Anidulafungin impurity B and a method of preparation thereof

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to an anidofencil impurity B and its preparation method. The invention involves reacting anidofencil with 4”-pentoxy-1,1':4',1”-terphenyl-4-carboxylic acid HOBT ester to obtain anidofencil impurity B. This invention features a simple synthetic operation and high yield, filling a gap in the preparation methods for this impurity. The obtained anidofencil impurity has a purity of up to 98.97%, and can be used as an impurity reference standard, facilitating the detection and control of the purity of anidofencil raw materials and / or preparations, thus having significant practical value for its quality research.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an anidoxurine impurity B and its preparation method. Background Technology

[0002] Echinocandins are a new class of antifungal drugs that have been used clinically since the early 21st century. They inhibit fungal cell wall synthesis by inhibiting the activity of β-1,3-glucan synthase, exhibiting low toxicity and favorable kinetic properties. Anidulafungin (CAS: 166663-25-8) is a third-generation echinocandin semi-synthetic antifungal drug developed by Vicuron Pharmaceuticals in the United States, later acquired by Pfizer. It was launched in the United States in December 2006. The dosage form is a lyophilized powder for injection, primarily used for the treatment of deep fungal infections, especially Candida infections. Its chemical structure is as follows:

[0003]

[0004] As is well known, only by ensuring drug quality can its safety and efficacy be guaranteed. Impurities are one of the main factors affecting drug quality, and the study of impurities is an important part of pharmaceutical research. According to ICH Q3A, impurities with an identification limit of 0.10% or higher need to be isolated and their structures confirmed in order to assess the impact of individual impurities on the quality control of the final product. Therefore, isolating individual impurities and confirming their structures plays a crucial role in establishing detection methods, analyzing impurity content, determining reasonable impurity limits, and conducting clinical drug safety testing.

[0005] The literature "Isolation, Identification and Characterization of Potential Impurities of Anidulafungin" (Lanning Zhaoa, Qilong Wangb, Yi Bieb, Xiaoxia Lua, Journal of Pharmaceutical and Biomedical Analysis, 2007, 114, 192–199) isolated four impurities from anidulafungin: impurity A, impurity C, impurity D, and impurity E, and identified and characterized them. Patent CN103965298B discloses a method for purifying anidulafungin using macroporous adsorption resin, mentioning two key anidulafungin impurities with molecular weights of 1126 and 1106, but does not confirm their structures. Patent application CN107365353A discloses methods for preparing impurities C and D, and patent application CN107383172A discloses a method for preparing impurity A; however, these methods require preparative liquid chromatography to obtain the target impurity with a purity of over 90%, which is cumbersome and costly. Currently, no literature discloses a method for preparing impurity B.

[0006]

[0007] The generation of these impurities poses a potential threat to the safety of anidoxane in clinical use. In order to better realize the economic and social benefits of this drug, the standard must strictly control all impurities, and clarifying each impurity item is an urgent problem to be solved. Summary of the Invention

[0008] The purpose of this invention is to provide an anidoxurine impurity B and its preparation method. The prepared anidoxurine impurity B can be used as an impurity reference standard to study its impact on the quality control of the final product. At the same time, it plays an important role in impurity content analysis and determining reasonable impurity limits.

[0009] The specific technical solution of the present invention is as follows:

[0010] An anidifenesin B, as shown in Formula I, has the following structural formula:

[0011]

[0012] A method for preparing anisfentanil impurity B as shown in Formula I, wherein anisfentanil is reacted with compound II to obtain anisfentanil impurity B.

[0013]

[0014] Preferably, a method for preparing anisfentanyl impurity B as shown in Formula I specifically includes the following steps:

[0015] Anidoxane was added to an organic solvent and dissolved completely. Then compound II was added, followed by the addition of alkali. The mixture was heated and stirred until the reaction was complete. The mixture was then filtered, and the filtrate was added to water. Finally, a liquid filter aid was added, stirred, filtered, and dried to obtain anidoxane impurity B.

[0016] Preferably, the molar ratio of anidoxane, compound II and alkali is 1:1-1.5:1.5-2.5, and particularly preferably 1:1.3:2.

[0017] Preferably, the organic solvent is one or a combination of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, isopropanol, and methanol, with dimethyl sulfoxide being particularly preferred.

[0018] Preferably, the base is one of triethylamine, diethylamine, and diisopropylethylamine, with diethylamine being particularly preferred.

[0019] Preferably, the weight-to-volume ratio of anidoxane to the organic solvent is 1:6-9, g / ml, with a particularly preferred ratio of 1:8.

[0020] Preferably, the heating reaction temperature is 40-50℃; the reaction time is 8-10h.

[0021] Preferably, the liquid filter aid is methyl tert-butyl ether or diethyl ether.

[0022] Preferably, the volume ratio of the liquid filter aid to the organic solvent is 1:1-3, and particularly preferably 1:2.

[0023] Preferably, the stirring time is 5-15 minutes.

