CN111943891B - Rosuvastatin calcium impurity and rosuvastatin calcium quality control method - Google Patents
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Abstract
The invention provides an unknown impurity of rosuvastatin calcium and a preparation method thereof. The invention also provides a method for controlling the content of impurities in rosuvastatin calcium, wherein the content of the impurities is controlled by controlling the content of the compound (RC) in the R1 compound. The invention also provides a method for controlling the quality of rosuvastatin calcium by controlling the content of impurities of rosuvastatin calcium.
Description
The application is a divisional application of Chinese patent application No. 201910267433.6 with the application date of 03/04/2019 and the invention name of a rosuvastatin calcium impurity and a rosuvastatin calcium quality control method.
Technical Field
The invention relates to the field of organic synthetic pharmaceutical chemistry, in particular to a rosuvastatin calcium unknown impurity type RC-Ca compound and a preparation method thereof.
Background
Rosuvastatin (rosuvastatin) was developed by astrazen, first approved in the netherlands in 2002 by 11 months, approved by FDA in the united states in 2003 by 8 months, approved and marketed in china in 2006, and is currently marketed in many countries and is one of the widely used statins.
Impurities are an important factor influencing the quality of medicines, and in the process of medicine quality research, the structure of the impurities must be confirmed and the content of the impurities must be controlled. In the registration of the drug application, the impurities in the finished product must be strictly controlled according to the requirements of FDA and CFDA, the impurities present in the final product must be subjected to structural analysis and quality control, and the source and removal thereof need to be described in the registration document.
Most of the impurities in the general medicines have potential biological activity, and some impurities interact with the medicines, which can affect the safety and the efficiency of the medicines and even generate toxic effects. Such as residual trace protein polypeptide impurities in the final product of the beta-lactam antibiotics and penicillin thiazole protein produced by the action of the protein polypeptide impurities and the beta-lactam ring, has immunity. The epidemic eosinophilia-induced muscle syndrome (EMS) in the united states in 1989 was also caused by impurities in the production process of l-tryptophan. In addition, in the event of naffinasteride mesylate (vilapartisone) in Roche pharmaceutical system in 2007, the overproof impurity ethyl methanesulfonate in the raw material drug causes DNA sequence abnormality of 6 patients. Therefore, the control of impurities in the medicine has important significance on the safety of the medicine, and the control and research on the impurities are necessarily enhanced in the future research and development process of new medicines.
Rosuvastatin calcium is prepared by the synthetic route provided in the original patent WO00/149014, and impurities are generally present. The identification of the structure of impurities is a basic requirement for drug registration, and because the content of the impurities is small, the difficulty of obtaining the impurities through enrichment and purification is high.
At present, the quality standards of rosuvastatin calcium mainly comprise USP draft, EP standard, CP standard, Indian pharmacopoeia and imported preparation standard; the following impurities are mainly controlled in these standards.
Disclosure of Invention
As described above, the identification of the structure of impurities is a basic requirement for drug registration, and in order to further improve the quality of rosuvastatin calcium and control the impurity content of rosuvastatin calcium, one of the objects of the present invention is to provide a compound of the following formula (RC-Ca),
the compound of the formula (RC-Ca) can be used as a standard substance in detection and analysis of finished rosuvastatin calcium products, and is favorable for strengthening the safety control of medicines.
The inventors have found that the compound of formula (RC-Ca) is an unknown impurity which has not been found so far in the production of rosuvastatin calcium, which is generated during the reaction of the compound R1 with the compound D7. The structure of the rosuvastatin calcium impurity RC-Ca is similar to that of the R1 compound, and the R1 compound can participate in the reaction in the subsequent reaction and is finally transmitted to a finished product to influence the quality of the product, so that the preparation method of the rosuvastatin calcium impurity RC-Ca has important significance for controlling the impurity.
