Ganciclovir compatible impurity as well as preparation method and application thereof

Abstract

The invention relates to a novel ganciclovir compatible impurity as shown in a formula (I). Repeated tests show that the impurity is very easy to generate in the compatibility process of ganciclovir and a 5% glucose solution. The structure of the impurity is determined by characterizing the impurity shown in the formula (I), and the impurity can be used as a reference substance for quality research of ganciclovir preparations (such as ganciclovir preparations for injection), has important significance, and can avoid reduction of the clinical curative effect of ganciclovir due to too high impurity content. The invention further relates to a preparation method of the ganciclovir compatible impurity shown in the formula (I), the method is simple to operate, and the purity of the obtained product can reach 95% or above. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to but is not limited to the field of organic chemistry, and in particular to a ganciclovir compatible impurity and a preparation method and application thereof. Background Art

[0002] Ganciclovir for injection is mainly composed of ganciclovir, whose chemical name is 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine. It was developed by Roche Pharma Ltd. and was first approved for marketing in the UK in June 1988 under the trade name

[0003] The dosage form is injection, with a specification of 0.5g; in June 1989, this product was approved for marketing in the United States under the trade name The dosage form is injection, with a specification of 500 mg. In December 2000, it was launched in China under the trade name The specification is 0.5g. It is used to prevent and treat immunodeficient patients infected with cytomegalovirus that threatens life or vision, and to prevent organ transplant patients related to cytomegalovirus infection. Its structural formula is shown in formula (II):

[0004]

[0005] Ganciclovir is a synthetic guanine homologue. After being phosphorylated to monophosphate in cells infected with cytomegalovirus (CMV), this drug is further phosphorylated to ganciclovir triphosphate by induction of several cellular kinases. The concentrations of cellular kinases and ganciclovir triphosphate in CMV-infected cells are higher than those in uninfected cells. Therefore, phosphorylation of ganciclovir is more likely to occur in virus-infected cells. Ganciclovir triphosphate is metabolized slowly in virus-infected cells. After ganciclovir in the extracellular fluid is cleared for 18 hours, 60-70% of ganciclovir triphosphate is still maintained in the cells. The antiviral effect of this drug is due to the inhibition of viral DNA synthesis: the three phosphates of this product competitively inhibit the binding of deoxyguanosine triphosphate to DNA polymerase; bind to viral DNA and prevent the extension of the DNA chain.

[0006] In clinical practice, ganciclovir is often used in combination with 5% glucose solution. At present, reports on ganciclovir impurities mainly focus on high temperature degradation impurities, oxidation impurities, acid degradation impurities, etc. of the main component of ganciclovir, and no reports have been seen on compatible impurities.

[0007] Therefore, it is particularly important to obtain reference materials for incompatible impurities produced when ganciclovir is used in combination with glucose solution and to conduct corresponding quality research in clinical applications. Summary of the invention

[0008] The present invention discovers a new impurity related to ganciclovir compatibility, the impurity has a novel structure, can be applied to reference product research, and is helpful for quality control of ganciclovir preparations. At the same time, the present invention also discloses a preparation method of the impurity, which has the characteristics of simple operation and high purity of the obtained product.

[0009] Specifically, the first aspect of the present invention provides a new ganciclovir compatible impurity, the structural formula of which is shown in formula (I):

[0010]

[0011] In some embodiments, the ganciclovir compatible impurities are compatible impurities generated when ganciclovir for injection is used in combination with glucose solution, so they can also be called ganciclovir compatible impurities for injection.

[0012] The second aspect of the present invention provides a method for preparing the ganciclovir compatible impurity, comprising the following steps:

[0013] Glyoxal is reacted with ganciclovir in a solvent to obtain a compound represented by formula (I).

[0014] In some embodiments, the preparation method comprises: mixing glyoxal with the solvent to prepare a glyoxal solution, and then mixing the glyoxal solution with ganciclovir for reaction. The reaction route is as follows:

[0015]

[0016] Preferably, the mass percentage concentration of the glyoxal solution can be 1% to 40%, for example, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40%. By optimizing the concentration of the glyoxal solution, it is beneficial to promote the reaction and improve the purity of the compound shown in formula (I), i.e., the compatible impurities. Too high or too low a concentration is not conducive to improving the purity.

