Method for synthesizing 2-morpholone and derivatives thereof

Abstract

The invention discloses a method for synthesizing 2-morpholone and derivatives thereof, and belongs to the technical field of synthesis of drug intermediates. According to the method, diethanol amine or a derivative thereof is contacted with a solid dehydrogenation catalyst, 2-morpholone and a derivative thereof are synthesized through a dehydrocyclization reaction, and hydrogen is produced at the same time. The reaction process is simple, the reaction conditions are mild, and the reaction raw materials are low in price and easy to obtain; the solid catalyst is adopted, separation is easy, and large-scale production is facilitated; the method has the advantages of green reaction process, high product selectivity, low energy consumption, low cost and better industrial application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of pharmaceutical intermediates, and more specifically, relates to a method for synthesizing 2-morpholinone and its derivatives. Background Art

[0002] 2-Morpholinone is an important pharmaceutical intermediate, mainly used in the synthesis of quinazoline drugs, which are mainly used for the treatment of cancer. Chinese Patent Invention CN108640884B discloses a method for preparing 2-morpholinone with an amino protecting group by using strong acid to catalyze N-(2-hydroxyethyl)glycine, and then acidifying and removing the protecting group from the 2-morpholinone with an amino protecting group to obtain 2-morpholinone salt, and 2-morpholinone is obtained by reacting the 2-morpholinone salt with a base in a solvent... The synthesis process is complex and highly polluting, which is not conducive to large-scale production. Chinese Patent Invention CN102260224B discloses a method for synthesizing 2-morpholinone derivatives by reacting amino alcohol and ester under the action of microwave, and the catalyst is a base or activated molecular sieve. The reaction by microwave is not conducive to large-scale production, and a large amount of solvent is used in the reaction process. Summary of the Invention

[0003] In order to overcome the disadvantages and deficiencies of the existing technology, the purpose of the present invention is to provide a method for synthesizing 2-morpholinone and its derivatives with a simple reaction process.

[0004] The purpose of the present invention is achieved by the following technical solutions:

[0005] The present invention provides a method for synthesizing 2-morpholinone and its derivatives, which comprises contacting diethanolamine or its derivatives with a solid dehydrogenation catalyst, and synthesizing 2-morpholinone and its derivatives and hydrogen through a dehydrogenation cyclization reaction. The synthesis route is as follows:

[0006]

[0007] wherein, R 1 is selected from H, C 1-3 alkyl, R 2 is selected from H, C 1-3 alkyl, R 3 is selected from H, C 1-3 alkyl, R 4 is selected from H, phenyl or substituted phenyl, and the substituent is selected from OH, OCH 3 , I, Br, Cl, NO 2 , CN, CF 3 .

[0008] Based on the above technical solution, further, the dehydrogenation cyclization reaction is carried out in a reaction kettle, the reaction temperature is 100 - 280 °C, preferably 180 - 240 °C, the hydrogen pressure in the reaction kettle is 0.1 - 5 bar, preferably 0.1 - 3 bar, and the stirring speed is 100 - 1000 rpm, preferably 500 - 700 rpm.

[0009] Based on the above technical solution, further, the mass ratio of the diethanolamine or its derivative to the catalyst is 1000:1 - 1:1, preferably 100:1 - 1:1.

[0010] Based on the above technical solution, further, the diethanolamine derivatives include the following 6 compounds:

[0011]

[0012] Based on the above technical solution, further, the solvent for the dehydrogenation cyclization reaction is at least one of 1,4 - dioxane, tetrahydrofuran, dimethyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol methyl ethyl ether, ethyl acetate, acetone, methyl isobutyl ketone, acetonitrile, toluene, and xylene.

[0013] Based on the above technical solution, further, the volume percentage content of the solvent is 0 - 80%.

[0014] Based on the above technical solution, further, the solid dehydrogenation catalyst is composed of an active component, a promoter, and a carrier. The active component is Cu and Zn, the molar ratio of Cu to Zn is 10:1 - 1:1, and the total mass of Cu and Zn accounts for 25 - 85% of the total mass of the solid dehydrogenation catalyst.

[0015] Based on the above technical solution, further, the promoter is at least one of La, Mn, Ce, Cr, Fe, Ca, Co, and Ni, and the total mass of the promoter accounts for 0 - 14% of the total mass of the solid dehydrogenation catalyst.

[0016] Based on the above technical solution, further, the carrier is at least one of silica, alumina, magnesia, and titania.

[0017] Based on the above technical solution, further, the solid dehydrogenation catalyst is prepared by the co - precipitation method. The specific process is as follows: While stirring, a basic solution is slowly added dropwise to an aqueous solution containing the active component, the promoter, and the carrier component until complete precipitation occurs. Aging is carried out at 50 - 70 °C for 12 - 36 h; filtration is carried out, and the filter cake is washed with water until neutral. The obtained filter cake is dried and ground to obtain a catalyst precursor; the catalyst precursor is calcined in an air atmosphere at 400 - 500 °C for 3 - 10 h, and then reduced in a hydrogen atmosphere at 250 - 350 °C for 1 - 5 h to obtain the solid dehydrogenation catalyst.

