Preparation method of moroxydine and application thereof in preparation

Abstract

The application provides a high-yield and high-purity preparation method of moroxydine, and 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole is used as a starting material, and moroxydine is obtained through ring-opening condensation reaction under the catalysis of DBU and crystallization. The preparation method is simple in steps and convenient in operation, the prepared moroxydine has high yield and good quality, and is convenient for preparing moroxydine preparations for clinical use.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of synthetic chemistry of pharmaceuticals, and in particular, the present application provides a preparation method of moricizine. BACKGROUND

[0002] Moricizine, structural formula: . Chemical name is 1-[3-(4-morpholinyl)-2-hydroxypropyl]-2-methyl-5-nitro-1 H imidazole, is a third-generation new nitroimidazole antibiotic developed by Jiangsu Haosen Pharmaceutical Co., Ltd., and its mechanism of action may be that the nitro group in its molecule is reduced to amino group in an anaerobic environment or forms free radicals to interact with cell DNA components, thereby causing the death of microorganisms. Moricizine was approved for marketing by the China Food and Drug Administration (CFDA) on February 24, 2014, and its trade name is Mylin, which is suitable for the following infections caused by sensitive bacteria (mainly anaerobic bacteria) in adults (≥18 years old): gynecological pelvic inflammatory disease (including endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis) caused by Peptostreptococcus, Bacteroides fragilis, Veillonella, Bacteroides distasonis, etc., and suppurative appendicitis and gangrenous appendicitis caused by Bacteroides, Clostridium, Fusobacterium, and Anaerococcus.

[0003] The most valuable and industrialized preparation method of moricizine is as follows:

[0004] ,

[0005] This preparation method uses ornidazole as a raw material, and moricizine is prepared through intramolecular SN2 ring formation reaction and morpholine ring opening reaction. In the literature "Journal of Medicinal Chemistry, 1974. Vol. 17, No. 9, p1019" ," European Journal of Medicinal Chemistry 124 (2016) 820-839 ", CN200310100057.0, CN200510134254.3 have related reports.

[0006] In the second step of the preparation method, the ring opening reaction of compound II to prepare moricizine, there are two reaction sites, and side reactions exist, generating compound III (moricizine position isomer), which will affect the quality of the product and even increase the risk of patient use. As follows:

[0007] .

[0008] To solve this problem, patent CN201510225004 reports that when the compound of formula II is reacted with morpholine, by using the method of "adding a catalyst halide, and through ring-opening, salting, isolation, recrystallization and other processes", the problem of morpholine nitazoxanide positional isomer impurities is better solved.

[0009] Although the method reported in patent CN201510225004 can prepare morpholine nitazoxanide with high selectivity and high purity, and better control the generation of positional isomers, the preparation yield is low, and the highest yield (Example 2) is only 63.7%; in addition, the method has many processes and the operation is complex. Therefore, there is still a need for a better technical solution.

[0010] In summary, there is still no simple method for preparing morpholine nitazoxanide with high selectivity, high purity and high yield in the prior art. SUMMARY

[0011] The preparation method of morpholine nitazoxanide provided by the present application is characterized by using 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole of formula II as the starting material, and preparing morpholine nitazoxanide by ring-opening reaction with morpholine under the catalysis of DBU.

[0012] The reaction temperature of the preparation method is preferably 35-40℃, the reaction solvent is acetonitrile or tetrahydrofuran, the chemical full name of the catalyst DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, and the amount of catalyst used is 5-10% of the weight of the compound of formula II.

[0013] The HPLC chromatographic conditions used in the preparation method are as follows: octadecylsilane-bonded silica gel is used as the filler; the flow rate is 1 mL per minute; the UV detector has a detection wavelength of 319 nm; the diluent is water-methanol-acetonitrile= (87-6.5-6.5); the mobile phase A is 0.05 mol / L phosphate buffer (take 6.8 g of potassium dihydrogen phosphate, dissolve in about 1000 ml of water, add 10 ml of triethylamine, and adjust the pH value to 6.5 with phosphoric acid), and the mobile phase B is acetonitrile-methanol (1:1), gradient elution, gradient program:

[0014] Time (min) Mobile phase A (%) Mobile phase B (%) 0 87 13 5 87 13 8 80 20 15 80 20 30 50 50 35 50 50 35.1 87 13 40 87 13 .

[0015] The document "Study on Impurities of Nitroimidazole Drugs, He Jiajia, Zhejiang University of Technology, 2013 Master's Degree Thesis" reports that nitroimidazole drugs are easily degraded to generate various impurities under high temperature and strong alkaline conditions, and even the aromatic ring is degraded to open ring to generate some impurities without response of ultraviolet detector, further affecting the yield and purity. Therefore, it is inferred that the low yield of the compound of formula II when reacting with morpholine may be due to: the reaction temperature is too high, and the reaction system is strong alkaline. The alkalinity of the reaction system cannot be avoided because morpholine is one of the reaction raw materials.