[0017] In some embodiments, the solvent may be selected from an organic solvent, water and a mixture thereof. Preferably, the organic solvent may be selected from one or more of methanol, ethanol, propanol, butanol, acetone, tetrahydrofuran, dichloromethane, DMF and DMSO.

[0018] In some embodiments, the solvent can be water, methanol, DMF, DMSO, a mixture of methanol and water, a mixture of DMF and water, or a mixture of DMSO and water.

[0019] Optimizing the type of solvent can help promote the reaction and improve the purity of the compound represented by formula (I).

[0020] In some embodiments, the molar ratio of glyoxal to ganciclovir may be 15: 1-1: 1, for example, 15: 1, 14: 1, 13: 1, 12: 1, 11: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1, preferably 12: 1-8: 1. By optimizing the molar ratio of glyoxal to ganciclovir, it is beneficial to promote the reaction.

[0021] In some embodiments, the reaction temperature may be 0-100°C, preferably 25-60°C.

[0022] In some embodiments, the reaction time may be 0.5-3 h, preferably 1-2 h.

[0023] Optimizing the reaction temperature and time can help promote the reaction and improve the purity of the compound represented by formula (I).

[0024] In some embodiments, after the reaction is completed, the compound represented by formula (I) is obtained by separation and purification. Preferably, the separation and purification comprises: using C 18 The separation is performed by a preparative column, the mobile phase is a formic acid aqueous solution, the elution is isocratic, and the detection wavelength is 254 nm; and the obtained fractions are concentrated under reduced pressure and spin-dried. Preferably, the mobile phase is a formic acid aqueous solution with a volume percentage concentration of 0.1%.

[0025] The purity of the ganciclovir compatibility impurity prepared by the method of the present invention can reach more than 95%, and can be used as a reference substance in the quality research of ganciclovir preparations (such as ganciclovir preparations for injection).

[0026] The third aspect of the present invention provides the use of the ganciclovir compatible impurity as a reference substance in the quality research of ganciclovir preparations.

[0027] In some embodiments, the ganciclovir formulation is an injectable ganciclovir formulation.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. The present invention provides a new ganciclovir compatibility impurity, as shown in formula (I). After repeated experiments, it was found that the impurity is very easy to be produced during the compatibility of ganciclovir and 5% glucose solution. The present invention characterizes the impurity shown in formula (I) and determines the structure of the impurity. The impurity can be used as a reference substance for the quality research of ganciclovir preparations (such as ganciclovir preparations for injection), which is of great significance and can avoid the impurity content being too high and reducing the clinical efficacy of ganciclovir.

[0030] 2. The present invention also provides a method for preparing the ganciclovir compatible impurity shown in formula (I). The method is simple to operate and the purity of the obtained product can reach more than 95%. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The chromatogram is of the ganciclovir compatibility impurity shown in formula (I).

[0032] Figure 2 is the chromatogram of the test solution. DETAILED DESCRIPTION

[0033] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0034] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments and equipment used in the following examples, etc., can all be purchased on the market or can be obtained by existing methods; the amounts of the experimental reagents, unless otherwise specified, are the amounts of reagents used in conventional experimental operations; the experimental methods, unless otherwise specified, are all conventional methods.

[0035] Preparation of Ganciclovir Compatible Impurities

[0036] Example 1

[0037] Prepare a 20% glyoxal aqueous solution. Place 20% glyoxal (10.0 eq.) aqueous solution and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 25°C for 1 hour, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, isocratic elution, the detection wavelength was 254 nm, the fractions were concentrated under reduced pressure and dried, and 5.6 g of the product was obtained as a white solid with a purity of 98.21%. The characterization data are as follows:

[0038] 1 H-NMR (DMSO-d6, 400MHz) δ (ppm): 8.86 (s, 1H, -NH-), 7.85 (s, 1H, = CH-), 5.48 (s, 1H, CH), 5.46 (s, 2H, -CH2-), 4.8 8(s,1H,CH), 3.53(p,J=5.2Hz,1H,CH), 3.42(dd,J=11.4,4.9Hz,2H,-CH2-), 3.29(dd,J=11.4,5.8Hz,2H,-CH2-).

