Preparation method of 2-bromo-5-morpholinyl methyl benzoate

Abstract

The invention relates to a preparation method of 2-bromine-5-morpholinyl methyl benzoate, which comprises the following steps: (1) taking 2-bromine-5-methyl iodobenzoate and morpholine as raw materials, adding the raw materials into an organic solvent, then adding 18-crown ether-6, cuprous iodide and strong alkali and weak acid salt into the system, and mixing to obtain a reaction solution; (2) heating the reaction solution to 120 to 140 DEG C, and reacting for 9 to 12 hours to obtain a solution containing 2-bromo-5-morpholinyl methyl benzoate; and (3) carrying out post-treatment on the solution containing the 2-bromo-5-morpholinyl methyl benzoate, so as to obtain the 2-bromo-5-morpholinyl methyl benzoate. The preparation method of the 2-bromo-5-morpholinyl methyl benzoate provided by the invention is simple, few in side reaction and high in yield.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediate preparation, and specifically relates to a method for preparing methyl 2-bromo-5-morpholinobenzoate. Background Art

[0002] In the field of organic compounds, morpholinyl, as a substituent of an aromatic group, is usually used alone or together with an aromatic group as a selectable substituent of a functional compound. As disclosed in US20020165218A1, DNA-PK inhibitors are disclosed, wherein compound 47 is 2-hydroxy-5-morpholine-4-yl methyl benzoate, which needs to first prepare 2-(tert-butyldimethylsilyl-, oxy)-5-morpholine-4-yl methyl benzoate, and then remove tert-butylsiloxane, which is complicated to operate, has low atom utilization, and is relatively costly. WO2014165816A1 discloses a glutamate dehydrogenase activator, and compound 91 is 3-chloro-4-{[2-hydroxy-5-(morpholine-4-, yl) benzyl] amido} methyl benzoate, which needs to be on 2-hydroxy-5-amino-methyl benzoate, using dichloroethyl ether to carry out morpholine ring closure, which is complicated to operate and is costly.

[0003] There is a need in the art to develop a preparation method capable of introducing a morpholine group into a compound to reduce the synthesis cost of the corresponding compound. Summary of the invention

[0004] In view of the deficiencies in the prior art, one of the objects of the present invention is to provide a method for preparing methyl 2-bromo-5-morpholinobenzoate, comprising the following steps:

[0005] (1) using methyl 2-bromo-5-iodobenzoate and morpholine as raw materials, adding the raw materials into an organic solvent, then adding 18-crown ether-6, cuprous iodide and a strong base and weak acid salt into the system, and mixing to obtain a reaction solution;

[0006] (2) raising the temperature of the reaction solution to 120-140° C. (e.g., 123° C., 127° C., 132° C., 138° C., etc.), reacting for 9-12 hours (e.g., 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, etc.) to obtain a solution containing methyl 2-bromo-5-morpholinobenzoate;

[0007] (3) Post-treating the solution containing methyl 2-bromo-5-morpholinobenzoate to obtain methyl 2-bromo-5-morpholinobenzoate.

[0008] The preparation method of 2-bromo-5-morpholinyl methyl benzoate provided by the application is simple to operate and has high yield. The application uses 18-crown ether-6 as a ligand, complexed with metal ions (cuprous ions and potassium ions), can generate an organometallic intermediate with the iodine of 2-bromo-5-iodobenzoic acid methyl esters, and promotes its reaction with the nitrogen atom of morpholine, so that morpholine replaces the iodine atom of 2-bromo-5-iodobenzoic acid methyl esters, generates 2-bromo-5-morpholinyl methyl benzoate. 18-crown ether-6 can improve reaction rate and productive rate, and the special structure of 18-crown ether-6 simultaneously improves the stability of intermediate, reduces the occurrence of side reactions, and improves productive rate.

[0009] Preferably, the organic solvent includes any one of N-methylpyrrolidone, dimethyl sulfoxide, toluene, and xylene, or a combination of at least two thereof, preferably N-methylpyrrolidone.