On this basis, it is an object of the present invention to provide a process for the preparation of a compound of formula (RC-Ca), said process comprising the steps of:
(1) reacting the compound of the formula (RC) with acid to obtain a compound of a formula (RC-1);
(2) reacting the compound of the formula (RC-1) with alkali to obtain a compound of a formula (RC-2);
(3) reacting the compound of the formula (RC-2) with calcium salt to obtain a compound of the formula (RC-Ca);
according to a particular embodiment of the invention, in the preparation of the compound of formula (RC-Ca), the acid is selected from hydrochloric acid, sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, preferably hydrochloric acid.
According to a particular embodiment of the invention, in the preparation of the compound of formula (RC-Ca), the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, preferably sodium hydroxide.
According to a particular embodiment of the invention, in the preparation of the compound of formula (RC-Ca), the calcium salt is selected from calcium chloride, calcium oxalate, calcium acetate, calcium carbonate, calcium bromide, preferably calcium chloride.
The structures of the compound of the formula (RC), the compound of the formula (RC-1) and the compound of the formula (RC-2) are respectively as follows:
the invention also provides a compound shown as the following structural formula (RC)
The present invention also provides a process for preparing a compound represented by the formula (RC), which comprises:
(1) reacting the compound of formula (DPPO) with the compound of formula (D7) to obtain a compound of formula (R1);
(2) reacting the compound of formula (R1) with the compound of formula (D7) to obtain the compound of formula (RC).
The structure of the compound of formula (DPPO) is shown below:
according to a specific embodiment of the present invention, wherein step (1) of the preparation process of the compound represented by formula (RC) is performed in the presence of a strong base selected from the group consisting of sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium tert-butoxide, sodium methoxide, sodium hydride, sodium ethoxide, preferably sodium hexamethyldisilazide.
According to a specific embodiment of the present invention, wherein the molar ratio of the compound of formula (DPPO) and the compound of formula (D7) in step (1) of the preparation process of the compound of formula (RC) is 1:1.0 to 1.5, preferably 1:1.0 to 1.1, most preferably 1: 1.05.
According to a specific embodiment of the present invention, step (1) and step (2) of the preparation process of the compound represented by formula (RC) are performed in the presence of a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane or diethyl ether, or a combination thereof, preferably tetrahydrofuran.
According to a specific embodiment of the present invention, wherein step (2) in the preparation process of the compound represented by formula (RC) is performed in the presence of a strong base selected from the group consisting of n-butyllithium, Lithium Diisopropylamide (LDA), sodium hexamethyldisilazide (NaHMDS), lithium hexamethyldisilazide (LiHMDS), preferably n-butyllithium.
According to a specific embodiment of the present invention, wherein the step (2) in the preparation process of the compound represented by the formula (RC) is carried out at-50 ℃ to-80 ℃, preferably at-60 ℃ to-75 ℃.
According to a specific embodiment of the present invention, wherein the molar ratio of the strong base described in step (2) to the compound of formula (R1) in the preparation of the compound of formula (RC) is 1:1.0 to 1.2; preferably 1.0: 1.1.
according to a specific embodiment of the invention, the molar ratio of the compound of formula (R1) to the compound of formula (D7) in step (2) of the preparation process of the compound of formula (RC) is 1: 1.0-1.5; preferably 1:1.0 to 1.1.
According to a specific embodiment of the present invention, there is provided a method for controlling the content of the compound of formula (RC-Ca) as a contaminant in rosuvastatin calcium by controlling the content of the compound of formula (RC) in the compound of R1.
According to a specific embodiment of the present invention, there is provided a method for controlling the content of the impurity compound of formula (RC-Ca) in rosuvastatin calcium, the content of the compound of formula (RC) is controlled by controlling the content of the compound of formula (RC) in the R1 compound, and the content of the impurity RC-Ca in rosuvastatin calcium is less than 0.10% by controlling the content of the compound of formula (RC) in the R1 compound to less than 0.25%.