[0016] The present application effectively reduces the activation energy required for the reaction by adding the catalyst DBU, reduces the reaction temperature, further reduces the impurities caused by the high temperature instability of nitroimidazole antibiotics, thereby improving the yield and purity. At the same time, for the morpholine nitrate position isomer impurity shown in formula III, due to the lower reaction temperature, there is basically no generation of position isomer impurity when the morpholine nitrate is opened ring.

[0017] In addition, the preparation method provided by the present application has mild reaction conditions and good purity of reaction liquid, and high-purity product can be obtained by simple crystallization treatment, without complex salting, free and other post-processing processes.

[0018] In summary, compared with the prior art, the preparation method provided by the present application can overcome the defects of the prior art, and can obtain morpholine nitrate with high yield, high purity and simple preparation process, and further obtain morpholine nitrate sodium chloride injection, which can play an important role in drug production and quality control. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 HPLC detection spectrum of the reaction liquid of morpholine nitrate obtained in Example 1 of the present application;

[0020] Figure 2 HPLC detection spectrum of the finished product of morpholine nitrate obtained in Example 1 of the present application;

[0021] Figure 3 HPLC spectrum of the standard sample mixed with morpholine nitrate, morpholine nitrate position isomer impurity of formula III and compound of formula II. DETAILED EMBODIMENTS

[0022] The present application will be further described below by examples, and various substitutions or combinations made according to the ordinary technical knowledge and conventional means in the art shall be included in the scope of the present application.

[0023] Example 1 Preparation of morpholine nitrate of formula I compound

[0024] The compound of formula II 549 g was added into acetonitrile 5400 mL, DBU 27.5 g (5%) and morpholine 393 g were added, and the reaction was carried out at 40°C for 4 h (the reaction solution was detected by HPLC as shown in Figure 1 After the reaction was completed, the reaction solution was filtered through a 0.45 um filter into a crystallizer in a general clean area, cooled to 0-5°C, and stirred for crystallization for 2 h, filtered, and the filter cake was washed with acetonitrile, and dried at 50°C under normal pressure to obtain a white to light yellow solid 696 g, with a molar yield of 86% and an HPLC purity of 99.9% (as shown in Figure 2 ).

[0025] Preparation of the compound of formula I morpholine nitazoxanide

[0026] The compound of formula II 549 g was added into acetonitrile 5400 mL, DBU 27.5 g (5%) and morpholine 393 g were added, and the reaction was carried out at 40°C for 4 h (the reaction solution was detected by HPLC as shown in Figure 1 After the reaction was completed, the reaction solution was filtered through a 0.45 um filter into a crystallizer in a general clean area, cooled to 0-5°C, and stirred for crystallization for 2 h, filtered, and the filter cake was washed with acetonitrile, and dried at 50°C under normal pressure to obtain a white to light yellow solid 696 g, with a molar yield of 86% and an HPLC purity of 99.9% (as shown in Figure 2 ).

[0027] Preparation of morpholine nitazoxanide sodium chloride injection

[0028] 1.08 kg of sodium chloride for injection, 0.6 kg of morpholine nitazoxanide, and 118.8 kg of water for injection were added into a suitable size dilution tank, and stirred and dissolved at 40°C, and the pH value was adjusted to 7.0 with 2 mol / L hydrochloric acid solution, and the solution was uniformly mixed by continuing to circulate and stir for 20 min, and finally the circulation and stirring was stopped. The solution in the dilution tank was filtered through a 0.45 um polyether sulfone precision filter and a 0.22 um polyether sulfone bacteria removal filter, and filled into bottles according to the specification of "containing 0.5 g of morpholine nitazoxanide and 0.9 g of sodium chloride per 100 mL", and stoppered and capped. The preparation was placed into a water bath type sterilization cabinet, sterilized at 121°C for 15 min, and then subjected to lamp inspection and labeling to obtain the morpholine nitazoxanide sodium chloride injection.

Claims

1. A method for preparing morpholinidazole as shown in compound I, characterized in that: The compound 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole of formula II is prepared by the ring-opening reaction of morpholine at 35-40℃ in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and morpholine as the reaction solvent, and the compound 1-(2-morpholinopropyl)-2-methyl-5-nitroimidazole of formula I is prepared by the reduction reaction of the compound of formula II in the presence of sodium borohydride and methanol as the reaction solvent, 。 2. The method of claim 1, wherein: The amount of DBU is 5-10% of the weight of the compound of formula II.

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