Preparation method of tadalafil impurity I

Abstract

The present invention relates to a method for preparing a tadalafil impurity I, and belongs to the field of analytical chemistry. The method specifically relates to preparing a tadalafil impurity I by using a preparative liquid phase, characterized in that tadalafil, hydrogen peroxide and a reaction solvent are mixed, reacted to an end point, a crude product containing the tadalafil impurity I is obtained, and then an organic acid buffer-acetonitrile is used as a mobile phase, and a C18 filler is used as a preparative column for elution separation, and the tadalafil impurity I peak flow fraction is collected, and after removing the solvent, a high-purity tadalafil impurity I is obtained. The method of the present invention has simple steps, cheap and easily available raw materials, and high product purity.

Description

Technical Field

[0001] The present invention relates to the field of analytical chemistry, and in particular to a method for preparing tadalafil impurity I. Background Art

[0002] Tadalafil is a PDE5 inhibitor that can be used to treat erectile dysfunction, pulmonary hypertension, and benign prostatic hyperplasia. The chemical name of tadalafil is (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, with a molecular weight of 387.41. The molecular formula of tadalafil is C 22 H 19 N3O4, chemical structure is as follows:

[0003]

[0004] Tadalafil has been included in pharmacopoeias such as USP, EP, and BP. The European Pharmacopoeia EP9.0 Tadalafil quality standards require the control of related substances A, B, C, D, E, F, G, H, and I. Current laws and regulations in various countries have set very high requirements for the quality of generic drugs. Therefore, if they want to be successfully approved for marketing, pharmaceutical companies must conduct in-depth and detailed research on the related substances of generic drugs so that the quality of generic drugs reaches or even exceeds the standards of the original manufacturers. In this process, obtaining related substance reference substances is an indispensable link. Combining EP9.0 and other literature searches, we know that related substances A, B, C, D, E, F, G, H, and I have been reported in the literature; among them, the structure of related substance I is as follows:

[0005]

[0006] The preparation of tadalafil related substance I (also called tadalafil impurity I) is the most technically demanding and difficult. Patent application CN109796461 reports a method for preparing tadalafil impurity I, but the preparation method of the patent requires multiple reagents, the reaction steps are cumbersome, the post-processing is also complicated, and it is difficult to obtain impurity I according to this method.

[0007] In view of this, the inventors of the present invention have developed a preparation method suitable for tadalafil impurity I through research. The method of the present invention can prepare tadalafil impurity I, the method is simple, the raw materials for the oxidation reaction are cheap and readily available, the method is environmentally friendly, the prepared product has high purity, and can be used for quality control of tadalafil. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing tadalafil impurity I, so as to obtain high-purity tadalafil impurity I for quality control of tadalafil.

[0009] A method for preparing tadalafil impurity I comprises the following steps:

[0010] (1) mixing tadalafil, hydrogen peroxide and a reaction solvent, and reacting at a certain temperature to an end point to obtain a crude product containing tadalafil impurity I; the reaction scheme is as follows:

[0011]

[0012] In some embodiments, the reaction solvent in step (1) is at least one of acetone or ethanol.

[0013] In some embodiments, the certain temperature in step (1) is 50°C to 80°C.

[0014] In some embodiments, the hydrogen peroxide described in step (1) can be of any suitable concentration. In some embodiments, the hydrogen peroxide described in step (1) is 30% hydrogen peroxide (hydrogen peroxide: water = 30:70, V / V), which is conducive to obtaining the target product.

[0015] In some embodiments, a method for preparing tadalafil impurity I further comprises the following steps:

[0016] (2) filtering the crude product of tadalafil impurity I obtained in step (1) through a filter membrane, and then injecting it into a preparative liquid phase, using an organic acid buffer-acetonitrile as a mobile phase and a C18 filler column as a preparative column for elution and separation, and collecting the tadalafil impurity I peak fraction;

[0017] (3) removing the solvent from the tadalafil impurity I peak fraction collected in step (2) to obtain tadalafil impurity I.

[0018] In some embodiments, the organic filter membrane described in step (2) can be a 0.45 um organic filter membrane.

[0019] In some embodiments, the prepared liquid phase described in step (2) can be a semi-industrial to industrial grade prepared liquid phase, such as a semi-industrial to industrial grade prepared liquid phase manufactured by Jiangsu Hanbang Technology Co., Ltd.

