was used to monitor the completion of the reaction. The solids in the system were removed by suction filtration and the solids were washed with 500 ml of dichloromethane. The filtrates were combined and rotary distilled under reduced pressure until no significant liquid had evaporated, the residue remaining approximately 600 ml.

Rectifying and purifying, namely distilling the product S-3-methylmorpholine by using a glass packing rectifying column with the diameter of 40mm and the height of 500 mm and the vacuum degree of 50 mm Hg and 62 degrees, wherein LCMS (ESI): 102 (M+H), 55 g of a colorless liquid. The total yield of the three steps is 12.3%, the GC of the product is 97%, and the EE is more than 99%.

During the experiment, as monitored by TLC, the inventors found that the starting material was not completely reacted in the first step of example 2, which eventually resulted in a decrease in the yield of the final product.

Example 3

In a first step, a 5 liter glass reaction flask was charged with 1.5 liters of tetrahydrofuran, 300 g of L-alaninol (4 moles) was added, cooled to 5℃with ice water, 784 g of chloroacetaldehyde hydrate (40%, 4 moles) was added dropwise, and the temperature was controlled at 5 to 10 ℃. The reaction was completed for about 1 hour and was carried out at 5 to 10℃for 3 hours. The reaction solution is directly put into the next step

In the second step 300 g of potassium hydroxide (5.4 moles) were added to 1.5 liters of methanol in portions with stirring and the solution was stirred for further use. Gradually dripping the alkali liquor into the reaction liquid in the first step, controlling the temperature to be 10-15 ℃ and finishing dripping in about one hour. After completion of the dropwise addition, the reaction was carried out at 15-20℃for 16 hours, and the starting material of the TLC plate (DCM: meOH=20:1, one drop of ammonia water was added) was completed, and the reaction solution was directly fed to the next step.

The third step, controlling the temperature to be less than 15-20 degrees, adds 57 g sodium borohydride (1.5 mol) in batches of 10 g each, 1 hour apart. The reaction was completed at 15-20℃for 15 hours, and TLC (DCM: meOH=20:1, one drop of ammonia water) was used to monitor the completion of the reaction. The solids in the system were removed by suction filtration and the solids were washed with 500 ml of dichloromethane. The filtrates were combined and rotary distilled under reduced pressure until no significant liquid had evaporated, the residue remaining approximately 600 ml.

Rectifying and purifying, namely distilling the product S-3-methylmorpholine by using a glass packing rectifying column with the diameter of 40mm and the height of 500 mm and the vacuum degree of 50 mm Hg and 62 degrees, wherein LCMS (ESI): 102 (M+H), 96 g of a colorless liquid. The total yield of the three steps is 23.7%, the GC of the product is 98%, and EE is more than 99.5%.

Example 4

In a first step, a 5 liter glass reaction flask was charged with 1.5 liters of methylene chloride, 300 g of L-alaninol (4 moles) was added, cooled to 5℃with ice water, 784 g of chloroacetaldehyde hydrate (40%, 4 moles) was added dropwise, and the temperature was controlled at 5 to 10 ℃. The reaction was completed for about 1 hour at 5-10℃for 1 hour. The reaction solution is directly put into the next step

In the second step 300 g sodium hydroxide (7.5 moles) was added to 1.5 liters of methanol in portions with stirring and the solution was stirred for further use. Gradually dripping the alkali liquor into the reaction liquid in the first step, controlling the temperature to be 10-15 ℃ and finishing dripping in about one hour. After completion of the dropwise addition, the reaction was carried out at 15-20℃for 20 hours, and the starting material of the TLC plate (DCM: meOH=20:1, one drop of ammonia water was added) was completed, and the reaction solution was directly fed to the next step.

The third step, controlling the temperature to be less than 15-20 degrees, adds 57 g sodium borohydride (1.5 mol) in batches of 10 g each, 1 hour apart. The reaction was completed at 15-20℃for 20 hours, and TLC (DCM: meOH=20:1) was used to monitor the completion of the reaction of the starting materials. The solids in the system were removed by suction filtration and the solids were washed with 500 ml of dichloromethane. The filtrates were combined and rotary distilled under reduced pressure until no significant liquid had evaporated, the residue remaining at about 500 ml.

Rectifying and purifying, namely distilling the product S-3-methylmorpholine by using a glass packing rectifying column with the diameter of 40mm and the height of 500 mm and the vacuum degree of 50 mm Hg and 62 degrees, wherein LCMS (ESI): 102 (M+H), 112 g of a colorless liquid. The total yield of the three steps is 27.7%, the GC of the product is 97%, and the EE is more than 99%.

Example 5

In a first step, a 5 liter glass reaction flask was charged with 1.5 liters of methylene chloride, 412 g of L-valinol (4 moles) was added, cooled to 5℃with ice water, 784 g of chloroacetaldehyde hydrate (40%, 4 moles) was added dropwise, and the temperature was controlled at 5 to 10 ℃. The reaction was completed for about 1 hour at 5-10℃for 1 hour. The reaction solution is directly put into the next step

In the second step 300 g of potassium hydroxide (5.4 moles) were added to 1.5 liters of methanol in portions with stirring and the solution was stirred for further use. Gradually dripping the alkali liquor into the reaction liquid in the first step, controlling the temperature to be 10-15 ℃ and finishing dripping in about one hour. After completion of the dropwise addition, the reaction was carried out at 15-20℃for 16 hours, and the starting material of the TLC plate (DCM: meOH=20:1, one drop of ammonia water was added) was completed, and the reaction solution was directly fed to the next step.