[0010] Compared with other organic solvents, N-methylpyrrolidone can obtain a higher yield of methyl 2-bromo-5-morpholinobenzoate.

[0011] Preferably, the strong base weak acid salt comprises any one of potassium carbonate, potassium phosphate, sodium carbonate or a combination of at least two thereof, preferably potassium phosphate.

[0012] Preferably, the molar amount of morpholine added is 1.1 to 1.3 times the molar amount of methyl 2-bromo-5-iodobenzoate, for example, 1.13 times, 1.17 times, 1.20 times, 1.23 times, 1.25 times, 1.28 times, etc.

[0013] Preferably, the molar amount of the strong base weak acid salt added is 1.2 to 1.5 times the molar amount of methyl 2-bromo-5-iodobenzoate, for example, 1.23 times, 1.25 times, 1.28 times, 1.34 times, 1.37 times, 1.42 times, 1.48 times, etc.

[0014] Preferably, the molar addition amount of cuprous iodide is 3-10% of the molar amount of methyl 2-bromo-5-iodobenzoate, for example, 3.2%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9.4%, 9.8%, etc.

[0015] Preferably, the molar addition amount of 18-crown ether-6 is 3 to 10% of the molar amount of methyl 2-bromo-5-iodobenzoate, for example, 3.2%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9.4%, 9.8%, etc.

[0016] Preferably, the molar ratio of the 18-crown ether-6 to cuprous iodide is 1:0.95-1.05, for example, 1:0.98, 1:1, 1:1.03, etc.

[0017] Preferably, the water content of the 18-crown ether-6 is ≤1%, such as 0.5%, 0.2%, 0.05%, 0.02%, etc.

[0018] Preferably, the post-treatment comprises concentrating the "solution containing methyl 2-bromo-5-morpholinobenzoate", adding dichloromethane, mixing silica gel particles therein, evaporating to dryness, filling the silica gel particles into a glass column, eluting the silica gel particles with a mixed solvent of ethyl acetate and n-heptane, and concentrating the eluate to obtain methyl 2-bromo-5-morpholinobenzoate.

[0019] Preferably, the mixing ratio of ethyl acetate and n-heptane is 1:4-1:5, for example, 1:4.1, 1:4.3, 1:4.6, 1:4.8, etc.

[0020] Compared with the prior art, this application has the following beneficial effects:

[0021] (1) The preparation method of methyl 2-bromo-5-morpholinobenzoate provided in the present application is simple, has few side reactions and high yield.

[0022] (2) The methyl 2-bromo-5-morpholinobenzoate provided in the present application can be used as a substrate for the introduction of a morpholino group. Bromine is prone to undergo conventional reactions such as substitution and hydrolysis, thus providing the possibility of introducing a morpholino group or an aromatic group substituted with a morpholino group. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The liquid chromatogram of methyl 2-bromo-5-morpholinobenzoate is given;

[0024] Figure 2 The NMR of the product methyl 2-bromo-5-morpholinobenzoate is given;

[0025] Figure 3 The mass spectrum of methyl 2-bromo-5-morpholinobenzoate is given. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is further explained below in conjunction with specific implementation methods. However, it should be noted that the specific implementation methods are only a specific implementation and explanation of the essence of the technical solution of the present invention, and should not be understood as a limitation on the protection scope of the present invention.

[0027] The reagents and instruments used in the examples can all be purchased from commercial products, and the detection methods are conventional methods well known in the art.

[0028] Example 1

[0029] A method for preparing methyl 2-bromo-5-morpholinobenzoate comprises the following steps:

[0030] (1) methyl 2-bromo-5-iodobenzoate (341.1 g, about 1 mol) and morpholine (105.3 g, about 1.2 mol) were used as raw materials, and the raw materials were added to 3000 mL of N-methylpyrrolidone, and then 18-crown ether-6 (22.6 g, about 0.086 mol), cuprous iodide (16.20 g, about 0.085 mol) and potassium phosphate (276 g, about 1.3 mol) were added to the system, and a reaction solution was obtained after mixing;

