CN113311091A - Preparation method of tadalafil impurity I - Google Patents
Preparation method of tadalafil impurity I Download PDFInfo
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- JLEQLXGZAIAEFX-DMXYAQSFSA-N (8'aR)-6'-(1,3-benzodioxol-5-yl)-2'-methylspiro[1H-indole-3,7'-3,6,8,8a-tetrahydropyrrolo[1,2-a]pyrazine]-1',2,4'-trione Chemical compound CN1CC(=O)N2[C@H](CC3(C2c2ccc4OCOc4c2)C(=O)Nc2ccccc32)C1=O JLEQLXGZAIAEFX-DMXYAQSFSA-N 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 38
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims abstract description 30
- 229960000835 tadalafil Drugs 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 27
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 24
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 32
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 16
- 235000019253 formic acid Nutrition 0.000 claims description 16
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- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000001514 detection method Methods 0.000 claims description 14
- 239000012528 membrane Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 238000010829 isocratic elution Methods 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
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- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
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- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 150000002500 ions Chemical group 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
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- 150000001875 compounds Chemical class 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 2
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- -1 1, 3-benzodioxol-5-yl Chemical group 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- RQBBFKINEJYDOB-UHFFFAOYSA-N acetic acid;acetonitrile Chemical compound CC#N.CC(O)=O RQBBFKINEJYDOB-UHFFFAOYSA-N 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
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- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Images
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/065—Preparation using different phases to separate parts of sample
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a method for preparing tadalafil impurity I, and belongs to the field of analytical chemistry. The method is characterized in that tadalafil, hydrogen peroxide and a reaction solvent are mixed and react to the end point to obtain a crude product containing the tadalafil impurity I, an organic acid buffer solution-acetonitrile is used as a mobile phase, a C18 filler is used as a preparation column for elution and separation, a tadalafil impurity I peak fraction is collected, and the high-purity tadalafil impurity I is obtained after the solvent is removed. The method has the advantages of simple steps, cheap and easily-obtained raw materials and high product purity.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a preparation method of tadalafil impurity I.
Background
Tadalafil (tadalafil) is a PDE5 inhibitor and is useful for the treatment of 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, 3,6,7,12,12 a-hexahydropyrazino [1',2' -1,6]-pyrido [3,4-b]Indole-1, 4-dione with molecular weight of 387.41, and Tadalafil molecular formula of C22H19N3O4The chemical structure is shown as the following formula:
tadalafil has been recorded by pharmacopoeia such as USP, EP, BP, etc., wherein the european pharmacopoeia EP9.0 requires A, B, C, D, E, F, G, H, I for controlling related substances in the quality standard of tadalafil. The legal regulations of various countries put high demands on the quality of the imitation drugs, so if the imitation drugs are successfully approved to be on the market, pharmaceutical companies must carry out intensive research on the relevant substances of the imitation drugs so that the quality of the imitation drugs reaches or even exceeds the standard of the original manufacturers. In the process, obtaining the related substance reference is an indispensable link. In combination with EP9.0 and other literature searches, the substance A, B, C, D, E, F, G, H, I is reported in the literature; the structure of the related substance I is shown as follows:
the preparation of tadalafil related substance I (also known as tadalafil impurity I) is the most technically demanding and difficult. Patent application CN109796461 reports a preparation method of tadalafil impurity I, but the preparation method of the patent requires a plurality of reagents, the reaction steps are complicated, the post-treatment is also complicated, and according to the method, the impurity I is difficult to obtain.
In view of the above, the present inventors have developed a preparation method suitable for tadalafil impurity I through research. The method can be used for preparing the tadalafil impurity I, is simple, has cheap and easily-obtained oxidation reaction raw materials, is environment-friendly, has high purity of the prepared product, and can be used for quality control of tadalafil.
Disclosure of Invention
The invention aims to provide a method for preparing tadalafil impurity I, so that the high-purity tadalafil impurity I can be obtained and used for the quality control of tadalafil.
A process for preparing tadalafil impurity I comprising the steps of:
(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:
in some embodiments, the reaction solvent in step (1) is at least one of acetone or ethanol.
In some embodiments, the certain temperature described in step (1) is 50 ℃ to 80 ℃.
In some embodiments, the hydrogen peroxide solution in step (1) may be in any suitable concentration. In some embodiments, the hydrogen peroxide solution in step (1) is 30% hydrogen peroxide solution (hydrogen peroxide solution: water: 30:70, V/V), which is beneficial to obtain the target product.