[0024] As shown in Formula I, anidoxane impurity B is used as a reference standard in the quality study of anidoxane raw material and its compound preparations.

[0025] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0026] 1. This invention provides a method for preparing anisfentanyl impurity B, which fills the gap in the current lack of a preparation method for this impurity, and the process route is simple and easy to operate.

[0027] 2. The preparation method of this invention does not require liquid chromatography separation and purification, which simplifies the production operation. The purity of impurity B in the obtained product, anidoxane, is as high as 98.97%, which can be used as an impurity reference standard. This facilitates the detection and control of the purity of anidoxane raw materials and / or preparations, and has important practical value for its quality research. Detailed Implementation

[0028] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0029] The raw materials, anidoxane, compound II (4”-pentoxy-1,1':4',1”-terphenyl-4-carboxylic acid HOBT ester), and reagents used in the embodiments of this invention are all commercially available; the ultra-high performance liquid chromatograph used is an Agilent 1290 Infinity II, the mass spectrometer is a Waters SQD2, and the nuclear magnetic resonance spectrometer is an Avance III.

[0030] This invention uses HPLC to determine the purity of anidoxurine impurity B. The chromatographic conditions are as follows: column: Sepax C18-5-120AA; mobile phase: purified water-ethanol (30:70), isocratic elution; flow rate: 60 ml / min; column temperature: 30 ℃; online detection with UV detector, detection wavelength: 210 nm.

[0031] Example 1: Preparation of Anidifene Net Impurity B

[0032] Anidofenel (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofenel impurity B with a molar yield of 93.5% and a purity of 98.97%.

[0033] Example 2: Preparation of net impurity B in anidofen

[0034] Anidofene (11.40 g, 0.01 mol) was added to tetrahydrofuran (79.8 ml) and completely dissolved. Then, compound II (5.73 g, 0.012 mol) was added, followed by the dropwise addition of triethylamine (1.82 g, 0.018 mol). The mixture was heated to 40 °C and stirred for 8 h. After filtration, the filtrate was poured into water (700 ml), and diethyl ether (79.8 ml) was added. The mixture was stirred for 5 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 89.7% and a purity of 98.86%.

[0035] Example 3: Preparation of Anidifene Net Impurity B

[0036] Anidofenel (11.40 g, 0.01 mol) was added to methanol (91.2 ml) and completely dissolved. Then, compound II (7.16 g, 0.015 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 50 °C and stirred for 10 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofenel impurity B with a molar yield of 90.6% and a purity of 98.92%.

[0037] Example 4: Preparation of Anidifene Net Impurity B

[0038] Anidofenel (11.40 g, 0.01 mol) was added to N,N-dimethylformamide (68.4 ml) and completely dissolved. Then, compound II (4.78 g, 0.01 mol) was added dropwise, followed by the addition of triethylamine (1.52 g, 0.015 mol). The mixture was heated to 40 °C and stirred for 8 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (22.8 ml) was added. The mixture was stirred for 5 min, filtered, and dried under vacuum to obtain anidofenel impurity B with a molar yield of 87.9% and a purity of 98.80%.

[0039] Example 5: Preparation of Anidifene Net Impurity B

[0040] Anidofene (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (102.6 ml) and completely dissolved. Then, compound II (7.16 g, 0.015 mol) was added, followed by the dropwise addition of diethylamine (1.83 g, 0.025 mol). The mixture was heated to 50 °C and stirred for 10 h. After filtration, the filtrate was poured into water (700 ml), and finally, methyl tert-butyl ether (102.6 ml) was added. The mixture was stirred for 15 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 88.6% and a purity of 98.83%.

[0041] Example 6: Preparation of Anidifene Net Impurity B

[0042] Anifenidine (11.40 g, 0.01 mol) was added to tetrahydrofuran (79.8 ml) and completely dissolved. Then, compound II (7.16 g, 0.015 mol) was added dropwise, followed by diisopropylethylamine (1.94 g, 0.015 mol). The mixture was heated to 45 °C and stirred for 10 h. After filtration, the filtrate was poured into water (700 ml). Finally, methyl tert-butyl ether (39.9 ml) was added, stirred for 10 min, filtered, and dried under vacuum to obtain anifenidine impurity B with a molar yield of 87.5% and a purity of 98.77%.

[0043] Example 7 Preparation of Anidifene Net Impurity B

[0044] Anidofenel (11.40 g, 0.01 mol) was added to isopropanol (91.2 ml) and completely dissolved. Then, compound II (4.78 g, 0.01 mol) was added dropwise, followed by diethylamine (1.83 g, 0.025 mol). The mixture was heated to 40 °C and stirred for 8 h. After filtration, the filtrate was poured into water (700 ml), and finally, diethyl ether (30.4 ml) was added. The mixture was stirred for 5 min, filtered, and dried under vacuum to obtain anidofenel impurity B with a molar yield of 86.8% and a purity of 98.75%.

[0045] Example 8: Preparation of Anidifene Net Impurity B

[0046] Anidofene (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (9.55 g, 0.002 mol) was added, followed by the dropwise addition of diethylamine (0.73 g, 0.01 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 81.6% and a purity of 94.45%.