[0020] In some embodiments, the organic acid described in step (2) is at least one of formic acid, acetic acid or trifluoroacetic acid. In some embodiments, the organic acid described in step (2) is formic acid.

[0021] In some embodiments, the mobile phase in step (2) can be one of 0.1% formic acid aqueous solution-acetonitrile, 0.1% acetic acid aqueous solution-acetonitrile or 0.1% trifluoroacetic acid aqueous solution-acetonitrile.

[0022] In some embodiments, the mobile phase in step (2) is 0.1% formic acid aqueous solution-acetonitrile, and the volume ratio of 0.1% formic acid aqueous solution to acetonitrile in the mobile phase is 70:30 to 80:20. In some embodiments, the mobile phase in step (2) is 0.1% formic acid aqueous solution-acetonitrile, and the volume ratio of 0.1% formic acid aqueous solution to acetonitrile in the mobile phase is 75:25. It is more conducive to separation and determination.

[0023] In some embodiments, the preparative column packing material in step (2) may be EternityXT-10-C18.

[0024] In some embodiments, the elution separation in the preparative liquid phase described in step (2) can be isocratic elution, and the flow rate of the preparative liquid phase can be 90 mL / min-120 mL / min.

[0025] In some embodiments, the detection wavelength in the preparation liquid phase described in step (2) can be 280-290nm.

[0026] In some embodiments, the column temperature in the preparation liquid phase described in step (2) can be 20°C-40°C.

[0027] In some embodiments, the elution separation in the preparative liquid phase described in step (2) can be isocratic elution, the flow rate of the preparative liquid phase can be 90mL / min-120mL / min; the detection wavelength can be 280-290nm; and the column temperature can be 20℃-40℃.

[0028] In some embodiments, the elution separation in the preparation liquid phase described in step (2) can be isocratic elution, the flow rate of the preparation liquid phase is 90mL / min-120mL / min, the detection wavelength is 280-290nm, and the column temperature is 20°C-40°C. In some embodiments, the elution separation in the preparation liquid phase described in step (2) can be isocratic elution, the flow rate of the preparation liquid phase is 110mL / min, the detection wavelength is 285nm, and the column temperature is 20°C-40°C.

[0029] In some embodiments, the collection of the tadalafil impurity I peak fractions in step (2) may start when the tadalafil impurity I peak begins to elute and end at the tail.

[0030] In some embodiments, in step (3), the solvent can be removed by evaporating under reduced pressure using a rotary evaporator.

[0031] In some embodiments, step (2) in the aforementioned preparation method may include the following steps:

[0032] a) taking the crude tadalafil impurity I product of step (1) and passing it through an organic filter membrane to obtain a sample solution;

[0033] b) using organic acid buffer-acetonitrile as the mobile phase and C18 filler as the preparative column;

[0034] c) Set the instrument parameters: flow rate of the mobile phase, detection wavelength, and column box temperature of the chromatographic column;

[0035] d) taking an appropriate amount of the sample solution of step a), injecting it into the preparative liquid phase, performing preparative separation, and collecting the tadalafil impurity I peak fraction.

[0036] In some embodiments, step (2) in the aforementioned preparation method may include the following steps:

[0037] a) taking the crude tadalafil impurity I product of step (1) and passing it through an organic filter membrane to obtain a sample solution;

[0038] b) using 0.1% formic acid aqueous solution-acetonitrile (70:30 to 80:20, V / V) as the mobile phase and EternityXT-10-C18 as the preparative column packing;

[0039] c) Set the instrument parameters: flow rate of the mobile phase, detection wavelength, and column box temperature of the chromatographic column;

[0040] d) taking 5 mL to 20 mL of the sample solution of step a), injecting it into the preparative liquid phase, performing separation preparation, and collecting the tadalafil impurity I peak fraction.

[0041] The tadalafil impurity I described in step a) above may be of any purity.

[0042] The mobile phase in step b) can be 0.1% formic acid aqueous solution-acetonitrile, and the volume ratio of 0.1% formic acid aqueous solution to acetonitrile in the mobile phase is 70:30 to 80:20, which is more conducive to separation and determination.

[0043] The C18 filler described in the above step b) may be EternityXT-10-C18.

[0044] The flow rate of the mobile phase in step c) can be 90 ml / min to 120 ml / min.