In some embodiments, a method of making tadalafil impurity I, further comprises the steps of:
(2) filtering the crude product of the tadalafil impurity I obtained in the step (1) by using a filter membrane, injecting the filtered product into a prepared liquid phase, eluting and separating by using an organic acid buffer solution-acetonitrile as a mobile phase and a column filled with C18 as a preparation column, and collecting the tadalafil impurity I peak fraction;
(3) and (3) separating the Tadalafil impurity I peak collected in the step (2), and removing the solvent to obtain the Tadalafil impurity I.
In some embodiments, the organic filter membrane described in step (2) may be a 0.45um organic filter membrane.
In some embodiments, the preparation liquid phase in step (2) may be a semi-industrial-grade preparation liquid phase, such as the semi-industrial-grade preparation liquid phase from Jiangsu Hanbang technologies, Inc.
In some embodiments, the organic acid 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.
In some embodiments, the mobile phase of step (2) may be one of 0.1% aqueous formic acid-acetonitrile, 0.1% aqueous acetic acid-acetonitrile, or 0.1% aqueous trifluoroacetic acid-acetonitrile.
In some embodiments, the mobile phase of step (2) is 0.1% aqueous formic acid solution-acetonitrile, and the volume ratio of the 0.1% aqueous formic acid solution to the acetonitrile in the mobile phase is 70:30 to 80: 20. In some embodiments, the mobile phase of step (2) is 0.1% aqueous formic acid solution-acetonitrile, and the volume ratio of 0.1% aqueous formic acid solution to acetonitrile in the mobile phase is 75: 25. Is more favorable for separation and determination.
In some embodiments, the preparative column packing described in step (2) can be EternitylXT-10-C18.
In some embodiments, the elution separation in the preparative liquid phase described in step (2) may be isocratic elution, and the flow rate of the preparative liquid phase may be from 90mL/min to 120 mL/min.
In some embodiments, the detection wavelength in the preparative liquid phase described in step (2) can be 280-290 nm.
In some embodiments, the column temperature in the preparative liquid phase described in step (2) may be from 20 ℃ to 40 ℃.
In some embodiments, the elution separation in the preparative liquid phase described in step (2) may be isocratic elution, and the flow rate of the preparative liquid phase may be from 90mL/min to 120 mL/min; the detection wavelength can be 280-290 nm; the column temperature can be 20-40 ℃.
In some embodiments, the elution separation in the preparative liquid phase described in step (2) may be isocratic elution, with the flow rate of the preparative liquid phase being from 90mL/min to 120 mL/min; the detection wavelength is 280-290 nm; the column temperature is 20-40 ℃. In some embodiments, the elution separation in the preparative liquid phase described in step (2) may be isocratic elution, with the flow rate of the preparative liquid phase being 110 mL/min; the detection wavelength is 285 nm; the column temperature is 20-40 ℃.
In some embodiments, the collecting the tadalafil impurity I peak fraction in step (2) may be starting to collect the fraction when the tadalafil impurity I peak begins to peak and ending at the tail.
In some embodiments, the solvent may be removed in step (3) by evaporation under reduced pressure using a rotary evaporator.
In some embodiments, step (2) of the aforementioned preparation method may comprise the following steps:
a) taking the crude product of the tadalafil impurity I in the step (1), and filtering the crude product through an organic filter membrane to obtain a sample solution;
b) taking organic acid buffer solution-acetonitrile as a mobile phase, and taking C18 filler as a preparation column;
c) setting instrument parameters: the flow rate of the mobile phase, the detection wavelength and the temperature of a column box of the chromatographic column;
d) and (b) injecting a proper amount of the sample solution obtained in the step a) into a prepared liquid phase, performing preparation separation, and collecting the Tadalafil impurity I peak fraction.
In some embodiments, step (2) of the aforementioned preparation method may comprise the following steps:
a) taking the crude product of the tadalafil impurity I in the step (1), and filtering the crude product through an organic filter membrane to obtain a sample solution;
b) 0.1% aqueous formic acid-acetonitrile (70:30 to 80:20, V/V) as mobile phase and EternitylXT-10-C18 as preparative column packing;
c) setting instrument parameters: the flow rate of the mobile phase, the detection wavelength and the temperature of a column box of the chromatographic column;
d) and (b) injecting 5-20 mL of the sample solution obtained in the step a) into a prepared liquid phase for separation preparation, and collecting the Tadalafil impurity I peak fraction.