The invention achieves the following beneficial effects:
1) the invention discloses the structure of the rosuvastatin calcium unknown impurity type (RC-Ca) compound for the first time, and has important significance for the quality research of rosuvastatin calcium;
2) the invention discloses a preparation method of a rosuvastatin calcium unknown impurity formula (RC-Ca) compound for the first time, provides an impurity reference substance for the quality research of rosuvastatin calcium, and provides an effective method for controlling the impurity to ensure that the impurity is less than 0.10% in a rosuvastatin calcium finished product.
The invention provides a preparation method of a compound of a formula (RC-Ca), which has the advantages of simple and efficient operation, moderate reaction conditions, strong safety and easy control, and is suitable for preparing impurities as a reference substance. To monitor product quality.
Drawings
FIG. 1RC liquid phase detection spectrum
FIG. 2RC nuclear magnetic hydrogen spectrum
FIG. 3RC NMR spectrum
FIG. 4 shows liquid phase detection spectrum of compound (RC-Ca)
FIG. 5 nuclear magnetic hydrogen spectrum of compound of formula (RC-Ca)
FIG. 6 nuclear magnetic carbon spectrum of a compound of formula (RC-Ca)
FIG. 7R 1 liquid phase detection spectrum
FIG. 8 spectrum of rosuvastatin calcium detection
Detailed Description
The following exemplary reactions serve to illustrate the invention. The invention is protected by the technical scheme that simple replacement or improvement and the like of the invention are made by those skilled in the art.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein. In the present invention, NaHMDS means sodium hexamethyldisilazane, n-BuLi means n-butyllithium, THF means tetrahydrofuran, h means hour, ml means mL, and M means mol/L.
The HPLC and isomerism detection methods are as follows
The instrument comprises the following steps: agilent 1206
And (3) analyzing the column: zorbax SB-C18, 4.6mm X250 mm, 5 μm (or equivalent column)
Mobile phase A: buffer-acetonitrile 95: 5.
Mobile phase B: water-acetonitrile 5:95
Diluent agent: acetonitrile (ACN)
Buffer solution: 1.36g of monopotassium phosphate is precisely weighed and dissolved in 1000mL of water, the mixture is stirred evenly, the PH value is adjusted to 3.0 +/-0.05 by phosphoric acid, and the mixture is filtered and degassed by ultrasound.
Gradient:
| time (min) | Mobile phase A% | Mobile phase B% |
| 0.01 | 10 | 90 |
| 15.0 | 0 | 100 |
| 25.0 | 0 | 100 |
| 30.0 | 10 | 90 |
| 35.0 | 10 | 90 |
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
A detector: ultraviolet detector, wavelength 240nm
Sample introduction amount: 10 μ l
Operating time: 35 minutes
Example 1: preparation of RC compounds
Adding 40.0g of compound (DPPO) and 500ml of THF into a 1000ml four-neck flask, stirring for dissolving, replacing with nitrogen for 3 times, reducing the internal temperature to-75.0 ℃ under the protection of nitrogen, slowly dropwise adding 79.0ml of 1.0M NaHMDS/THF solution, controlling the internal temperature to-80.0 to-75.0 ℃, after the dropwise addition, keeping the temperature for reaction for 2.0 hours, after the heat preservation reaction is finished, controlling the internal temperature to-80.0 to-75.0 ℃, dropwise adding compound (D7) THF solution (D7: 23.1g, THF:20ml), and after the dropwise addition is finished, keeping the temperature for reaction for 1.0 hour; sampling and controlling until the residue of the compound (DPPO) in the reaction liquid is less than or equal to 1.0 percent, and finishing the reaction. Heating to room temperature, adding 100ml of saturated ammonium chloride solution to quench reaction, after quenching, distilling the material under reduced pressure, heating the material to 50.0 ℃, keeping the vacuum degree less than or equal to-0.09 MPa, after drying, adding 400.0g of toluene to dissolve, washing with water, concentrating, and crystallizing with 400.0g of methanol to obtain 30.0g of a compound (R1).