The third step, controlling the temperature to be less than 15-20 degrees, adds 57 g sodium borohydride (1.5 mol) in batches of 10 g each, 1 hour apart. The reaction was completed at 15-20℃for 20 hours, and TLC (DCM: meOH=20:1) was used to monitor the completion of the reaction of the starting materials. The solids in the system were removed by suction filtration and the solids were washed with 500 ml of dichloromethane. The filtrates were combined and rotary distilled under reduced pressure until no significant liquid had evaporated, the residue remaining at about 500 ml.

Rectifying and purifying, namely distilling the product S-3-isopropyl morpholine by using a glass packing rectifying column with the diameter of 40mm and the height of 500 mm, a vacuum degree of 50 mm Hg and 70 degrees, and LCMS (ESI): 130.2 (M+H), 163 g of a colourless liquid. The total yield of the three steps is 31.5%, the GC of the product is 98%, and the EE is more than 99.5%.

Example 6

In a first step, a 5 liter glass reaction flask was charged with 2 liters of methylene chloride, 548.7 g of L-phenylglycinol (4 moles) was added, cooled to 5℃with ice water, 784 g of chloroacetaldehyde hydrate (40%, 4 moles) was added dropwise, and the temperature was controlled to 5 to 10 ℃. After about 1 hour of completion, the reaction was carried out at 5-10℃for 0.5 hour. The reaction solution is directly put into the next step

In the second step 300 g of potassium hydroxide (5.4 moles) were added to 1.5 liters of methanol in portions with stirring and the solution was stirred for further use. Gradually dripping the alkali liquor into the reaction liquid in the first step, controlling the temperature to be 10-15 ℃ and finishing dripping in about one hour. After completion of the dropwise addition, the reaction was carried out at 15-20℃for 10 hours, and the starting material of the TLC plate (DCM: meOH=20:1, one drop of ammonia water was added) was completed, and the reaction solution was directly fed to the next step.

The third step, controlling the temperature to be less than 15-20 degrees, adds 57 g sodium borohydride (1.5 mol) in batches of 10 g each, 1 hour apart. The reaction was completed at 15-20℃for 20 hours, and TLC (DCM: meOH=20:1) was used to monitor the completion of the reaction of the starting materials. The reaction solution was poured into a knockout vessel containing 5 l of water, stirred for half an hour, the lower dichloromethane layer was separated by standing, the aqueous phase was extracted with 2l of dichloromethane, the dichloromethane phases were combined, saturated brine was washed with water, dried over anhydrous sodium sulfate, the dichloromethane was distilled off by rotary evaporation, and the residue was transferred to a 500 ml single-port bottle.

Rectifying and purifying, namely distilling the product S-3-phenyl morpholine by using a glass filling rectifying column with the diameter of 40mm and the height of 300 mm, a vacuum degree of 0.5 mm Hg and 85 degrees, and LCMS (ESI): 164.2 (M+H), 231 g of colorless liquid. The total yield of the three steps is 35.3%, the GC of the product is 99%, and EE is more than 99.5%.

All documents in the volume of the present application are incorporated by reference in the present application as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. A continuous process for the preparation of a compound of formula II, comprising the steps of:

wherein R is a C1-C4 alkyl group or phenyl group;

1) Reacting a compound of formula I with chloroacetaldehyde in an inert solvent, thereby obtaining a first reaction mixture;

2) Mixing the first reaction mixture obtained in the step 1) with a solution of alkali and reacting to obtain a second reaction mixture;

3) Mixing the second reaction mixture obtained in the step 2) with a reducing agent and carrying out a reduction reaction to obtain the compound of the formula II.

2. The continuous production process according to claim 1, wherein R is methyl, ethyl, n-propyl, isopropyl or phenyl.

3. The continuous production process according to claim 1, wherein in step 1), the inert solvent is selected from the group consisting of: dichloromethane, methanol, tetrahydrofuran, and combinations thereof.

4. The continuous production process according to claim 1, wherein in step 1), the inert solvent is methylene chloride.

5. The continuous production process according to claim 1, wherein in step 2), the base is potassium hydroxide, sodium hydroxide or a combination thereof.

6. The continuous process of claim 1, wherein in step 2), the base is potassium hydroxide.

7. The continuous production process according to claim 1, wherein in step 2), the reaction is carried out at 15 to 20 degrees.

8. The continuous production method according to claim 1, wherein step 3) is: mixing the second reaction mixture obtained in the step 2) with a reducing agent and carrying out reduction reaction so as to obtain a crude product containing the compound of the formula II; the crude product is rectified to give the compound of formula II.

9. The continuous production process according to claim 8, wherein in step 3), the conditions of the rectification are selected from one or more of the following groups:

a) A glass filler rectifying column with the diameter of 40mm and the height of 300-500 mm is adopted;

b) Vacuum degree 50 mmHg;

c) 60-90 degrees.

10. The continuous production process according to claim 1, wherein in step 3), the reducing agent is sodium borohydride.