[0045] The flow rate of the mobile phase in step c) above may be 90 mL / min-120 mL / min, the detection wavelength may be 280-290 nm, and the column temperature may be 20° C.-40° C. In some embodiments, the flow rate of the mobile phase in step c) above is 110 mL / min, the detection wavelength is 285 nm, and the column temperature is 20° C.-40° C.

[0046] The appropriate amount in step d) is 5 mL to 20 mL.

[0047] In the above step d), the sample solution injection volume is 5 ml to 20 ml. In some embodiments, the sample solution injection volume is 5 ml. In some embodiments, the sample solution injection volume is 10 ml.

[0048] In the method provided by the present invention, the preparative liquid chromatograph can be a semi-industrial to industrial grade preparative liquid chromatograph, and the manufacturer is Jiangsu Hanbang Technology Co., Ltd.

[0049] In some embodiments, the preparation method described in the present invention includes: mixing tadalafil, 30% hydrogen peroxide and acetone or ethanol, stirring and reacting at 50°C to 80°C to the end point to obtain a crude product containing tadalafil impurity I; passing the crude tadalafil impurity I through a 0.45um organic filter membrane as a sample solution, and then taking 5mL-20mL of the sample solution and injecting it into the preparation liquid phase, using 0.1% formic acid aqueous solution-acetonitrile as the mobile phase, and using C18 filler as the preparation column, eluting and separating, and collecting the tadalafil impurity I peak fraction; the collected tadalafil impurity I peak fraction is concentrated under reduced pressure, and after removing the solvent, a high-purity tadalafil impurity I is obtained; the volume ratio of 0.1% formic acid aqueous solution to acetonitrile in the mobile phase is 70:30 to 80:20; the C18 filler is EternityXT-10-C18.

[0050] In some embodiments, the preparation and separation method described in the present invention includes: mixing tadalafil, 30% hydrogen peroxide and acetone, stirring and reacting at 50°C to 80°C to the end point to obtain a crude product containing tadalafil impurity I; passing the crude tadalafil impurity I through a 0.45um organic filter membrane as a sample solution, and then taking 5mL-20mL of the sample solution and injecting it into the preparation liquid phase, using 0.1% formic acid aqueous solution-acetonitrile as the mobile phase, and using C18 filler as the preparation column, eluting and separating, and collecting the tadalafil impurity I peak fraction; the collected tadalafil impurity I peak fraction is concentrated under reduced pressure, and after removing the solvent, a high-purity tadalafil impurity I is obtained; the volume ratio of 0.1% formic acid aqueous solution to acetonitrile in the mobile phase is 70:30 to 80:20; the C18 filler is EternityXT-10-C18.

[0051] In some embodiments, the preparation and separation method described in the present invention includes: mixing tadalafil, 30% hydrogen peroxide and ethanol, stirring and reacting at 50°C to 80°C to the end point to obtain a crude product containing tadalafil impurity I; passing the crude tadalafil impurity I through a 0.45um organic filter membrane as a sample solution, and then taking 5mL-20mL of the sample solution and injecting it into the preparation liquid phase, using 0.1% formic acid aqueous solution-acetonitrile as the mobile phase, and using C18 filler as the preparation column, eluting and separating, and collecting the tadalafil impurity I peak fraction; the collected tadalafil impurity I peak fraction is concentrated under reduced pressure, and after removing the solvent, a high-purity tadalafil impurity I is obtained; the volume ratio of 0.1% formic acid aqueous solution to acetonitrile in the mobile phase is 70:30 to 80:20; the C18 filler described is EternityXT-10-C18.

[0052] The tadalafil impurity I prepared by the preparation method of the present invention is confirmed to be tadalafil impurity I after being characterized by nuclear magnetic resonance and high-resolution mass spectrometry, and the purity thereof is above 98% or above 99%.

[0053] The preparation method of the present invention has simple steps, and the oxidation reaction adopts cheap and easily available raw material hydrogen peroxide, which has low cost, and after the reaction, except that the product is water, it is environmentally friendly; after obtaining the crude product, the liquid phase separation and purification is prepared, and the mobile phase adopted is a volatile buffer salt, so the prepared flow fraction can be directly evaporated under reduced pressure, the post-processing is simple, the cost is low, and the obtained product has high purity, which can be used as a reference substance for quality control. Therefore, the preparation method of the tadalafil impurity I of the present invention can simply and efficiently obtain high-purity tadalafil impurity I, which is of great significance for the quality control of tadalafil.