[0039] 13 C NMR (DMSO-d6, 100MHz) δ (ppm): 60.9, 60.9, 71.6, 80.1, 83.8, 84.2, 117.3, 138.1, 151.3, 155.0, 155.1.

[0040] High-resolution mass spectrometry results:

[0041] The samples were analyzed by mass spectrometry using electrospray ionization (HESI) and a full-scale MS scan was performed in the positive ion mode. The quasi-molecular ion peak [M+H] + The m / z is 314.10904, and the molecular weight is C 11 H 16 N5O6, with an unsaturation degree of 6.5, has one more unsaturation degree than API ganciclovir, and is consistent with the molecular formula of the expected structure ([M+H] + The possible fragmentation pathway of the impurity proposed is shown below, and its fragmentation characteristics are consistent with the expected structure.

[0042]

[0043] In summary, through comprehensive analysis of NMR data combined with LC-HRMS data, it was inferred and verified that the structure of the sample was the structure shown in formula (I).

[0044] Example 2

[0045] Prepare a 1% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 25°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm) with a 0.1% formic acid aqueous solution as the mobile phase, isocratic elution, and a detection wavelength of 254 nm. The fractions were concentrated under reduced pressure and dried to obtain 4.4 g of the product as a white solid with a purity of 95.42%.

[0046] Example 3

[0047] Prepare a 30% aqueous solution of glyoxal by mass percentage. Place 30% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 25°C for 1 hour, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 4.0 g of product as a white solid with a purity of 96.46%.

[0048] Example 4

[0049] Prepare a 40% glyoxal aqueous solution. Place 40% glyoxal (10.0 eq.) solution and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 25°C for 1 hour. After decompression and concentration to remove the solvent, separate and purify by preparative liquid phase. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 1.5 g of product as a white solid with a purity of 95.12%.

[0050] Example 5

[0051] Prepare a 25% aqueous solution of glyoxal by mass percentage. Place 25% aqueous solution of glyoxal (15.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 25°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 5.0 g of product as a white solid with a purity of 97.32%.

[0052] Example 6

[0053] Prepare a 40% aqueous solution of glyoxal by mass percentage. Place 40% aqueous solution of glyoxal (1 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 25°C for 1 hour, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 1.3 g of product as a white solid with a purity of 95.45%.

[0054] Example 7

[0055] Prepare a 40% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle and stir at 60°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 1.3 g of product as a white solid with a purity of 96.12%.

[0056] Example 8

[0057] Prepare a 40% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-necked bottle and stir for 1 h in an ice bath (0°C), concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 1.0 g of product as a white solid with a purity of 95.32%.

[0058] Example 9

[0059] Prepare a 40% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle, heat and stir at 100°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 2.5 g of product as a white solid with a purity of 95.78%.

[0060] Example 10

[0061] Prepare a 40% glyoxal methanol solution. Heat 40% glyoxal (10.0 eq.) methanol solution and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle at 60°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 4.2 g of product as a white solid with a purity of 96.35%.

[0062] Embodiment 11

[0063] A solution of glyoxal in methanol and water (50:50) with a mass percentage concentration of 20% was prepared. The prepared 20% glyoxal solution (10.0 eq.) and ganciclovir (10 g, 1 eq.) were heated and stirred at 60° C. in a 250 mL single-mouth bottle for 1 h, and the solvent was removed by concentration under reduced pressure and then purified by preparative liquid phase separation. The separation and purification conditions were: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 3.6 g of product as a white solid with a purity of 97.11%.

[0064] The ganciclovir compatibility impurities obtained in Example 2-11 were characterized by ESI-MS and 1 HNMR is the same as Example 1.

[0065] Comparative Example 1

[0066] Prepare a 40% aqueous solution of glyoxal (18.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle, heat and stir at 60°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 1.0 g of product as a white solid with a purity of 50.23%.

[0067] Comparative Example 2

[0068] Prepare a 40% glyoxal toluene solution. Heat 40% glyoxal (10.0 eq.) toluene solution and ganciclovir (10 g, 1 eq.) at 60°C in a 250 mL single-mouth bottle and stir for 1 h. Concentrate under reduced pressure to remove the solvent and then separate and purify by preparative liquid phase. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried to obtain 0.5 g of product as a white solid with a purity of 30.25%.

