阅读说明：本技术 一种硝呋太尔相关物质及其制备方法和用途 (Nifuratel related substance and preparation method and application thereof ) 是由 邢峻豪 窦晓巍 许洋 江玉琳 于 2021-08-27 设计创作，主要内容包括：本发明涉及医药化工领域,公开了一种硝呋太尔相关物质及其制备方法和用途。该相关物质的结构式如IMP-1所示,其制备方法为：化合物I与化合物II进行缩合反应,得到目标产物IMP-1。本发明公开的硝呋太尔相关物质IMP-1可作为标准品使用,对硝呋太尔的制备过程进行质量控制研究,不仅有望进一步提高硝呋太尔的生产质量标准,而且也为化合物IMP-1的进一步安全性评估提供了可靠的物质保障。(The invention relates to the field of pharmaceutical chemicals, and discloses a nifuratel related substance, and a preparation method and application thereof. The structural formula of the related substance is shown as IMP-1, and the preparation method comprises the following steps: and carrying out condensation reaction on the compound I and the compound II to obtain the target product IMP-1. The nifuratel related substance IMP-1 disclosed by the invention can be used as a standard substance, and the quality control research on the preparation process of nifuratel is carried out, so that the production quality standard of nifuratel is expected to be further improved, and a reliable substance guarantee is provided for the further safety evaluation of the compound IMP-1.)

1. A nifuratel related substance IMP-1 is characterized in that the structural formula is as follows:

2. a method for preparing nifuratel related substance IMP-1 according to claim 1, characterized by using the following synthetic route:

the method comprises the following operation steps:

dissolving a raw material I in an organic solvent, adding a condensing agent, stirring and reacting for 0.5h at room temperature, then adding a compound II and an organic base, continuing to react at room temperature, detecting by TLC until the compound I disappears, adding water into a reaction solution, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, evaporating the solvent under reduced pressure, and purifying to obtain the compound IMP-1.

3. A method for preparing nifuratel related substance IMP-1 according to claim 2, wherein the organic solvent is any one or any combination of two or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide.

4. The preparation method of nifuratel related substance IMP-1 according to claim 2, characterized in that 5-10 mL of organic solvent is added to 1g of compound I.

5. The method for preparing nifuratel related substance IMP-1 according to claim 2, wherein the condensing agent is any one or any combination of two or more of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate.

6. A method for preparing nifuratel related substance IMP-1 according to claim 2, wherein the organic base is one or any combination of more than two of triethylamine, N-diisopropylethylamine and pyridine.

7. A process for producing nifuratel-related substance IMP-1 according to claim 2, wherein the molar ratio of raw material I to condensing agent to raw material II to organic base is 1:1.1:1: 1.1.

8. Use of nifuratel-related substance IMP-1 according to claim 1, as an impurity control in nifuratel quality studies.

Technical Field

The invention relates to the field of pharmaceutical chemicals, and particularly relates to a nifuratel related substance, and a preparation method and application thereof.

Background

Nifuratel (Nifuratel) has a structural formula shown in III and a chemical name of 5- [ (methylthio) methyl ] -3- [ (5-nitrofurfurylidene) amino ] -2-oxazolidinone, and is a medicament which is developed by Italian pril chemical industry company and is mainly used for gynecological mixed infection.

The applicant has studied the synthetic process of nifuratel (CN 112457304A). In the subsequent hybrid mass spectrometry study, the content of the impurity 2 is found to exceed the limit requirement (figure 1), the mass spectrometry result (figure 2) shows that the molecular ion peak of the compound is 302.2, and the compound is presumed to be a compound IMP-1 by combining the process route in CN112457304A and the mass spectrometry result. To further verify the results of this speculation, we performed directed synthesis on IMP-1, and finally confirmed that both are the same structure by comparing the liquid phase peak time of impurity 2 with that of IMP-1 (fig. 3, which is consistent with that of impurity 2 in fig. 1) and nuclear magnetism (fig. 4).

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a nifuratel related substance and a preparation method and application thereof.