The tadalafil impurity I in step a) above can be of any purity.
The mobile phase in the step b) can be 0.1% aqueous formic acid solution-acetonitrile, and the volume ratio of the 0.1% aqueous formic acid solution to the acetonitrile in the mobile phase is 70:30 to 80:20, so that the separation and the determination are facilitated.
The C18 filler in the step b) can be EternitylXT-10-C18.
The flow rate of the mobile phase in the step c) can be 90ml/min to 120 ml/min.
The flow rate of the mobile phase in the step c) can be 90mL/min to 120mL/min, the detection wavelength can be 280-290nm, and the column temperature can be 20 ℃ to 40 ℃. In some embodiments, the flow rate of the mobile phase in step c) above is 110mL/min, the detection wavelength is 285nm, and the column temperature is 20 ℃ to 40 ℃.
The proper amount in the step d) is 5mL to 20 mL.
The sample amount of the sample solution in the step d) is 5ml to 20 ml. In some embodiments, the sample solution is introduced in an amount of 5 ml. In some embodiments, the sample solution is introduced in an amount of 10 ml.
In the method provided by the invention, the preparative liquid chromatograph can be a semi-industrial-grade preparative liquid phase, and the manufacturer is Jiangsu Hanbang science and technology Limited company.
In some embodiments, the methods of making described herein comprise: mixing tadalafil, 30% hydrogen peroxide and acetone or ethanol, and stirring at 50-80 ℃ to react to the end point to obtain a crude product containing tadalafil impurity I; the crude product of the tadalafil impurity I passes through a 0.45um organic filter membrane to be used as a sample solution, then 5mL-20mL of the sample solution is injected into a prepared liquid phase, 0.1% formic acid water solution-acetonitrile is used as a mobile phase, C18 filler is used as a preparation column for elution and separation, and the tadalafil impurity I peak fraction is collected; concentrating the collected tadalafil impurity I peak fraction under reduced pressure, and removing the solvent to obtain high-purity tadalafil impurity I; the volume ratio of the 0.1% formic acid aqueous solution to the acetonitrile in the mobile phase is 70:30 to 80: 20; the C18 filler is EternitylXT-10-C18.
In some embodiments, the preparative separation method of the invention comprises: mixing tadalafil, 30% hydrogen peroxide and acetone, and stirring at 50-80 ℃ to react to an end point to obtain a crude product containing tadalafil impurity I; the crude product of the tadalafil impurity I passes through a 0.45um organic filter membrane to be used as a sample solution, then 5mL-20mL of the sample solution is injected into a prepared liquid phase, 0.1% formic acid water solution-acetonitrile is used as a mobile phase, C18 filler is used as a preparation column for elution and separation, and the tadalafil impurity I peak fraction is collected; concentrating the collected tadalafil impurity I peak fraction under reduced pressure, and removing the solvent to obtain high-purity tadalafil impurity I; the volume ratio of the 0.1% formic acid aqueous solution to the acetonitrile in the mobile phase is 70:30 to 80: 20; the C18 filler is EternitylXT-10-C18.
In some embodiments, the preparative separation method of the invention comprises: mixing tadalafil, 30% hydrogen peroxide and ethanol, and stirring at 50-80 ℃ to react to an end point to obtain a crude product containing tadalafil impurity I; the crude product of the tadalafil impurity I passes through a 0.45um organic filter membrane to be used as a sample solution, then 5mL-20mL of the sample solution is injected into a prepared liquid phase, 0.1% formic acid water solution-acetonitrile is used as a mobile phase, C18 filler is used as a preparation column for elution and separation, and the tadalafil impurity I peak fraction is collected; concentrating the collected tadalafil impurity I peak fraction under reduced pressure, and removing the solvent to obtain high-purity tadalafil impurity I; the volume ratio of the 0.1% formic acid aqueous solution to the acetonitrile in the mobile phase is 70:30 to 80: 20; the C18 filler is EternitylXT-10-C18.
The tadalafil impurity I prepared by the preparation method is identified as the tadalafil impurity I after nuclear magnetism and high-resolution mass spectrum characterization, and the purity of the tadalafil impurity I is more than 98% or more than 99%.