[0069] Comparative Example 3

[0070] Prepare a 50% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle, heat and stir at 60°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm) with a 0.1% formic acid aqueous solution as the mobile phase, isocratic elution, and a detection wavelength of 254 nm. The fractions were concentrated under reduced pressure and dried to obtain 0.2 g of the product as a white solid with a purity of 35.21%.

[0071] Comparative Example 4

[0072] Prepare a 20% aqueous solution of glyoxal by mass percentage. Heat 20% aqueous solution of glyoxal (10.0 eq.) and ganciclovir (10 g, 1 eq.) in a 250 mL single-mouth bottle at 100°C for 1 h, concentrate under reduced pressure to remove the solvent, and then separate and purify by preparative liquid phase separation. The separation and purification conditions are: C 18 Separation was performed on a preparative column (50 mm*250 mm, 10 μm) with a 0.1% formic acid aqueous solution as the mobile phase, isocratic elution, and a detection wavelength of 254 nm. The fractions were concentrated under reduced pressure and dried to obtain 0.13 g of the product as a white solid with a purity of 45.21%.

[0073] Comparative Example 5

[0074] Prepare a 60% glyoxal chloroform solution. Heat 60% glyoxal (20.0 eq.) chloroform solution and ganciclovir (10 g, 1 eq.) at 100°C in a 250 mL single-mouth bottle and stir for 1 h. Concentrate under reduced pressure to remove the solvent and then separate and purify by preparative liquid phase. The separation and purification conditions are: C 18 The separation was carried out using a preparative column (50 mm*250 mm, 10 μm), the mobile phase was 0.1% formic acid aqueous solution, the elution was isocratic, the detection wavelength was 254 nm, and the fractions were concentrated under reduced pressure and dried by spin drying, but the product could not be obtained.

[0075] Application of Ganciclovir Compatible Impurities as Reference Substances

[0076] Example 12

[0077] Ganciclovir compatibility impurities were used to test the sample of ganciclovir-5% glucose compatibility solution for injection.

[0078] Instrument and chromatographic conditions:

[0079] Agilent 1260 high performance liquid chromatograph was used, with octadecylsilane bonded silica gel as the filler, column temperature at 35°C, flow rate at 1.0 ml / min, detection wavelength at 254 nm, injection volume at 20 μl.

[0080] Mobile phase A: 0.1% formic acid solution

[0081] Mobile phase B: acetonitrile

[0082] Elution degree: gradient elution

[0083] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 20 100 0 30 90 10 35 80 20 40 50 50 48 50 50 50 100 0 60 100 0

[0084] Prepare the solution:

[0085] Reference solution (0.5%): Accurately weigh an appropriate amount of ganciclovir compatible impurities, dilute with water to a concentration of about 1.25 μg / ml of ganciclovir compatible impurities per ml. See the typical spectrum for details. Figure 1 .

[0086] Test solution 1 (0.075 mg / ml) (lower limit of concentration specified in the instructions): Take 1 bottle of self-developed ganciclovir for injection (specification 0.25 g) and add 5 ml of water to dilute to a concentration of 50 mg / ml. Accurately pipette about 375 μl into 250 ml of 5% glucose injection (purchased from Chenxin Pharmaceutical) and mix well.

[0087] Test solution 2 (0.075 mg / ml) (lower limit of concentration specified in the instructions): Take 1 bottle of self-developed ganciclovir for injection (specification 0.25 g) and add 5 ml of water to dilute to a concentration of 50 mg / ml. Accurately pipette about 375 μl into 250 ml of 5% glucose injection (purchased from Shandong Kelun) and mix well.

[0088] Test solution 3 (0.075 mg / ml) (lower limit of concentration specified in the instructions): Take 1 bottle of self-developed ganciclovir for injection (specification 0.25 g) and add 5 ml of water to dilute to a concentration of 50 mg / ml. Accurately pipette about 375 μl into 250 ml of 5% glucose injection (purchased from Anhui Shuanghe) and mix well.

[0089] Test solution 4 (1.0 mg / ml) (common clinical concentration): Take 1 bottle of self-developed ganciclovir for injection (specification 0.25 g) and add 5 ml of water to dilute to a concentration of 50 mg / ml. Transfer 5 ml completely to 250 ml of 5% glucose injection (purchased from Chenxin Pharmaceutical) and mix well. The typical spectrum is shown in Figure 2 .