[0054] In the above or below, regardless of whether the words "about" or "approximately" are used, all the numbers disclosed herein are approximate values. The value of each number may differ by 1%, 2%, 5%, 7%, 8% or 10%.

[0055] In the present invention, EternityXT-10-C18 represents a C18 prepared filler model;

[0056] In the present invention, LCMS means liquid chromatography-mass spectrometry;

[0057] In the present invention, NBS represents N-bromosuccinimide;

[0058] In the present invention, room temperature means 20°C to 40°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 The compound obtained by the preparation method in Comparative Example 1 is shown 1 H spectrum;

[0060] Figure 2 The compound obtained by the preparation method in Comparative Example 1 is shown 13 C spectrum;

[0061] Figure 3 The high-resolution mass spectrum of tadalafil impurity I obtained by the preparation method of Example 1 is shown;

[0062] Figure 4 Example 1 Preparation method to obtain tadalafil impurity I 1 H spectrum;

[0063] Figure 5 Example 1 Preparation method to obtain tadalafil impurity I 13 C spectrum;

[0064] Figure 6 The LCMS spectrum in Comparative Example 2 is shown. DETAILED DESCRIPTION

[0065] The embodiment of the present invention discloses a method for preparing and separating tadalafil impurity I. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0066] In order to further understand the present invention, the present invention is described in detail below in conjunction with embodiments.

[0067] Specifications of the instrument and preparative column: semi-industrial-grade preparative liquid phase, manufactured by Jiangsu Hanbang Technology Co., Ltd.; manual injection;

[0068] Preparative columns Specification filler DAC-HB50 50x250mm, 10um EternityXT-10-C18

[0069] Example 1-3: Preparation of tadalafil impurity I using DAC-HB50, EternityXT-10-C18, and preparative columns.

[0070] Example 1

[0071] (1) 1 g of tadalafil (purity 95% or more) and 30% hydrogen peroxide (5 ml) were dissolved in acetone (50 ml), and the mixture was refluxed and stirred in a 60° C. heat-collecting constant temperature heating magnetic stirrer for 5 hours to obtain a crude product of tadalafil impurity I;

[0072] (2) The crude product of tadalafil impurity I obtained in step (1) was filtered through a 0.45 um organic filter membrane as a sample solution, and then 10 mL of the sample solution was injected into the preparative liquid phase, and 0.1% formic acid aqueous solution-acetonitrile (70:30 to 80:20, V / V) was used as the mobile phase for isocratic elution; the flow rate was 110 mL / min; the detection wavelength was 285 nm; the column temperature was room temperature, and preparative separation was performed; the tadalafil impurity I fraction was collected when the tadalafil impurity I peak just appeared, and the tadalafil impurity I fraction was collected until the end of the peak, and the tadalafil impurity I fraction was stored at room temperature. Repeat several times and combine all the tadalafil impurity I fractions.

[0073] (3) The tadalafil impurity I fraction obtained in step (2) was evaporated to dryness under reduced pressure at 40° C. using a rotary evaporator to obtain 400 mg of tadalafil impurity I with a purity of 99.20% and a yield of about 40%.

[0074] The tadalafil impurity I of Example 1 was subjected to high-resolution mass spectrometry and nuclear magnetic resonance analysis under the following conditions: 1 H analysis and NMR 13 C analysis, record its mass spectrum, H spectrum and C spectrum, the results are shown in Figure 3 , Figure 4 and Figure 5 .

[0075] High-resolution mass spectrometry detection conditions: LC-Q-TOF (the instruments are Agilengt's 1260HPLC and 6545Q-TOF); Q-OTF parameters are: Ion Source: AJS Dual ESI; Ion Polarity: Positive; Gas temp: 325°C; Drying gas: 10.0L / min; Nebulizer: 40psig; Fragmentor: 125V; Sheath Gas Temp: 300°C; Sheath Gas Flow: 11L / min.