[0031] (2) heating the reaction solution to 130° C. and reacting for 10 hours to obtain a solution containing methyl 2-bromo-5-morpholinobenzoate;

[0032] (3) The solution containing methyl 2-bromo-5-morpholinobenzoate was concentrated and then added with dichloromethane. 4 times the weight of the concentrated solution was mixed with silica gel particles (200-300 meshes). After the dichloromethane was removed by rotary evaporation, 8 times the weight of the concentrated solution was mixed with silica gel particles (200-300 meshes). The silica gel particles were filled into a glass column to obtain a silica gel column. The silica gel column was eluted with a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:5. The eluate was concentrated to obtain methyl 2-bromo-5-morpholinobenzoate (276.9 g, purity 98.66%). The molar yield was calculated to be 91.4%.

[0033] Figure 1 The liquid chromatogram of methyl 2-bromo-5-morpholinobenzoate is given. After normalization calculation, the purity is 98.66%.

[0034] Figure 2 The NMR of the product 2-bromo-5-morpholinobenzoic acid methyl ester is given. Figure 2 The nuclear magnetic resonance results are H-NMR (DMSO-d6), chemical shift: 7.51, d, 1H; 7.25, d, 2H; 7.05, t, 3H; 3.85, s, 3H; 3.73, t, 3H; 3.14, t, 3H, which are consistent with the analytical results of methyl 2-bromo-5-morpholinobenzoate.

[0035] Figure 3 The mass spectrum of methyl 2-bromo-5-morpholinobenzoate is given, which is consistent with the analytical results of methyl 2-bromo-5-morpholinobenzoate.

[0036] Example 2

[0037] A method for preparing methyl 2-bromo-5-morpholinobenzoate comprises the following steps:

[0038] (1) methyl 2-bromo-5-iodobenzoate (340.9 g, about 1 mol) and morpholine (113.5 g, about 1.2 mol) were used as raw materials, and the raw materials were added to 3000 mL of N-methylpyrrolidone, and then 18-crown ether-6 (26.4 g, about 0.1 mol), cuprous iodide (19.1 g, about 0.1 mol) and potassium phosphate (256 g, about 1.2 mol) were added to the system, and a reaction solution was obtained after mixing;

[0039] (2) heating the reaction solution to 120° C. and reacting for 9 hours to obtain a solution containing methyl 2-bromo-5-morpholinobenzoate;

[0040] (3) The solution containing methyl 2-bromo-5-morpholinobenzoate was concentrated and then added with dichloromethane. 4 times the weight of the concentrate was mixed with silica gel particles (200-300 meshes). After the dichloromethane was removed by rotary evaporation, 8 times the weight of the concentrate was mixed with silica gel particles (200-300 meshes). The silica gel particles were filled into a glass column to obtain a silica gel column. The silica gel column was eluted with a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:5. The eluate was concentrated to obtain methyl 2-bromo-5-morpholinobenzoate (275.95 g, purity 98.58%). The molar yield was calculated to be 91.0%.

[0041] Example 3

[0042] A method for preparing methyl 2-bromo-5-morpholinobenzoate comprises the following steps:

[0043] (1) methyl 2-bromo-5-iodobenzoate (340.0 g, about 1 mol) and morpholine (95.9 g, about 1.1 mol) were used as raw materials, and the raw materials were added to 3000 mL of N-methylpyrrolidone, and then 18-crown ether-6 (8.1 g, about 0.031 mol), cuprous iodide (5.8 g, about 0.030 mol) and potassium phosphate (318 g, about 1.5 mol) were added to the system, and a reaction solution was obtained after mixing;

[0044] (2) heating the reaction solution to 120-140° C. and reacting for 9-12 hours to obtain a solution containing methyl 2-bromo-5-morpholinobenzoate;

[0045] (3) The solution containing methyl 2-bromo-5-morpholinobenzoate was concentrated and then added with dichloromethane. 4 times the weight of the concentrated solution was mixed with silica gel particles (200-300 meshes). After the dichloromethane was removed by rotary evaporation, 8 times the weight of the concentrated solution was mixed with silica gel particles (200-300 meshes). The silica gel particles were filled into a glass column to obtain a silica gel column. The silica gel column was eluted with a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:5. The eluate was concentrated to obtain methyl 2-bromo-5-morpholinobenzoate (270.36 g, purity 98.72%). The molar yield was calculated to be 83.3%.

