Preparation method of atorvastatin calcium impurity J

Abstract

The invention discloses a preparation method of an atorvastatin calcium impurity J. The preparation method relates to the technical field of preparation of drug impurity standard substances, and specifically comprises the following steps: S1, carrying out heating reflux reaction on atorvastatin calcium 1 in a formula I under a strong acid condition to obtain a compound 2 and an atorvastatin calcium impurity H; and S2, hydrolyzing an atorvastatin calcium impurity J by using the compound 2 in the formula II under the action of second alkali. The method is reasonable in design and convenient to operate, and has the advantages of cheap and easily available raw materials, simple operation, short preparation period, easy purification, high yield and low production cost, and the prepared atorvastatin calcium impurity J is high in purity, has no obvious impurity points, meets the requirements of impurity reference substances, can be used as a standard substance of the atorvastatin calcium impurity J, and has wide application prospects. The method is applied to qualitative and quantitative research and detection of the atorvastatin calcium impurity J, and has certain significance on quality control of atorvastatin calcium bulk drugs and related preparations thereof.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of drug impurity standards, and in particular to a method for preparing atorvastatin calcium impurity J. Background Art

[0002] Atorvastatin calcium is a kind of powerful lipid-lowering medicine that Pfizer of the U.S. launched in 1997. It is a medicine that can reduce total cholesterol and triglyceride at the same time, and belongs to 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitor. European Pharmacopoeia, United States Pharmacopoeia etc. all record this variety of atorvastatin calcium, and the determination of its related substances has also been elaborated in detail. The impurity reported in atorvastatin calcium raw material medicine or preparation has more than 20 kinds such as Imp-A, B, C, D, E, F, G, H, I, J, K, L, M, A1, O1, O2 and atorvastatin lactam sodium salt. Impurity is very important to the quality control of medicine. Many countries put forward clear technical requirements for the research of drug impurities in the guidance of drug quality research, and obtain its impurity standard product when carrying out quality research.

[0003] Atorvastatin calcium impurity J (Formula 1), with the chemical name of 5-(4-fluorophenyl)-2-isopropyl-1-(2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide, is a degradation product of atorvastatin calcium under acidic conditions and is also an impurity specified in the European Pharmacopoeia and the United States Pharmacopoeia. The preparation and research of this impurity are of great significance to the research on the process and quality control of atorvastatin raw materials and preparations.

[0004]

[0005] In 2013, Vukkum, P. et al. reported atorvastatin calcium impurity J in the study of atorvastatin calcium and its related substances (12 impurities) and the quantitative determination method of degradation impurities. In 2019, Jürgen Krau et al. studied the differences in the degradation products of atorvastatin calcium formed after treatment under different acidic conditions, described the preparation of atorvastatin calcium impurity H and the key intermediates for synthesizing atorvastatin calcium impurity J, but did not specifically describe the preparation method of atorvastatin calcium impurity J. At present, there are few reports on the preparation of atorvastatin calcium impurity J in China.

[0006] It can be seen that designing an efficient, economical and specific method for synthesizing atorvastatin calcium impurity J, simplifying operations, reducing production costs and improving product yields are the key to the entire preparation process research, and the existing technology cannot meet these requirements. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing atorvastatin calcium impurity J, specifically a method for preparing atorvastatin calcium impurity J with cheap and readily available raw materials, simple operation, short preparation cycle, few by-products, easy purification, high yield and low production cost, so as to solve the problems raised in the above background technology.

[0008] In order to achieve the above-mentioned invention object, the present invention adopts the following technical scheme:

[0009] The present invention provides a method for preparing atorvastatin calcium impurity J, comprising the following steps:

[0010]

[0011] S1: heating atorvastatin calcium 1 in formula I under strong acid conditions to reflux to obtain compound 2 and atorvastatin calcium impurity H;

[0012] S2: hydrolyzing the atorvastatin calcium impurity J with the compound 2 in formula II under the action of a second base.

[0013] Furthermore, the solvent used in step S1 is a 40% concentrated sulfuric acid solution, and the mass ratio of the volume of the solvent to the atorvastatin calcium 1 is 20-30:1.

[0014] Furthermore, the heating method in step S1 is 130° C. oil bath heating.