Adding 30.0g of compound (R1) and 500ml of THF into a 1000ml four-neck flask, stirring to dissolve the mixture, replacing the mixture with nitrogen for 3 times, reducing the internal temperature to-75.0 ℃ under the protection of nitrogen, controlling the internal temperature to-60.0 to-75.0 ℃, slowly dropwise adding 63ml of 1.66M n-BuLi n-hexane solution, keeping the temperature for reaction for 2.0h after the dropwise adding is finished, raising the temperature to 0 ℃ after the thermal reaction is finished, controlling the internal temperature to-5 to 0 ℃, dropwise adding a THF solution (D7:26.9g, THF:27ml) of compound (D7), and keeping the temperature for reaction for 1.0h after the dropwise adding is finished; after the reaction was completed, the temperature was raised to room temperature, 70ml of a saturated ammonium chloride solution was added thereto to quench the reaction, and after quenching, 600ml of Cl was used2CH2Extracting, washing with water, evaporating to dryness, and purifying R-1 crude product with column (Cl)2CH2:CH3OH 20:1) to yield RC 22.4g as an impurity (yield 52%). Liquid phase (HPLC) detection spectrum is shown in figure 1, and RC peak-off time is RT 15.7 min; the structure is confirmed, the hydrogen spectrum is shown in figure 2, and the carbon spectrum is shown in figure 3;
MS(ESI)m/z:837(M+H)+；835(M-H)-。
1H NMR(500MHz,DMSO)δ7.68(s,2H),7.30(s,2H),6.57(s,1H),5.42(s,1H),4.50(s,1H),4.16(s,2H),3.96(s,1H),3.86(s,2H),3.72(s,1H),3.45(s,2H),3.34(s,5H),2.53(s,8H),2.36(s,2H),2.21(s,2H),1.66(s,1H),1.47(s,1H),1.42(d,J＝6.5Hz,3H),1.40(s,7H),1.38(s,7H),1.31(s,2H),1.26(s,3H),1.20(s,5H),1.13(s,2H),1.05(s,2H)。
example 2: preparation of compounds of formula RC-Ca
Under the protection of nitrogen, 13.50g of RC compound and 74.6g of acetonitrile are put into a reaction bottle; stirring and heating, controlling the internal temperature to be 35.0-40.0 ℃, dropwise adding 40g of 0.02M hydrochloric acid, and keeping the temperature for 3.0-3.5 hours after adding; cooling after heat preservation, controlling the internal temperature to be 20.0-25.0 ℃, dropwise adding 60.0g of 1M sodium hydroxide, and preserving heat for 1.0-1.5 hours; after heat preservation is finished, regulating the pH value to 7.0-7.5 by using 1M hydrochloric acid solution, controlling the external temperature to be lower than 40 ℃, carrying out reduced pressure concentration, adding 50ml of ethyl acetate into the water phase for extraction, removing the organic phase, cooling the water phase to room temperature, adding 50ml of 10% calcium chloride water solution, stirring, filtering for 30 minutes, washing by using 150ml of ice, and carrying out vacuum drying at 45 ℃ to obtain 7.6g of the compound of the formula RC-Ca; liquid phase (HPLC) detection spectrum is shown in FIG. 4, and the time of R1 peak is RT ═ 1.4 min; the structure is confirmed by the hydrogen spectrum shown in figure 5 and the carbon spectrum shown in figure 6.