[0076] The observed m / z 406.1397 and m / z 833.2534 were the [M+H] + Ions and [2M+Na] + ion. Its molecule is calculated to be C 22 H 19 N3O5, the relative deviation between the calculated theoretical value and the actual measured value is 0.0ppm. Compared with tadalafil, the unsaturation degree of the prepared related substance I is the same as that of tadalafil, and the molecular formula has one more oxygen atom than that of tadalafil. Therefore, it can be inferred that the substance obtained in Example 1 meets the mass spectrum characteristics of tadalafil impurity I.

[0077] NMR conditions: 1H spectrum and 13 The C spectrum was measured on a Swiss Bruker AVANCE III HD 600 superconducting pulsed Fourier transform nuclear magnetic resonance spectrometer; the sample was dissolved in deuterated DMSO; the reference substance was TMS ( 1 H spectrum, 13 C spectrum). The analysis results are as follows:

[0078]

[0079]

[0080]

[0081] Nuclear Magnetic Resonance 1 H spectrum and 13 C spectrum shows that the substance obtained in Example 1 conforms to the NMR of tadalafil impurity I 1 H spectrum and 13 C spectrum characteristics.

[0082] Therefore, the substance obtained by the method of the present invention is tadalafil impurity I.

[0083] Example 2

[0084] (1) 1 g of tadalafil (purity 95% or more) and 30% hydrogen peroxide (5 ml) were dissolved in ethanol (50 ml), and the mixture was refluxed and stirred in a 70° C. heat-collecting constant temperature heating magnetic stirrer for 4 hours to obtain a crude product of tadalafil impurity I;

[0085] (2) The crude product of tadalafil impurity I obtained in step (1) was filtered through a 0.45 um organic filter membrane as a sample solution, and then 10 mL of the sample solution was injected into the preparative liquid phase, and 0.1% formic acid aqueous solution-acetonitrile (70:30 to 80:20, V / V) was used as the mobile phase for isocratic elution; the flow rate was 110 mL / min; the detection wavelength was 285 nm; the column temperature was room temperature, and preparative separation was performed; the tadalafil impurity I fraction was collected from the moment the tadalafil impurity I peak appeared, and the tadalafil impurity I fraction was collected until the end of the peak, and the tadalafil impurity I fraction was stored at room temperature.

[0086] Repeat several times and combine all tadalafil impurity I fractions.

[0087] (3) The tadalafil impurity I fraction obtained in step (2) was evaporated to dryness under reduced pressure at 40° C. using a rotary evaporator to obtain 350 mg of tadalafil impurity I with a purity of 99.52% and a yield of about 35%.

[0088] Example 3

[0089] (1) 1 g of tadalafil (purity 95% or more) and 30% hydrogen peroxide (5 ml) were dissolved in ethanol (50 ml), and the mixture was refluxed and stirred in a 60° C. heat-collecting constant temperature heating magnetic stirrer for 5 hours to obtain a crude product of tadalafil impurity I;

[0090] (2) The crude product of tadalafil impurity I obtained in step (1) was filtered through a 0.45 um organic filter membrane as a sample solution, and then 10 mL of the sample solution was injected into the preparative liquid phase, and 0.1% formic acid aqueous solution-acetonitrile (70:30 to 80:20, V / V) was used as the mobile phase for isocratic elution; the flow rate was 110 mL / min; the detection wavelength was 285 nm; the column temperature was room temperature, and preparative separation was performed; the tadalafil impurity I fraction was collected when the tadalafil impurity I peak just appeared, and the tadalafil impurity I fraction was collected until the end of the peak, and the tadalafil impurity I fraction was stored at room temperature. Repeat several times and combine all the tadalafil impurity I fractions.

[0091] (3) The tadalafil impurity I fraction obtained in step (2) was evaporated to dryness under reduced pressure at 40° C. using a rotary evaporator to obtain 300 mg of tadalafil impurity I with a purity of 98.59% and a yield of about 30%.

[0092] Comparative Example 1 (preparation method in patent CN109796461)

[0093] Tadalafil (1.0 g), NBS (0.3 g), acetone (10 mL), water (5 mL), and glacial acetic acid (5 mL) were added to a 50 mL reaction bottle in sequence and stirred rapidly at 50°C. LCMS reaction tracking, the reaction was stopped after 10 h. Na2CO3 aqueous solution was added to adjust the pH to 9.0, stirred for 30 min, the organic solvent was evaporated under reduced pressure, the remaining aqueous solution was extracted with dichloromethane, concentrated to obtain a crude product, then recrystallized with ethanol, filtered, and the solid was dried to obtain 0.3 g of a white solid with a purity of about 97.8%.