[0046] Comparative Example 1

[0047] A method for preparing methyl 2-bromo-5-morpholinobenzoate comprises the following steps:

[0048] (1) methyl 2-bromo-5-iodobenzoate (341.5 g, about 1 mol) and morpholine (106.4 g, about 1.2 mol) were used as raw materials, and the raw materials were added to 3000 mL of N-methylpyrrolidone, and then 1,2-diaminocyclohexane (9.82 g, about 0.086 mol), cuprous iodide (16.18 g, about 0.085 mol) and potassium phosphate (277 g, about 1.3 mol) were added to the system, and a reaction solution was obtained after mixing;

[0049] (2) heating the reaction solution to 130° C. and reacting for 10 hours to obtain a solution containing methyl 2-bromo-5-morpholinobenzoate;

[0050] (3) The solution containing methyl 2-bromo-5-morpholinobenzoate was concentrated and then added with dichloromethane. 4 times the weight of the concentrated solution was mixed with silica gel particles (200-300 meshes). After the dichloromethane was removed by rotary evaporation, 8 times the weight of the concentrated solution was mixed with silica gel particles (200-300 meshes). The silica gel particles were filled into a glass column to obtain a silica gel column. The silica gel column was eluted with a mixed solvent of ethyl acetate and n-heptane in a volume ratio of 1:5. The eluate was concentrated to obtain methyl 2-bromo-5-morpholinobenzoate (192.7 g, purity 78.52%). The molar yield was calculated to be 50.6%.

[0051] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing methyl 2-bromo-5-morpholinobenzoate, characterized in that: The preparation method comprises the following steps: (1) using methyl 2-bromo-5-iodobenzoate and morpholine as raw materials, adding the raw materials into an organic solvent, then adding 18-crown ether-6, cuprous iodide and a strong base and weak acid salt into the system, and mixing to obtain a reaction solution; (2) heating the reaction solution to 120-140° C. and reacting for 9-12 hours to obtain a solution containing methyl 2-bromo-5-morpholinobenzoate; (3) Post-treating the solution containing methyl 2-bromo-5-morpholinobenzoate to obtain methyl 2-bromo-5-morpholinobenzoate.

2. The preparation method according to claim 1, characterized in that The organic solvent includes any one of N-methylpyrrolidone, dimethyl sulfoxide, toluene, and xylene, or a combination of at least two thereof, preferably N-methylpyrrolidone.

3. The preparation method according to claim 1 or 2, characterized in that: The strong base weak acid salt includes any one of potassium carbonate, potassium phosphate, and sodium carbonate, or a combination of at least two thereof, preferably potassium phosphate.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar amount of the morpholine added is 1.1 to 1.3 times the molar amount of methyl 2-bromo-5-iodobenzoate.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The molar amount of the strong base and weak acid salt added is 1.2 to 1.5 times the molar amount of methyl 2-bromo-5-iodobenzoate.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molar amount of the cuprous iodide added is 3-10% of the molar amount of methyl 2-bromo-5-iodobenzoate.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The molar amount of the 18-crown ether-6 added is 3-10% of the molar amount of methyl 2-bromo-5-iodobenzoate.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The molar ratio of the 18-crown ether-6 to cuprous iodide is 1:0.95-1.05; Preferably, the water content of the 18-crown ether-6 is ≤1%.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The post-treatment comprises concentrating the "solution containing methyl 2-bromo-5-morpholinobenzoate", adding dichloromethane, mixing silica gel particles therein, evaporating and drying, filling the silica gel particles into a glass column, eluting the silica gel particles with a mixed solvent of ethyl acetate and n-heptane, and concentrating the eluate to obtain methyl 2-bromo-5-morpholinobenzoate.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The mixing ratio of the ethyl acetate and n-heptane is 1:4 to 1:5.

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