In order to solve the problems, the technical scheme of the invention is as follows: the invention provides a nifuratel related substance, which is IMP-1 and has a structural formula as follows:

the molecular formula is as follows: c₁₀H₁₁N₃O₆S; molecular weight: 301.2730.

the invention also provides a preparation method of IMP-1, which adopts the following technical route:

the method comprises the following operation steps:

dissolving a raw material I in an organic solvent, adding a condensing agent, stirring and reacting at room temperature for 0.5h, then adding a compound II and an organic base, continuing to react at room temperature, detecting by TLC until the compound I disappears, adding water into a reaction solution, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, evaporating under reduced pressure to remove the solvent, and performing column chromatography purification to obtain a compound IMP-1;

wherein the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide, preferably dichloromethane;

wherein, 5-10 mL of organic solvent is added into 1g of the compound I, and 5-6 mL of organic solvent is preferably added;

wherein the condensing agent is one or more of Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), preferably EDCI;

wherein, the organic base is one or the combination of more than one of triethylamine, N, N-diisopropylethylamine and pyridine, and triethylamine is preferred;

wherein, the raw material I and the condensing agent are mixed, and the molar ratio of the raw material II to the organic base is 1:1.1:1: 1.1.

The invention also protects the application of the nifuratel related substance as an impurity reference substance in nifuratel quality research.

The invention has the beneficial effects that:

1. the invention discovers a new related substance IMP-1 generated in the synthetic process of nifuratel for the first time, and is beneficial to further improving the production quality standard of nifuratel;

2. the invention provides a related substance IMP-1, confirms the structure of the substance and can be used as a standard substance in the quality control process of nifuratel;

3. the invention also provides a preparation method of the related substance IMP-1, the method can prepare the compound IMP-1 with high yield and high purity through one-step reaction, and provides an important material basis for subsequent safety evaluation of the IMP-1 and quality control research in the nifuratel preparation process.

Drawings

FIG. 1 is a HPLC assay chart of nifuratel impurity;

FIG. 2. mass spectrum of impurity 2;

FIG. 3.IMP-1 liquid phase diagram;

FIG. 4 IMP-1 hydrogen spectra.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), with the end of the reaction being at the time of disappearance of compound I.

The liquid phase conditions in the following examples were: gradient elution was performed using GL Sciences Inc. Inertsil ODS-SP C18(4.6 mm. times.250 mm, 5 μm) as column, pure water as mobile phase A, and 0.1% trifluoroacetic acid in acetonitrile as mobile phase B according to the following table:

time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	90	10
5	90	10
			15	70	30
20	10	90
			25	10	90
25.01	90	10
			35	90	10

The flow rate was 1.0mL/min, the column temperature was 35 ℃ and the detection wavelength was 254 nm.

Example 1:

embodiment 1 of the present invention provides a method for preparing IMP-1, which comprises the following steps:

the preparation method specifically comprises the following steps:

dissolve compound I (2.1g, 13.4mmol) in dichloromethane (45mL), add EDCI (2.8g, 14.7mmol) and stir at room temperature for 0.5 h; then compound II (2.2mmol, 13.4mmol) and triethylamine (1.5g, 14.7mmol) are added, the reaction is continued for 4h at room temperature, and compound I disappears by TLC; adding water (45mL) into the reaction solution, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, distilling off the solvent under reduced pressure, and carrying out column chromatography purification (100-mesh 200-mesh silica gel, wherein the mobile phase is petroleum ether and ethyl acetate which are 1:1, v/v) to obtain the compound IMP-1.

The method is adopted to prepare 3.97g of light yellow solid, the yield is 98.6%, and the purity is 98.8%.

