Preparation method of morphonidazole isomer

Abstract

The invention provides a preparation method of a morphonidazole isomer. According to the method, certain purity and yield of the morphonidazole isomer are guaranteed, enough reference substances can be conveniently prepared, detection of the morphonidazole isomer is facilitated, and then the quality of the morphonidazole is controlled.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a method for preparing morpholiniazole isomers. Background Art

[0002] Nitroimidazole antibiotics, traditional drugs sold on the market mainly include metronidazole, ornidazole, secnidazole, etc., especially metronidazole as a bactericide, which has a broad spectrum of anti-anaerobic bacteria. It is highly sensitive to Bacteroides fragilis, Eubacterium, and Clostridium perfringens, moderately sensitive to Peptococcus, Streptococcus, and Pleurotus eryngii, and less sensitive to non-spore-forming Gram-positive bacilli.

[0003] Morpholinazole, as a third-generation nitroimidazole derivative, has good anti-anaerobic, anti-trichomonal, and anti-amoeba properties and is highly safe.

[0004] Patent CN100427094 discloses a method for preparing morpholiniazole, which is prepared by a ring-opening reaction of an epoxy compound. In the ring-opening reaction, the epoxy compound has two reaction sites and a side reaction, which can produce a compound of formula I: 3-(2-methyl-5-nitro-1H-imidazol-1-yl)-2-morpholinopropanol, which is a morpholiniazole isomer:

[0005]

[0006] This isomer I is close to morpholine nidazole in nature and is not easy to separate, so it is mixed in morpholine nidazole to affect product quality. This morpholine nidazole isomer needs to be obtained by special reaction, but the method that can obtain required isomer efficiently and with high quality has not yet been found. Therefore, it is urgent to develop a simple method for preparing this isomer in high yield.

[0007] Patent CN201310546188.5 discloses a method for preparing morpholinonitrile isomer I, which is obtained by chlorination, rearrangement and hydrolysis, as shown in the following formula:

[0008]

[0009] However, the morpholiniazole isomers prepared by this method have the problems of extremely low yield and difficulty in purification and separation. This is because the rearrangement process of the preparation method is an equilibrium reaction, which increases the steric hindrance of the product. Summary of the invention

[0010] In order to improve the yield of morpholiniazole isomers and avoid the use of preparative column purification, the present invention intends to provide a method for preparing morpholiniazole isomers. The technical solution adopted by the present invention is:

[0011] The present invention provides a method for preparing morpholiniazole isomers, and the specific steps are as follows:

[0012]

[0013] Further, formula II is prepared by the following steps:

[0014]

[0015] In the present invention, morpholine and diethyl bromomalonate are used as raw materials to undergo nucleophilic substitution to generate a compound of formula III, and then the carboxylate is reduced to an alcohol to generate a compound of formula II, and finally reacted with 2-methyl-4-nitroimidazole to obtain a morpholinonitrile isomer of formula I. The reaction route is as follows:

[0016]

[0017] In the present invention, the solvent used in step (1) is at least one of dimethylformamide, dimethyl sulfoxide, diethylamine, triethylamine, and N,N-diisopropylethylamine, preferably dimethylformamide.

[0018] Wherein, step (1) is reacted in the presence of a base, and the base is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium tert-butoxide, preferably potassium carbonate.

[0019] Wherein, the reaction temperature of step (1) is 10°C to 30°C, and the reaction time is 1 hour to 3 hours.

[0020] Among them, the molar ratio of morpholine to diethyl bromomalonate is below 1:1. If diethyl bromomalonate is in excess, it is more conducive to the reaction. Taking the cost into consideration, the molar ratio of compound 5 to ethyl 4-bromobutyrate can be selected from 1:(1 to 1.2).

[0021] Among them, the molar ratio of morpholine to base can be less than 1:0.5, for example, it can be 1:(0.5-4), and can be selected from 1:0.5, 1:0.8, 1:1, 1:1.5, 1:1.7, 1:2, 1:2.5, 1:3, 1:3.3, 1:4, etc.

[0022] In the present invention, step (2) is a reduction reaction, and the carboxylic acid ester is relatively easy to be reduced to an alcohol. The commonly used reduction system is sodium alcoholate, such as sodium methoxide, sodium ethoxide, etc.; metal hydride such as lithium aluminum hydride (LAH), sodium (potassium) borohydride, etc.; wherein the reducing agent of step (2) is selected from sodium dihydrogen bis(2-methoxyethoxy)aluminate 70% toluene solution, lithium aluminum tetrahydride, preferably sodium dihydrogen bis(2-methoxyethoxy)aluminate 70% toluene solution.

[0023] Wherein, the molar ratio of compound III to the reducing agent is 1:(1-3), preferably 1:(1-2).