[0018] Based on the above technical solution, further, the solute of the alkaline solution is one or a combination of two or more of sodium hydroxide, sodium carbonate, and ammonia water.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The present invention synthesizes 2-morpholinone and its derivatives by one-step dehydrogenation reaction of diethanolamine and its derivatives. The reaction process is simple, and the reaction raw materials are low in price and easy to obtain.

[0021] 2. The synthesis method of the present invention uses a solid catalyst, and the separation of the catalyst and the product is easy, which is conducive to large-scale production.

[0022] 3. The synthesis method of the present invention only requires a small amount of solvent or does not need to add solvent, which can reduce energy consumption and save costs.

[0023] 4. The synthesis reaction process of the present invention is green and environmentally friendly, basically pollution-free, and meets the current requirements of energy conservation and emission reduction. Specific Embodiments

[0024] The present invention will be described in detail below in conjunction with embodiments. However, the embodiments of the present invention are not limited thereto. Obviously, the embodiments described below are only partial embodiments of the present invention. For those skilled in the art, without creative efforts, obtaining other similar embodiments will fall within the protection scope of the present invention.

[0025] Experimental process of gas chromatography analysis in the embodiment: An Agilent 7890B high-performance gas chromatograph was used to analyze the reaction products, and the external standard method was used for quantification; test conditions: the chromatographic column was FFAP, the hydrogen flame detector (FID), hydrogen was used as the carrier gas, the constant mode, the split ratio was 100:1, and the column oven temperature was 75 °C (2 min), rising to 280 °C at 30 °C / min (holding for 2 min).

[0026] Conversion rate of diethanolamine = (1 - (mass of diethanolamine after reaction / mass of diethanolamine before reaction)) × 100%

[0027] Selectivity of 2-morpholinone = (mass of 2-morpholinone / mass of diethanolamine before reaction (mass of diethanolamine before reaction - mass of diethanolamine after reaction)) × 100%

[0028] Example 1: Synthesis of 2-morpholinone

[0029] Synthesis of CuZnAl catalyst: Prepare 50 mL of an aqueous solution containing 0.02 mol of copper nitrate trihydrate, 0.01 mol of zinc nitrate hexahydrate, and 0.01 mol of aluminum nitrate nonahydrate. Heat it to 85 °C and slowly add ammonia water dropwise with stirring until complete precipitation. Age at 60 °C for 24 hours; filter, wash with deionized water until the pH of the filtrate is 7, dry the filter cake at 100 °C for 12 h, and grind to obtain the catalyst precursor; calcine the catalyst precursor in an air atmosphere at 450 °C for 5 hours, and then reduce it with >99.9% hydrogen at 300 °C for 2 hours to obtain the CuZnAl solid powder catalyst.

[0030] Catalytic reaction: Use a 25 mL batch reactor, 10 mL of diethanolamine, 500 mg of CuZnAl catalyst, charge 1.5 bar of hydrogen, reaction temperature 220 °C, react for 6 hours, stirring speed 600 rpm; during the reaction, maintain the reaction pressure at 1.5 bar.

[0031] The synthesis route of 2-morpholinone is as follows:

[0032]

[0033] After the reaction, use gas chromatography analysis. The conversion rate of diethanolamine is 98.2%, and the selectivity of 2-morpholinone is 99.1%.

[0034] Example 2

[0035] Catalytic reaction: Use a 25 mL batch reactor, 10 mL of diethanolamine, 500 mg of the CuZnAl catalyst from Example 1, charge 1.5 bar of hydrogen, reaction temperature 180 °C, react for 6 hours, stirring speed 600 rpm; during the reaction, maintain the reaction pressure at 1.5 bar.

[0036] After the reaction, use gas chromatography analysis. The conversion rate of diethanolamine is 41.4%, and the selectivity of 2-morpholinone is 99.8%.

[0037] Example 3

[0038] Catalytic reaction: Use a 25 mL batch reactor, 10 mL of diethanolamine, 500 mg of the CuZnAl catalyst from Example 1, charge 1.5 bar of hydrogen, reaction temperature 180 °C, react for 6 hours, stirring speed 600 rpm; during the reaction, maintain the reaction pressure at 5 bar.

[0039] After the reaction, use gas chromatography analysis. The conversion rate of diethanolamine is 18.6%, and the selectivity of 2-morpholinone is 99.5%.

[0040] Example 4: Synthesis of 4-phenyl-2-morpholinone

[0041] Using a 25 mL batch reactor, 1 g of N,N - dihydroxyethylaniline, 8 mL of ethylene glycol diethyl ether solvent, 500 mg of the CuZnAl catalyst of Example 1, charging 2.5 bar of hydrogen, reaction temperature 220 °C, reacting for 6 hours, stirring speed 600 rpm; during the reaction, maintain the reaction pressure at 1.5 bar.