The preparation method has simple steps, the oxidation reaction adopts the cheap and easily obtained raw material hydrogen peroxide, the cost is low, and the product after the reaction is water, so the preparation method is environment-friendly; after the crude product is obtained, the preparation liquid phase separation and purification are carried out, and the adopted mobile phase is volatile buffer salt, so the preparation flow can be directly decompressed and evaporated to dryness, the post-treatment is simple, the cost is lower, the purity of the obtained product is high, and the product can be used as a reference substance for quality control. Therefore, the preparation method of the tadalafil impurity I can simply and efficiently obtain the high-purity tadalafil impurity I, and has important significance for the quality control of tadalafil.
In the foregoing or following text, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, or 10%.
In the present invention, EternitylXT-10-C18 represents a C18 make filler type;
in the invention, LCMS represents liquid phase mass spectrum combination;
in the present invention, NBS represents N-bromosuccinimide;
in the present invention, room temperature means 20 ℃ to 40 ℃.
Drawings
FIG. 1 shows the preparation of the compound obtained in comparative example 11H spectrum atlas;
FIG. 2 shows the preparation of the compound obtained in comparative example 113C spectrum atlas;
FIG. 3 shows a high resolution mass spectrum of Tadalafil impurity I obtained by the preparation method of example 1;
FIG. 4 shows the preparation method of example 1 to obtain Tadalafil impurity I1H spectrum atlas;
FIG. 5 shows the preparation method of example 1 to obtain Tadalafil impurity I13C spectrum atlas;
FIG. 6 shows LCMS spectra in comparative example 2.
Detailed Description
The embodiment of the invention discloses a method for preparing and separating tadalafil impurity I. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as appropriate variations and combinations of the methods described herein, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
For a further understanding of the present invention, reference will now be made in detail to the following examples.
Specification of the instrument and preparation column: semi-industrial preparation of liquid phase, the manufacturer is Jiangsu Hanbang science and technology Limited; manually feeding samples;
| preparation column | Specification of | Filler material |
| DAC-HB50 | 50x250mm，10um | EternityXT-10-C18 |
Examples 1 to 3: tadalafil impurity I was prepared using DAC-HB50, EternitylXT-10-C18.
Example 1
(1) Dissolving 1g of tadalafil (with the purity of more than 95%) and 30% hydrogen peroxide (5ml) in acetone (50ml), and carrying out reflux stirring reaction for 5 hours in a 60 ℃ heat collection type constant-temperature heating magnetic stirrer to obtain a crude product of the impurity I of the tadalafil;
(2) passing the crude product of the tadalafil impurity I obtained in the step (1) through a 0.45um organic filter membrane to serve as a sample solution, then injecting 10mL of the sample solution into a prepared liquid phase, and carrying out isocratic elution by taking 0.1% formic acid aqueous solution-acetonitrile (70: 30-80: 20, V/V) as a mobile phase; the flow rate is 110 mL/min; the detection wavelength is 285 nm; the column temperature is room temperature, and the preparation and separation are carried out; and starting to collect the tadalafil impurity I flow fraction when the tadalafil impurity I peak just appears, ending at the tail part of the peak, and storing the tadalafil impurity I flow fraction at room temperature. Repeat several times, combine all tadalafil impurity I fractions.
(3) And (3) carrying out reduced pressure evaporation on the tadalafil impurity I flow obtained in the step (2) at 40 ℃ by using a rotary evaporator, and obtaining 400mg of the tadalafil impurity I with the purity of 99.20%, wherein the yield is about 40%.
Tadalafil impurity I in example 1 was taken and subjected to high resolution mass spectrometry and nuclear magnetic resonance under the following conditions1H analysis and nuclear magnetic resonance13C, analyzing, and recording the mass spectrum, the H spectrum and the C spectrum, wherein the result is shown in figure 3, figure 4 and figure 5.
High resolution mass spectrometry detection conditions: LC-Q-TOF (instrument Agilenggt 1260HPLC and 6545Q-TOF) was used; the Q-OTF parameter is Ion Source: AJS Dual ESI; ion policy: positive; gas temp: 325 ℃; drying gas: 10.0L/min; nebulizer: 40 psig; fragment: 125V; the shear Gas temp. is 300 ℃; shear Gas Flow: 11L/min.