[0024] The solvent used in step (2) is selected from one or more of tetrahydrofuran, dichloromethane and toluene, preferably toluene.

[0025] The reaction time is 4 to 6 hours, preferably 4 hours.

[0026] Wherein, the coupling reagent in step (3) is selected from one or more of diethyl azodicarboxylate, diisopropyl azodicarboxylate, triphenylphosphine and tributylphosphine, preferably diethyl azodicarboxylate and triphenylphosphine.

[0027] Wherein, the temperature of step (3) can be selected from 55°C to 75°C, for example, 55°C to 65°C, 65°C to 75°C, 60°C to 70°C, etc. More specifically, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75°C, etc.

[0028] The reaction time of step (3) is 1 to 4 hours, preferably 2 to 3 hours.

[0029] Wherein, the molar ratio of compound II to 2-methyl-5-nitroimidazole is 1:(1-5), further selected from 1:(1-2).

[0030] In the present invention, the solvent used in the reaction of step (3) is selected from one or more of benzene, toluene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, dimethylformamide, dimethylacetamide and dichloromethane, preferably dimethylformamide.

[0031] After the reaction of step (3) is completed, a purification step is further included. The purification of the present invention is carried out by using inorganic acid salt formation, inorganic base dissociation, and extraction.

[0032] Among them, the inorganic acid can be selected from but not limited to hydrogen chloride, acetic acid, methanesulfonic acid, sulfuric acid, preferably hydrogen chloride, and the non-polar base can be selected from but not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, preferably sodium carbonate.

[0033] Among them, the extraction can be carried out using an organic solvent and an aqueous phase in which compound I is well soluble, and commonly used organic solvents include but are not limited to ethyl acetate; the aqueous phase can be water or a sodium chloride aqueous solution. For ease of operation, hydrogen chloride can also be added in the form of a hydrogen chloride ethyl acetate solution, and sodium carbonate can be added in the form of a sodium carbonate aqueous solution. The solvent is single, which is convenient for extraction operation and removal.

[0034] The invention provides a method for preparing morpholinidazole isomers, which not only does not use a preparation column for purification, thereby reducing the cumbersome preparation process, but also ensures a high purity and yield, facilitates the preparation of sufficient reference substances, is beneficial to the detection of morpholinidazole isomers, and further controls the product quality of morpholinidazole. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with comparative examples and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, if not clearly stated, all reagents used in the following embodiments are commercially available, or can be synthesized according to this article or known methods, and for the reaction conditions not listed, they are also easily available to those skilled in the art.

[0036] Example 1

[0037] Preparation of compound III

[0038] Dissolve 2.0g of morpholine in 20mL of dimethyl sulfoxide, add 2.4g of sodium carbonate, control the temperature at 10-30°C, drop 5.5g of diethyl bromomalonate, and keep warm for 2 hours. After the reaction, add 20mL of ethyl acetate and 20mL of water, extract the organic phase, and concentrate to dryness to obtain 4.3g of white solid, namely compound III, with a molar yield of 77%. Compound III was characterized, ESI-MS: m / z246 (M+H + ).

[0039] Example 2

[0040] Preparation of compound III

[0041] 2.0 g of morpholine was dissolved in 20 mL of dimethylformamide, the temperature was controlled at 10-30 ° C, 3.2 g of potassium carbonate was added, 5.5 g of diethyl bromomalonate was added dropwise, and the reaction was kept warm for 2 hours. After the reaction, 20 mL of ethyl acetate and 20 mL of water were added, the organic phase was extracted, and concentrated to dryness to obtain 5.2 g of white solid, i.e., compound III, with a molar yield of 93%. Compound III was characterized in the same way as in Example 1.

[0042] Example 3

[0043] Preparation of Compound II

[0044] 5.0g of compound III was added to 30mL of tetrahydrofuran, and then 18mL of sodium dihydrobis(2-methoxyethoxy)aluminate 70% toluene solution was added, and the mixture was refluxed for 4 hours. After the reaction, the mixture was cooled to room temperature, 20mL of 10% sodium hydroxide solution was added, and then 50mL of ethyl acetate was added, and the mixture was filtered. The filtrate was allowed to stand, and the water phase was separated. The organic phase was washed twice with saturated sodium chloride solution, 20mL each time. The organic phase was concentrated under reduced pressure to obtain 2.1g of a light yellow oil, namely compound II, with a molar yield of 64%. Compound II was characterized, ESI-MS: m / z 162 (M+H + ).