[0094] The product obtained in Comparative Example 1 was characterized and detected under the following nuclear magnetic resonance conditions: 1 H spectrum and 13 The C spectrum was measured on a Swiss Bruker AVANCE III HD 600 superconducting pulsed Fourier transform nuclear magnetic resonance spectrometer; the sample was dissolved in deuterated DMSO; the reference substance was TMS ( 1 H spectrum, 13 C spectrum). 1 H spectrum and 13 The spectrum of C spectrum is as follows Figure 1 and Figure 2 As shown, the results are analyzed as follows:

[0095]

[0096]

[0097]

[0098] From the results of nuclear magnetic resonance, the hydrogen spectrum results of the product obtained by the inventor according to the method prepared by patent CN109796461 are consistent with those reported in patent CN109796461. After analyzing the hydrogen spectrum, it is found that the structural characteristics do not conform to the hydrogen spectrum characteristics of tadalafil impurity I, and the hydrogen spectrum is different from that of the product obtained in Example 1 of the present invention. The product obtained in Example 1 of the present invention is tadalafil impurity I. Therefore, it is explained that the compound prepared by patent CN109796461 is not tadalafil impurity I.

[0099] Comparative Example 2

[0100] Take 389.4 mg of tadalafil (purity above 95%) and 3-chloroperoxybenzoic acid (172.6 mg), dissolve in acetone (50 ml), reflux and stir in a 50°C constant temperature heating magnetic stirrer for 1 hour, monitor the reaction by LCMS, and perform LCMS test after the reaction ends. The spectrum is as follows: Figure 6 As shown, the spectrum shows that the peak at RRT = 10.81min is tadalafil, and the content is still about 63%, there are many residual reaction raw materials, and the reaction yield is not high; MS results show that the molecular weights of the peaks at RT = 6.35min and RT = 8.18min are both 421, and the molecular weight of the peak at RT = 9.65min is 378, and no impurity I or its isomers are found. Therefore, the tadalafil impurity I cannot be prepared by oxidizing tadalafil with peroxy acid.

Claims

1. A method for preparing tadalafil impurity I, characterized in that: The steps include: (1) Mix tadalafil, 30% hydrogen peroxide and a reaction solvent, and react at a certain temperature to an end point for 4-5 hours to obtain a crude product containing tadalafil impurity I. The reaction route is as follows: ； Wherein, the reaction solvent is one of acetone or ethanol; the certain temperature is 50°C to 80°C; (2) filtering the crude product of tadalafil impurity I obtained in step (1) through a filter membrane, and then injecting it into a preparative liquid phase, using an organic acid buffer-acetonitrile as a mobile phase and a C18 filler column as a preparative column, and performing isocratic elution separation; collecting the tadalafil impurity I peak fraction; wherein the organic acid buffer is one of a 0.1% formic acid aqueous solution, a 0.1% acetic acid aqueous solution or a 0.1% trifluoroacetic acid aqueous solution, and the volume ratio of the organic acid buffer to acetonitrile is 70:30 to 80:20; The conditions for the elution separation are: the flow rate of the preparative liquid phase is 90 mL / min-120 mL / min; the detection wavelength is 280 nm-290 nm; the column temperature is 20°C-40°C; (3) removing the solvent from the tadalafil impurity I peak fraction collected in step (2) to obtain tadalafil impurity I.

2. The method according to claim 1, wherein the organic acid in step (2) is at least one of formic acid, acetic acid or trifluoroacetic acid.

3. The method according to claim 1, wherein the C18 filler in step (2) is EternityXT-10-C18.

4. The method according to claim 1, wherein the collection of the tadalafil impurity I peak fraction in step (2) starts when the tadalafil impurity I peak begins to elute and ends at the end of the peak.

5. The method according to any one of claims 1 to 4, wherein the prepared liquid phase in step (2) is a semi-industrial to industrial grade prepared liquid phase.

6. The method according to any one of claims 1 to 4, comprising: The preparation column is EternityXT-10-C18; the mobile phase is 0.1% formic acid aqueous solution-acetonitrile, and the volume ratio of 0.1% formic acid aqueous solution to acetonitrile is 75:25.

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