Observed M/z406.1397 and M/z833.2534 are [ M + H ] respectively for preparing tadalafil impurity I]+Ions and [2M + Na]+Ions. Calculating the molecule to be C22H19N3O5And the calculated relative deviation of the theoretical value and the actually measured value is 0.0ppm, and compared with tadalafil, the prepared related substance I has the same unsaturation degree as tadalafil and the molecular formula of one more oxygen atom than tadalafil, so that the substance obtained in the example 1 can be concluded to be in accordance with the mass spectrum characteristics of the impurity I of tadalafil.
Nuclear magnetic resonance conditions:1h spectrum and13the C spectra were measured in a Bruker AVANCE III HD 600 Switzerland superconducting pulse Fourier transform nuclear magnetic resonance spectrometer; dissolving the sample in deuterated DMSO; reference substance: TMS (C: (1H spectrum,13C spectrum). The analytical results are shown below:
nuclear magnetic resonance1H spectrum and13the C spectrum represents: the material obtained in example 1 corresponds to the NMR of Tadalafil impurity I1H spectrum and13and C spectral characteristics.
Therefore, the substance obtained by the method is Tadalafil impurity I.
Example 2
(1) Dissolving 1g of tadalafil (with the purity of more than 95%) and 30% hydrogen peroxide (5ml) in ethanol (50ml), and carrying out reflux stirring reaction in a heat collection type constant-temperature heating magnetic stirrer at 70 ℃ for 4 hours to obtain a crude product of the impurity I of the tadalafil;
(2) passing the crude product of the tadalafil impurity I obtained in the step (1) through a 0.45um organic filter membrane to serve as a sample solution, then injecting 10mL of the sample solution into a prepared liquid phase, and carrying out isocratic elution by taking 0.1% formic acid aqueous solution-acetonitrile (70: 30-80: 20, V/V) as a mobile phase; the flow rate is 110 mL/min; the detection wavelength is 285 nm; the column temperature is room temperature, and the preparation and separation are carried out; and starting to collect the tadalafil impurity I flow fraction when the tadalafil impurity I peak just appears, ending at the tail part of the peak, and storing the tadalafil impurity I flow fraction at room temperature.
Repeat several times, combine all tadalafil impurity I fractions.
(3) And (3) carrying out reduced pressure evaporation on the tadalafil impurity I flow obtained in the step (2) at 40 ℃ by using a rotary evaporator, and obtaining 350mg of tadalafil impurity I with the purity of 99.52%, wherein the yield is about 35%.
Example 3
(1) Dissolving 1g of tadalafil (with the purity of more than 95%) and 30% hydrogen peroxide (5ml) in ethanol (50ml), and carrying out reflux stirring reaction for 5 hours in a heat collection type constant-temperature heating magnetic stirrer at the temperature of 60 ℃ to obtain a crude product of the impurity I of the tadalafil;
(2) passing the crude product of the tadalafil impurity I obtained in the step (1) through a 0.45um organic filter membrane to serve as a sample solution, then injecting 10mL of the sample solution into a prepared liquid phase, and carrying out isocratic elution by taking 0.1% formic acid aqueous solution-acetonitrile (70: 30-80: 20, V/V) as a mobile phase; the flow rate is 110 mL/min; the detection wavelength is 285 nm; the column temperature is room temperature, and the preparation and separation are carried out; and starting to collect the tadalafil impurity I flow fraction when the tadalafil impurity I peak just appears, ending at the tail part of the peak, and storing the tadalafil impurity I flow fraction at room temperature. Repeat several times, combine all tadalafil impurity I fractions.
(3) And (3) carrying out reduced pressure evaporation on the tadalafil impurity I flow obtained in the step (2) at 40 ℃ by using a rotary evaporator, and obtaining 300mg of tadalafil impurity I with the purity of 98.59% in total, wherein the yield is about 30%.
Comparative example 1 (preparation method in patent CN 109796461)
Tadalafil (1.0g), NBS (0.3g), acetone (10mL) were added to a 50mL reaction flask in this order,water (5mL), glacial acetic acid (5mL), and rapid stirring at 50 ℃. The reaction was followed by LCMS and stopped after 10 h. Adding Na2CO3Adjusting pH of the aqueous solution to 9.0, stirring for 30min, distilling off organic solvent under reduced pressure, extracting the residual aqueous solution with dichloromethane, concentrating to obtain crude product, recrystallizing with ethanol, filtering, and drying to obtain 0.3g white solid with purity of about 97.8%.