[0045] Example 4

[0046] Preparation of Compound II

[0047] 5.0g of compound III was added to 30mL of toluene, and then 18mL of 70% toluene solution of sodium dihydrobis(2-methoxyethoxy)aluminate was added, and the mixture was refluxed for 4 hours. After the reaction, the mixture was cooled to room temperature, and 20mL of 10% sodium hydroxide solution was added, and 50mL of ethyl acetate was added, and the mixture was filtered. The filtrate was allowed to stand, and the water phase was separated. The organic phase was washed twice with saturated sodium chloride solution, 20mL each time. The organic phase was concentrated under reduced pressure to obtain 2.6g of a light yellow oil, namely compound II, with a molar yield of 79%. Compound II was characterized in the same way as in Example 3.

[0048] Example 5

[0049] Preparation of Compound II

[0050] 5.0g of compound III was added to 30mL of tetrahydrofuran, and then 2.7g of lithium aluminum tetrahydride was added, and the reaction was refluxed for 4 hours. After the reaction, the temperature was cooled to room temperature, 20mL of 10% sodium hydroxide solution was added, 50mL of ethyl acetate was added, and the filtrate was allowed to stand, the water phase was separated, and the organic phase was washed twice with saturated sodium chloride solution, 20mL each time. The organic phase was concentrated under reduced pressure to obtain 1.7g of a light yellow oil, namely compound II, with a molar yield of 52%. Compound II was characterized in the same way as in Example 3.

[0051] Example 6

[0052] Preparation of Morpholinonitrile Isomers (Compound Ⅰ)

[0053] Under nitrogen protection, add 2.5 mL DEAD to 40 mL dimethylformamide, then add 2.0 g triphenylphosphine, keep warm for 0.5 hours, add 2.5 g compound II and 2.0 g 2-methyl-5-nitroimidazole in sequence, raise the temperature to 60-70°C, keep warm for 2 hours. After the reaction, cool to room temperature, add 50 mL ethyl acetate and 10 mL saturated sodium chloride, stir and stand for separation, separate the water phase, and wash the organic phase twice with saturated sodium chloride solution, 20 mL each time. The organic phase was concentrated under reduced pressure to obtain 6.7 g of yellow oil, 10 ml of hydrogen chloride ethyl acetate solution (2M) was added, a white solid was precipitated, and the hydrochloride was obtained by filtration. The hydrochloride was mixed with 20 ml of ethyl acetate solution, and a saturated sodium carbonate solution was added to adjust the pH to about 10, the organic phase was separated, the water phase was separated, and the organic phase was washed twice with a saturated sodium chloride solution, each time 20 mL, and the organic phase was concentrated under reduced pressure to obtain 3.0 g of off-white solid, i.e., morpholinonitrile isomer, with a molar yield of 72%. Compound I was characterized, 1 H NMR (400MHz, CDCl3): δ7.96(s,1H),4.63-4.58(m,1H),4.28-4.23(m,1H),3.68-3.58(m, 6H),2.89-2.82(m,1H),2.78-2.73(m,2H),2.69-2.64(m,2H),2.51(s,3H),2.28(s,1H).

[0054] Example 7

[0055] Preparation of Morpholinonitrile Isomers (Compound Ⅰ)

[0056] Under nitrogen protection, add 3.1mL DEAD to 40mL toluene, then add 3.9mL tributylphosphine, keep warm for 0.5 hours, add 2.5g compound II and 2.0g 2-methyl-5-nitroimidazole in turn, raise the temperature to 60-70℃, keep warm for 4 hours. After the reaction, cool to room temperature, add 50mL ethyl acetate and 10mL saturated sodium chloride, stir and stand for separation, separate the water phase, wash the organic phase with saturated sodium chloride solution twice, 20mL each time. Concentrate the organic phase under reduced pressure to obtain 7.6g of yellow oil, add 10ml hydrogen chloride ethyl acetate solution (2M), precipitate white solid, filter to obtain hydrochloride, mix the hydrochloride with 20ml ethyl acetate solution, add saturated sodium carbonate solution to adjust the pH to about 10, separate the organic phase, separate the water phase, wash the organic phase with saturated sodium chloride solution twice, 20mL each time, and concentrate the organic phase under reduced pressure to obtain 1.0g of off-white solid, i.e. morpholinonitrile isomer, with a molar yield of 24%. The characterization of compound I was the same as in Example 6.