[0047] Example 9: Preparation of Anidifene Net Impurity B

[0048] Anidofene (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 60 °C and stirred for 8 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 82.9% and a purity of 94.73%.

[0049] Example 10 Preparation of Anidifene Net Impurity B

[0050] Anidofene (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 6 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 83.6% and a purity of 95.21%.

[0051] Example 11 Preparation of Anidifene Net Impurity B

[0052] Anidofene (11.40 g, 0.01 mol) was added to acetone (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 84.0% and a purity of 97.16%.

[0053] Example 12 Preparation of Anidifene Net Impurity B

[0054] Anidofene (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (114 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (57 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 84.3% and a purity of 97.50%.

[0055] Example 13 Preparation of Anidifene Net Impurity B

[0056] Anidofenel (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by sodium carbonate (2.12 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofenel impurity B with a molar yield of 82.3% and a purity of 94.79%.

[0057] Example 14 Preparation of Anidifene Net Impurity B

[0058] Anidofenel (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by diethylamine (1.46 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and polyethyleneimine (45.6 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofenel impurity B with a molar yield of 83.9% and a purity of 97.99%.

[0059] Example 15 Preparation of Anidifene Net Impurity B

[0060] Anidofene (11.40 g, 0.01 mol) was added to dimethyl sulfoxide (91.2 ml) and completely dissolved. Then, compound II (6.21 g, 0.013 mol) was added, followed by the dropwise addition of diethylamine (1.46 g, 0.02 mol). The mixture was heated to 45 °C and stirred for 9 h. After filtration, the filtrate was poured into water (700 ml), and methyl tert-butyl ether (22.8 ml) was added. The mixture was stirred for 10 min, filtered, and dried under vacuum to obtain anidofene impurity B with a molar yield of 84.4% and a purity of 98.02%.

[0061] Structure confirmation of anidofen net impurity B in this invention embodiment:

[0062]

[0063] High-resolution mass spectrometry: ESI-HRMS (m / z): 1482.5771 [M+H] + ;

[0064] 1 H-NMR (400MHz, DMSO-d6): δ0.91(6H,t,J=6.99Hz),0.98(3H,d,J=6.61Hz),1.15(6H,m),1.40(8H,m),1.74(4H,m),1.91(2H,m),2.00 (1H,m),2.27(1H,m),2.37(1H,m),3.24(1H,m),3.77(2H,dd,J=9.34Hz,J=34.68Hz),3.92(2H,m),4.00(4H,m),4.04(3H,m),4.12(1H, m),4.19(1H,m),4.25(1H,m),4.37(2H,m),4.42(3H,m),4.72(1H,m),4.81(2H,m),5.05(1H,s),5.16(4H,m),5.44(1H,d),5.53(1H,d) ,7.04(4H,m),7.26(2H,m),7.37(3H,m),7.47(1H,m),7.67(4H,m),7.80(10H,m),7.97(2H,m),8.02(3H,m),8.22(3H,m),8.64(1H,m);

[0065] 13C NMR(400MHz,DMSO-d6):δ171.74,170.77,170.44,169.70,169.15,168.15,165.87,164.44,158.65,158.55,149.78,144.86,142.22,140.37,139.97,139.44,137.34,136.79,132.94,131.63,131.47,130.53,128.36,128.17,127.78,127.71,127.54,127.32,126.87,126.77,126.67,126.09,121.39,114.97,75.16,73.37,73.00,72.67,69.55,69.24,68.43,67.95,67.53,66.37,60.86,56.68,55.74,55.34,54.50,51.29,50.57,37.24,34.01,28.41,28.34,27.75,21.93,19.41,19.31,13.96,13.90,10.94.

Claims

1. A method for preparing an anidofenxin impurity B, as shown in Formula I, with the following structural formula: ， Its features are, Anidoxane was reacted with compound II to obtain anidoxane impurity B; ； Specifically, the steps include the following: Anidoxane was added to an organic solvent and dissolved completely. Then compound II was added, followed by the addition of alkali. The mixture was heated and stirred until the reaction was complete. The mixture was then filtered, and the filtrate was added to water. Finally, a liquid filter aid was added, stirred, filtered, and dried to obtain anidoxane impurity B. The organic solvent is one or a combination of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, isopropanol, and methanol; The base is one of triethylamine, diethylamine, and diisopropylethylamine; The heating reaction temperature is 40-50℃; The liquid filter aid is methyl tert-butyl ether or diethyl ether.

2. The method for preparing anisole net impurity B according to claim 1, characterized in that, The molar ratio of anidoxane, compound II, and alkali is 1:1-1.5:1.5-2.

5.

3. The method for preparing anisole net impurity B according to claim 1, characterized in that, The reaction time is 8-10 hours.

4. The method for preparing anisole net impurity B according to claim 1, characterized in that, The volume ratio of the liquid filter aid to the organic solvent is 1:1-3.

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