The identification of IMP-1 produced in this example gave the following results:

ESI-MS(m/z):302.2；

¹H NMR(300MHz,DMSO-d₆)δ11.31(s,1H),7.80(d,J＝3.9Hz,1H),7.54(d,J＝3.9Hz,1H),4.99–4.82(m,1H),3.90(t,J＝8.0Hz,1H),3.63–3.49(m,1H),2.88(dd,J＝5.9,3.1Hz,2H),2.16(s,3H).

example 2:

embodiment 2 of the present invention provides a method for preparing IMP-1:

dissolve compound I (2.1g, 13.4mmol) in tetrahydrofuran (45mL), add EDCI (2.8g, 14.7mmol) and stir at room temperature for 0.5 h; then compound II (2.2mmol, 13.4mmol) and triethylamine (1.5g, 14.7mmol) are added, the reaction is continued for 6h at room temperature, and compound I disappears by TLC; adding water (45mL) into the reaction solution, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, distilling off the solvent under reduced pressure, and carrying out column chromatography purification (100-mesh 200-mesh silica gel, wherein the mobile phase is petroleum ether and ethyl acetate which are 1:1, v/v) to obtain the compound IMP-1.

The method is adopted to prepare 3.54g of light yellow solid, the yield is 87.9 percent, and the purity is 98.5 percent.

Example 3:

embodiment 3 of the present invention provides a method for preparing IMP-1:

dissolving compound I (1.7g, 10.8mmol) in dichloromethane (40mL), adding DCC (2.5g, 11.9mmol), and stirring at room temperature for reaction for 0.5 h; then compound II (1.8g, 10.8mmol) and triethylamine (1.2g, 11.9mmol) are added, the reaction is continued for 10h at room temperature, and compound I disappears by TLC; adding water (40mL) into the reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, distilling off the solvent under reduced pressure, and carrying out column chromatography purification (100-200-mesh silica gel, wherein the mobile phase is petroleum ether and ethyl acetate which are 1:1, v/v) to obtain the compound IMP-1.

The method is adopted to prepare 2.8g of light yellow solid, the yield is 85.9 percent, and the purity is 98.2 percent.

Example 4:

embodiment 4 of the present invention provides a method for preparing IMP-1:

compound I (1.9g, 12.1mmol) was dissolved in dichloromethane (40mL), HBTU (5.1g, 13.3mmol) was added, and the reaction was stirred at room temperature for 0.5 h; then compound II (2.0g, 12.1mmol) and triethylamine (1.4g, 13.3mmol) are added, the reaction is continued for 4h at room temperature, and compound I disappears by TLC; adding water (40mL) into the reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, distilling off the solvent under reduced pressure, and carrying out column chromatography purification (100-200-mesh silica gel, wherein the mobile phase is petroleum ether and ethyl acetate which are 1:1, v/v) to obtain the compound IMP-1.

The method is adopted to prepare 3.2g of light yellow solid, the yield is 87.8 percent, and the purity is 98.0 percent.

Example 5:

example 5 of the present invention provides a method for preparing IMP-1:

dissolving compound I (1.5g, 9.6mmol) in DMF (30mL), adding HBTU (4.0g, 10.5mmol), and stirring at room temperature for reaction for 0.5 h; then compound II (1.6g, 9.6mmol) and triethylamine (1.1g, 10.5mmol) are added, the reaction is continued for 4h at room temperature, and compound I disappears by TLC; adding water (30mL) and ethyl acetate (50mL) into the reaction solution, separating and extracting, drying the organic layer by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying by column chromatography (100-200-mesh silica gel, wherein the mobile phase is petroleum ether and ethyl acetate is 1:1, v/v) to obtain the compound IMP-1.

The method is adopted to prepare 2.3g of light yellow solid, the yield is 80.0 percent, and the purity is 98.2 percent.

Example 6:

example 6 of the present invention provides a method for preparing IMP-1:

dissolving compound I (1.7g, 10.8mmol) in tetrahydrofuran (40mL), adding HBTU (4.5g, 11.9mmol), and stirring at room temperature for reaction for 0.5 h; then compound II (1.8g, 10.8mmol) and triethylamine (1.2g, 11.9mmol) were added and the reaction was continued at room temperature for 4h, and disappearance of compound I was detected by TLC; adding water (40mL) into the reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, distilling off the solvent under reduced pressure, and carrying out column chromatography purification (100-200-mesh silica gel, wherein the mobile phase is petroleum ether and ethyl acetate which are 1:1, v/v) to obtain the compound IMP-1.

The method is adopted to prepare 2.8g of light yellow solid, the yield is 85.9 percent, and the purity is 98.4 percent.

The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.