MS(ESI)m/z:682(M+H)+；680(M-H)-。
1H NMR(500MHz,DMSO)δ7.57(s,2H),7.22(s,2H),6.30(s,1H),5.30(s,1H),4.14(s,1H),3.62(s,1H),3.37(s,4H),2.81(s,3H),2.67(s,2H),2.37(s,2H),2.29(s,1H),1.98(s,1H),1.76(s,1H),1.58(s,3H),1.23(s,2H),1.15(s,6H),1.11(d,J＝1.7Hz,1H),1.09(s,1H),1.08(s,1H),1.00(t,J＝7.0Hz,1H)。
Example 3: preparation of R1 Compound
Adding 40.0g of compound (DPPO) and 500ml of THF into a 1000ml four-neck flask, stirring for dissolving, replacing 3 times with nitrogen, cooling the inner temperature to-75.0 ℃ under the protection of nitrogen, slowly adding 79.0ml of 1.0M NaHMDS/THF solution dropwise, keeping the inner temperature between-80.0 and-75.0 ℃, keeping the temperature for reaction for 2.0 hours after the dropwise addition is finished, keeping the temperature for reaction after the reaction is finished, keeping the inner temperature between-80.0 and-75.0 ℃, adding 23.1g of compound (D7) THF solution (D7: 23.1g, THF:20ml) dropwise, and keeping the temperature for reaction for 1.0 hour after the dropwise addition is finished; sampling and controlling until the residue of the compound (DPPO) in the reaction liquid is less than or equal to 1.0 percent, and finishing the reaction. Heating to room temperature, adding 100ml of saturated ammonium chloride solution to quench reaction, after quenching, distilling the material under reduced pressure, heating the material to 50.0 ℃, keeping the vacuum degree less than or equal to-0.09 MPa, after drying, adding 400.0g of toluene to dissolve, washing with water, concentrating, and crystallizing with 400.0g of methanol to obtain 30.0g of a compound (R1). The liquid phase HPLC detection spectrum is shown in FIG. 7. As shown in fig. 7, the peak at RT ═ 13.89min is R1, and the peak at TR ═ 15.68min is RC; thus indicating that the RC impurity did exist in the R1 reaction;
example 4: preparation of rosuvastatin calcium
Under the protection of nitrogen, putting R110.0 g and acetonitrile 70ml into a reaction bottle; stirring and heating; controlling the internal temperature to be 35.0-42.0 ℃, dropwise adding 19ml of 0.02M hydrochloric acid, and preserving the temperature for 3.0-4.0 hours after the addition is finished; cooling after heat preservation; controlling the internal temperature to be 20.0-25.0 ℃, dropwise adding 19ml of 1.0M sodium hydroxide solution, and keeping the temperature for 1.0-1.5 hours; after the temperature is kept, adding 4.8g of sodium chloride, continuously cooling, controlling the internal temperature to be 0.0-minus 5.0 ℃, adjusting the pH value to be 3.0-4.0 by using 1M hydrochloric acid and sodium chloride solution, and finishing the adjustment; standing for layering, and discarding the lower aqueous phase; controlling the temperature in the organic phase to be 0.0 to-5.0 ℃, adding 130ml of glacial acetonitrile, stirring for 0.5 to 1.0 hour, filtering after heat preservation, and adding 2.2ml of 40% methylamine water solution at the temperature of 0.0 to-5.0 ℃ in the organic phase; after the dripping is finished, stirring for 1.0 hour at the temperature of 0.0-5.0 ℃, filtering, and washing a filter cake with a small amount of acetonitrile; drying the wet product in a drying oven at 35 ℃ for 8.0 hours; collecting 8.0g of methylamine salt; dissolving methylamine salt solution in 40ml of purified water, controlling the internal temperature to be less than 20 ℃, dropwise adding 7.2ml of 8% sodium hydroxide solution, and stirring for 1.0 hour; after stirring, controlling the external temperature to be less than 40 ℃, and distilling under reduced pressure until the distilled water amount is 32 ml; adding 32ml of purified water after the distillation is finished; controlling the external temperature to be less than 40 ℃, and distilling under reduced pressure until the distilled water amount is 32 ml; adding 32ml of purified water after the distillation is finished; controlling the external temperature to be less than 40 ℃, and distilling under reduced pressure until the distilled water amount is 32 ml; and after the third distillation is finished, adding 40ml of purified water, cooling, controlling the internal temperature to be about 20 ℃, dropwise adding 8.4ml of calcium chloride dihydrate (1.45) solution, stirring, filtering for 30 minutes, washing with 60ml of ice, and drying in vacuum at 45 ℃ to obtain 8.8g of rosuvastatin calcium.