[0090] First, linearity tests and correction factor confirmation were performed on ganciclovir and its compatible impurities. The results are shown in Tables 1 to 3 below.

[0091] Table 1 Linearity results of ganciclovir

[0092]

[0093]

[0094] Table 2 Linear results of compatible impurities

[0095]

[0096] Table 3 Correction factors for compatible impurities

[0097] name Correction Factor Compatible impurities 1.5

[0098] It can be seen from Table 3 that the content of compatible impurities needs to be substituted into the correction factor (1.5) for calculation.

[0099] The test solutions 1-4 were prepared by mixing the self-developed ganciclovir injection preparation (specification: 0.25 g) with 5% glucose injection produced by different pharmaceutical companies. The freshly prepared test solutions were placed at 2-8°C for 24 hours, and the content of compatible impurities in the test solutions was detected. The results are shown in Table 4 below.

[0100] Table 4

[0101]

[0102]

[0103] Calculation method for the content of compatible impurities: area normalization determination method with correction factor added.

[0104] Because the compatibility impurity has a three-membered ring warning structure, the inventor conducted a bacterial recovery experiment, and the result showed negative. According to the ICH guidelines, the compatibility impurity is a non-genotoxic impurity, so it is controlled as a general impurity. The maximum daily dose of this product is 600 mg / day, and the impurity quality control limit is 0.5%. Therefore, in order to ensure the clinical efficacy and product safety of ganciclovir for injection in the process of compatibility with 5% glucose injection, the internal control limit of this impurity is set at 0.5%.

[0105] Under the above chromatographic conditions, the relative retention time of the compatible impurities shown in formula (I) is 0.69, which can be effectively separated from the main component peak of ganciclovir and the main impurities, and the separation degree between each other impurity is greater than 1.5, and has good accuracy and repeatability. The establishment of the impurity preparation process and analysis method provides an effective means for monitoring the content of the compatible impurities of ganciclovir for injection, and further ensures the product quality of ganciclovir for injection and the drug safety of patients.

[0106] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be based on the protection scope of the claims.

Claims

1. A ganciclovir compatibility impurity, characterized in that: The structural formula is shown in formula (I):

2. The method for preparing the ganciclovir compatible impurities according to claim 1, characterized in that: The steps include: Glyoxal is reacted with ganciclovir in a solvent to obtain a compound represented by formula (I).

3. The preparation method according to claim 2, characterized in that: Glyoxal is mixed with the solvent to prepare a glyoxal solution, and the glyoxal solution is then mixed with ganciclovir for reaction; preferably, the mass percentage concentration of the glyoxal solution is 1% to 40%.

4. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of glyoxal to ganciclovir is 15:1-1:1, preferably 15:1-8:1, and more preferably 10:

1.

5. The preparation method according to claim 2 or 3, characterized in that: The reaction temperature is 0-100°C, preferably 25-60°C; the reaction time is 0.5-3h, preferably 1-2h.

6. The preparation method according to claim 2 or 3, characterized in that: The solvent is selected from an organic solvent, water and a mixture thereof; preferably, the organic solvent is selected from one or more of methanol, ethanol, propanol, butanol, acetone, tetrahydrofuran, dichloromethane, DMF and DMSO.

7. The preparation method according to claim 6, characterized in that: The solvent is water, methanol, DMF, DMSO, a mixture of methanol and water, a mixture of DMF and water, or a mixture of DMSO and water.

8. The preparation method according to claim 2 or 3, characterized in that: After the reaction is completed, the compound represented by formula (I) is obtained by separation and purification; preferably, the separation and purification comprises: using C 18 The separation was performed using a preparative column, the mobile phase was an aqueous formic acid solution, the elution was isocratic, and the detection wavelength was 254 nm; and the obtained fractions were concentrated under reduced pressure and dried by spin drying.

9. Use of the ganciclovir compatible impurity according to claim 1 as a reference substance in the quality study of ganciclovir preparations.

10. The use according to claim 9, characterized in that The ganciclovir preparation is an injectable ganciclovir preparation.

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