[0042] The synthetic route of 4 - phenyl - 2 - morpholinone is as follows:

[0043]

[0044] After the reaction, gas chromatography analysis was used. The conversion rate of N,N - dihydroxyethylaniline was 97.1%, and the selectivity of 4 - phenyl - 2 - morpholinone was 98.4%.

[0045] Example 5:

[0046] Using a 25 mL batch reactor, 1 g of N,N - dihydroxyethylaniline, 8 mL of ethylene glycol diethyl ether solvent, 500 mg of the CuZnAl catalyst of Example 1, charging 2.5 bar of hydrogen, reaction temperature 180 °C, reacting for 6 hours, stirring speed 600 rpm; during the reaction, maintain the reaction pressure at 1.5 bar.

[0047] After the reaction, gas chromatography analysis was used. The conversion rate of N,N - dihydroxyethylaniline was 32.5%, and the selectivity of 4 - phenyl - 2 - morpholinone was 99.6%.

[0048] Example 6:

[0049] Using a 25 mL batch reactor, 1 g of N,N - dihydroxyethylaniline, 8 mL of ethylene glycol diethyl ether solvent, 500 mg of the CuZnAl catalyst of Example 1, charging 2.5 bar of hydrogen, reaction temperature 180 °C, reacting for 6 hours, stirring speed 600 rpm; during the reaction, maintain the reaction pressure at 5 bar.

[0050] After the reaction, gas chromatography analysis was used. The conversion rate of N,N - dihydroxyethylaniline was 8.2%, and the selectivity of 4 - phenyl - 2 - morpholinone was 99.7%.

[0051] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present invention, not to limit it; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing examples, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing 2-morpholinone and its derivatives, characterized in that: Diethanolamine or its derivatives are contacted with a solid dehydrogenation catalyst to synthesize 2-morpholinone and its derivatives and hydrogen through a dehydrogenation cyclization reaction. The synthesis route is as follows: Wherein, R1 is selected from H, C 1-3 alkyl, R2 is selected from H, C 1-3 alkyl, R3 is selected from H, C 1-3 alkyl, R4 is selected from H, phenyl or substituted phenyl, and the substituent is selected from OH, OCH3, I, Br, Cl, NO2, CN, CF3.

2. The method according to claim 1, characterized in that The dehydrogenation cyclization reaction is carried out in a reactor at a reaction temperature of 100 to 280° C., preferably 180 to 240° C., a hydrogen pressure of 0.1 to 5 bar, preferably 0.1 to 3 bar, and a stirring speed of 100 to 1000 rpm, preferably 500 to 700 rpm.

3. The method according to claim 1, characterized in that: The mass ratio of the diethanolamine or its derivative to the catalyst is 1000:1 to 1:1, preferably 100:1 to 1:

1.

4. The method according to claim 1, characterized in that Diethanolamine derivatives include the following 6 compounds:

5. The method according to claim 1, characterized in that: The solvent for the dehydrogenation cyclization reaction is at least one of 1,4-dioxane, tetrahydrofuran, dimethyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol methyl ethyl ether, ethyl acetate, acetone, methyl isobutyl ketone, acetonitrile, toluene and xylene, and the volume percentage content of the solvent is 0-80%.

6. The method according to claim 1, characterized in that The solid dehydrogenation catalyst consists of active components, auxiliary agents and carriers. The active components are Cu and Zn. The molar ratio of Cu and Zn is 10:1 to 1:

1. The total mass of Cu and Zn accounts for 25 to 85% of the total mass of the solid dehydrogenation catalyst.

7. The method according to claim 6, characterized in that The auxiliary agent is at least one of La, Mn, Ce, Cr, Fe, Ca, Co and Ni, and the total mass of the auxiliary agent accounts for 0 to 14% of the total mass of the solid dehydrogenation catalyst.

8. The method according to claim 6, characterized in that The carrier is at least one of silicon oxide, aluminum oxide, magnesium oxide and titanium oxide.

9. The method according to any one of claims 6 to 8, characterized in that: The solid dehydrogenation catalyst is prepared by a coprecipitation method, and the specific process is as follows: slowly adding an alkaline solution to an aqueous solution containing active components, auxiliary agents, and carrier components under stirring until complete precipitation, and aging at 50-70° C. for 12-36 hours; filtering, washing with water until neutral, drying the obtained filter cake, and grinding to obtain a catalyst precursor; calcining the catalyst precursor at 400-500° C. in an air atmosphere for 3-10 hours, and then reducing it at 250-350° C. in a hydrogen atmosphere for 1-5 hours to obtain a solid dehydrogenation catalyst.

10. The method according to claim 9, characterized in that The solute of the alkaline solution is one or a combination of two or more of sodium hydroxide, sodium carbonate and ammonia water.

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