[0057] Example 8

[0058] Preparation of Morpholinonitrile Isomers (Compound Ⅰ)

[0059] Under nitrogen protection, add 2.5 mL DEAD to 40 mL tetrahydrofuran, then add 2.0 g triphenylphosphine, keep warm for 0.5 hours, add 2.5 g compound II and 2.0 g 2-methyl-5-nitroimidazole in sequence, raise the temperature to 60-70°C, keep warm for 4 hours. After the reaction, cool to room temperature, add 50 mL ethyl acetate and 10 mL saturated sodium chloride, stir and stand for separation, separate the water phase, and wash the organic phase twice with saturated sodium chloride solution, 20 mL each time. The organic phase was concentrated under reduced pressure to obtain 4.6 g of yellow oil, 10 ml of hydrogen chloride ethyl acetate solution (2M) was added, a white solid was precipitated, and the hydrochloride was obtained by filtration. The hydrochloride was mixed with 20 ml of ethyl acetate solution, and a saturated sodium carbonate solution was added to adjust the pH to about 10, the organic phase was separated, the water phase was separated, the organic phase was washed twice with a saturated sodium chloride solution, 20 ml each time, and the organic phase was concentrated under reduced pressure to obtain 0.5 g of an off-white solid, i.e., morpholinonitrile isomer, with a molar yield of 12%. Compound I was characterized, which was the same as Example 6.

[0060] Example 9

[0061] Preparation of Morpholinonitrile Isomers (Compound Ⅰ)

[0062] Under nitrogen protection, add 2.5 mL DEAD to 40 mL dimethylacetamide, then add 2.0 g triphenylphosphine, keep warm for 0.5 hours, add 2.5 g compound II and 2.0 g 2-methyl-5-nitroimidazole in sequence, raise the temperature to 60-70°C, keep warm for 4 hours. After the reaction, cool to room temperature, add 50 mL ethyl acetate and 10 mL saturated sodium chloride, stir and stand for separation, separate the water phase, and wash the organic phase twice with saturated sodium chloride solution, 20 mL each time. The organic phase was concentrated under reduced pressure to obtain 6.5 g of yellow oil, 10 ml of hydrogen chloride ethyl acetate solution (2M) was added, a white solid was precipitated, and the hydrochloride was obtained by filtration. The hydrochloride was mixed with 20 ml of ethyl acetate solution, and a saturated sodium carbonate solution was added to adjust the pH to about 10, the organic phase was separated, the water phase was separated, the organic phase was washed twice with a saturated sodium chloride solution, each time 20 ml, and the organic phase was concentrated under reduced pressure to obtain 2.8 g of off-white solid, i.e., morpholinonitrile isomer, with a molar yield of 67%. Compound I was characterized, which was the same as Example 6.

[0063] The present invention is described in detail above through specific and preferred embodiments, but those skilled in the art should understand that the present invention is not limited to the embodiments described above, and any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing morpholiniazole isomers, characterized in that: It includes the following steps:

2. The method according to claim 1, characterized in that: Formula II is prepared by the following steps:

3. The method according to claim 2, characterized in that: The solvent used in step (1) is at least one of dimethylformamide, dimethyl sulfoxide, diethylamine, triethylamine, and N,N-diisopropylethylamine, preferably dimethylformamide.

4. The method according to claim 2, characterized in that: Step (1) is reacted in the presence of a base, wherein the base is selected from one or more of sodium hydroxide, potassium carbonate, sodium carbonate and sodium tert-butoxide, preferably potassium carbonate; further, the reaction temperature is 10° C. to 30° C., and the reaction time is 1 hour to 3 hours.

5. The method according to claim 2, characterized in that: The molar ratio of morpholine to diethyl bromomalonate is less than 1:1, and further selected from 1:1 to 1.

2.

6. The method according to claim 2, characterized in that: Step (2) is a reduction reaction, the reducing agent is selected from 70% toluene solution of sodium dihydrogen bis(2-methoxyethoxy)aluminate and lithium aluminum tetrahydride, preferably 70% toluene solution of sodium dihydrogen bis(2-methoxyethoxy)aluminate; the solvent used in step (2) is selected from one or more of tetrahydrofuran, dichloromethane and toluene.

7. The method according to claim 1, characterized in that: The coupling reagent in step (3) is selected from one or more of diethyl azodicarboxylate, diisopropyl azodicarboxylate, triphenylphosphine and tributylphosphine, preferably diethyl azodicarboxylate and triphenylphosphine.

8. The method according to claim 1, characterized in that: The molar ratio of compound II to 2-methyl-5-nitroimidazole is 1:1-5, and further selected from 1:1-2.

9. The method according to claim 1, characterized in that: The solvent used in the reaction of step (3) is selected from one or more of benzene, toluene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, dimethylformamide, dimethylacetamide and dichloromethane, preferably dimethylformamide.

10. The method according to claim 1, characterized in that: After the reaction of step (3) is completed, a purification step is further included, including the following contents: (1) extracting and adding an inorganic acid to the organic phase containing compound I to form a salt; (2) dissociation by adding inorganic base; (3) Extraction: taking the organic phase and removing the solvent to obtain compound I.

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