The liquid phase (HPLC) detection spectrum is shown in FIG. 8. Fig. 8 shows that rosuvastatin calcium peak time RT ═ 4.585min, where TR ═ 1.419min, is a compound of formula RC-Ca, thus demonstrating that the compound of formula RC-Ca is indeed present in rosuvastatin calcium.
Example 5: preparation of R1 samples with different RC contents
Preparing R1 samples with different purities by adding impurities; specific experimental operations:
weighing a proper amount of R1 and RC, and acetonitrile dissolved in four times of R1; HPLC detection of sampling after stirring, temperature rise and dissolution
| Serial number | RC content | Number of RC | Number of R1 | Acetonitrile |
| A | 0.10％ | 0.010g | 9.990g | 40g |
| B | 0.13％ | 0.013g | 9.987g | 40g |
| C | 0.16％ | 0.016g | 9.984g | 40g |
| D | 0.19％ | 0.019g | 9.981g | 40g |
| E | 0.22％ | 0.022g | 9.978g | 40g |
| F | 0.25％ | 0.025g | 9.975g | 40g |
| G | 0.28％ | 0.028g | 9.972g | 40g |
Example 6: preparation of rosuvastatin calcium using R1 samples with different RC contents
Seven groups of A, B, C, D, E, F, G samples in example 4 were taken, different rosuvastatin calcium samples were prepared according to the method of example 4 for detection, and the results are summarized as follows:
the European pharmacopoeia and the United states pharmacopoeia require that the single impurity in the rosuvastatin calcium finished product is less than 0.10 percent, and the single impurity in the finished product is strictly controlled, so that the quality of the rosuvastatin calcium can be qualified.
The data show that RC is really existed in R1, and the residual RC impurity in R1 is correspondingly converted into the impurity type RC-Ca compound in the preparation process of rosuvastatin calcium; in order to ensure that the impurity RC-Ca compound in the finished product of rosuvastatin calcium is less than or equal to 0.10 percent, the RC content in R1 needs to be controlled below 0.25 percent.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.
Claims (8)
1. A compound of formula (RC)
2. A process for the preparation of a compound of formula (RC) as claimed in claim 1, comprising the steps of:
(1) reacting the compound of formula (DPPO) with the compound of formula (D7) to obtain a compound of formula (R1);
(2) reacting the compound of the formula (R1) with the compound of the formula (D7) to obtain a compound of the formula (RC);
the structures of the compound of formula (DPPO), the compound of formula (D7), the compound of formula (R1) and the compound of formula (RC) are respectively as follows:
3. the process of claim 2, wherein the steps (1) and (2) are carried out in the presence of a strong base selected from the group consisting of sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium tert-butoxide, sodium methoxide, sodium hydride, sodium ethoxide.
4. The process of claim 2, wherein the molar ratio of the compound of formula (DPPO) to the compound of formula (D7) in step (1) is 1:1.0 to 1.5; the molar ratio of the compound of the formula (R1) to the compound of the formula (D7) in the step (2) is 1: 1.0-1.5.
5. The process of claim 4, wherein the molar ratio of the compound of formula (DPPO) and the compound of formula (D7) in step (1) is 1:1.0 to 1.1; the molar ratio of the compound of the formula (R1) to the compound of the formula (D7) in the step (2) is 1: 1.0-1.1.
6. The process of claim 5, wherein the molar ratio of the compound of formula (DPPO) and the compound of formula (D7) in step (1) is 1: 1.05.
7. The process of claim 2, wherein the step (2) is carried out in the presence of a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, or diethyl ether, or a combination thereof.
8. The method of claim 7, the solvent being tetrahydrofuran.
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Non-Patent Citations (2)
| Title |
|---|
| a HMG-CoA reductase inhibitor.《Tetrahedron Letters》.2017,第58卷第2614-2617页. * |
| Young Hee Lee，等.Synthesis and characterization of Rosuvastatin calcium impurity A * |
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| Publication number | Publication date |
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| CN109824606B (en) | 2020-11-13 |
| CN111943891A (en) | 2020-11-17 |
| CN109824606A (en) | 2019-05-31 |
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