The product obtained in comparative example 1 was characterized and examined under the following nuclear magnetic resonance conditions:1h spectrum and13the C spectra were measured in a Bruker AVANCE III HD 600 Switzerland superconducting pulse Fourier transform nuclear magnetic resonance spectrometer; dissolving the sample in deuterated DMSO; reference substance: TMS (C: (1H spectrum,13C spectrum). To obtain1H spectrum and13the spectrum of the spectrum C is shown in FIG. 1 and FIG. 2, and the obtained result is analyzed as follows:
from the results of nuclear magnetic resonance, the hydrogen spectrum of the product obtained by the inventor according to the method of patent CN109796461 is consistent with that reported in patent CN109796461, and the analysis of the hydrogen spectrum shows that: the structural characteristics do not accord with the hydrogen spectrum characteristics of the tadalafil impurity I, the hydrogen spectrum of the product is different from that of the product obtained in the embodiment 1 of the invention, and the product obtained in the embodiment 1 of the invention is the tadalafil impurity I, so that the compound obtained by the preparation of the patent CN109796461 is not tadalafil impurity I.
Comparative example 2
389.4mg of tadalafil (purity more than 95%) and 3-chloroperoxybenzoic acid (172.6mg) are taken and dissolved in acetone (50ml), the mixture is refluxed and stirred in a heat collection type constant temperature magnetic stirrer at 50 ℃ for reaction for 1 hour, the reaction is monitored by LCMS, and after the reaction is finished, LCMS test is carried out, and the spectrum is shown in figure 6 and shows: the RRT is 10.81min, the peak is tadalafil, the content is about 63 percent, more reaction raw materials remain, and the reaction yield is not high; MS results showed that the molecular weight of both RT 6.35min and RT 8.18min peaks was 421 and RT 9.65min peak was 378, and no impurity I or its isomer was found, so oxidation of tadalafil with peroxy acid did not produce tadalafil impurity I.
Claims (10)
1. A method for preparing tadalafil impurity I, comprising the steps of:
(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:
2. the method of claim 1, wherein the reaction solvent is one of acetone or ethanol; and/or the certain temperature is 50-80 ℃.
3. The method of claim 1, further comprising the steps of:
(2) filtering the crude product of the tadalafil impurity I obtained in the step (1) by using a filter membrane, injecting the filtered product into a prepared liquid phase, eluting and separating by using an organic acid buffer solution-acetonitrile as a mobile phase and a column filled with C18 as a preparation column, and collecting the tadalafil impurity I peak fraction;
(3) and (3) separating the Tadalafil impurity I peak collected in the step (2), and removing the solvent to obtain the Tadalafil impurity I.
4. The method according to claim 3, wherein the organic acid in step (2) is at least one of formic acid, acetic acid or trifluoroacetic acid.
5. The process of claim 3, the C18 filler in step (2) being EternitylXT-10-C18.
6. The method of claim 3, wherein collecting the tadalafil impurity I peak fraction in step (2) comprises beginning to collect the fraction when the tadalafil impurity I peak begins to peak and ending at the tail of the peak.
7. The method of claim 3, wherein the organic acid buffer in step (2) is one of 0.1% aqueous formic acid, 0.1% aqueous acetic acid, or 0.1% aqueous trifluoroacetic acid, and/or the volume ratio of the organic acid buffer to acetonitrile is 70:30 to 80: 20.
8. The process according to any one of claims 3 to 7, wherein the preparative liquid phase in step (2) is a semi-technical grade preparative liquid phase.
9. The method according to any one of claims 3 to 8, wherein the conditions for the elution separation in step (2) are as follows: the flow rate of the prepared liquid phase is 90mL/min-120 mL/min; the detection wavelength is 280nm-290 nm; the column temperature is 20-40 ℃.
10. The method according to any one of claims 3-8, comprising: the elution separation in the preparation liquid phase in the step (2) is isocratic elution; the flow rate of the prepared liquid phase is 90mL/min-120 mL/min; the detection wavelength is 280nm-290 nm; the column temperature is 20-40 ℃; the preparation column is EternitylXT-10-C18; the mobile phase is 0.1% formic acid water solution-acetonitrile, and the volume ratio of the 0.1% formic acid water solution to the acetonitrile is 75: 25.
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