[0015] Furthermore, the second base in step S2 includes at least any one of lithium hydroxide, sodium hydroxide and potassium hydroxide, and the molar ratio of the second base to compound 2 is 1.0 to 3.0:1.

[0016] Furthermore, the solvent used in step S2 is a mixed solvent consisting of tetrahydrofuran and water, and the volume ratio of the two is 1:1.

[0017] Compared with the prior art, one or more of the above technical solutions have the following beneficial effects:

[0018] The invention has reasonable design, convenient operation, the advantages of cheap and readily available raw materials, simple operation, short preparation cycle, easy purification, high yield and low production cost. The prepared atorvastatin calcium impurity J has high purity and no obvious impurity points, meets the requirements of impurity reference substances, can be used as an atorvastatin calcium impurity J standard substance, is applied to qualitative and quantitative research and detection of atorvastatin calcium impurity J, and has certain significance for the quality control of atorvastatin calcium raw materials and related preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0020] Figure 1 is the molecular structural formula of the atorvastatin calcium impurity J in the present invention;

[0021] Figure 2 is the MS spectrum of the atorvastatin calcium impurity J in the present invention;

[0022] Figure 3 is the 1HNMR spectrum of the atorvastatin calcium impurity J in the present invention;

[0023] Figure 4 It is the HPLC spectrum of impurity J of atorvastatin calcium in the present invention. DETAILED DESCRIPTION

[0024] In order to enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of this application.

[0025] See also Figure 1-Figure 4 , a method for preparing atorvastatin calcium impurity J, comprising the following steps:

[0026]

[0027] S1: Combined with Formula I, add atorvastatin calcium (10 g, 8.65 mmol) and 250 mL of 40% concentrated sulfuric acid solution into a round-bottom flask, heat to 120°C and reflux for 10 hours, monitor the reaction of atorvastatin calcium 1 by TLC, cool to room temperature, extract with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine, separate the phases, dry the organic phases with anhydrous Na2SO4, concentrate and pass through a column (PE:EA=2:1) ​​to obtain 3.24 g of intermediate Formula 2 compound, with a yield of 71.68%; 1.25 g of atorvastatin impurity H compound;

[0028] S2: Based on Formula II, compound 2 (3 g, 5.75 mmol, 1.0 eq) was added to the reaction flask, dissolved in a mixed solution of THF / H2O with a volume ratio of 1:1, and then sodium hydroxide (0.92 g, 23 mmol, 4.0 eq) was added. The reaction was stirred at room temperature for 0.5 h. After the reaction of compound 2 was completed as monitored by TLC, an appropriate amount of water was added to the reaction flask, and Ph was adjusted to 5 with 0.5 N hydrochloric acid solution. The mixture was extracted with ethyl acetate (30 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=2:1) ​​to obtain 2.97 g of atorvastatin impurity J product with a yield of 95.8%.

[0029] Molecular formula of Atorvastatin impurity J: C 33 H 33 FN2O4; The molecular weight of atorvastatin impurity J is 540.24.

[0030] The synthetic product atorvastatin impurity J was analyzed by mass spectrometry, and its MS spectrum is shown in Figure 1 As shown, in the mass spectrum, the peak of m / z=539.2 is the molecular ion peak MH- of atorvastatin impurity J, which is consistent with the molecular weight of atorvastatin impurity J.

[0031] The synthetic product atorvastatin impurity J was analyzed by nuclear magnetic resonance, and its 1HNMR spectrum is as follows: Figure 2 As shown, 1HNMR (600MHz, DMSO-d6): 9.82 (s, 1H), 7.52 (d, 2H), 7.24 (m, 6H), 7.07 (m, 4H), 6.98 (m, 2H), 5.72 (d, 1H ), 5.56 (m, 1H), 3.97 (m, 1H), 3.78 (m, 1H), 3.37 (s, 1H), 3.25 (m, 1H), 2.48 (m, 2H), 1.53 (m, 2H), 1.37 (d, 6H).

[0032] The purity of the synthetic product atorvastatin impurity J was analyzed by HPLC, and the conditions of the HPLC detection method were as follows: chromatographic column: DikmaC184.6×250mm, 5μm; flow rate: 1.0mL / min; detection wavelength: Sig=210nm; injection volume: 5μL; column temperature: 30°C; mobile phase: A: 80% methanol; B: 20% water; Figure 3 This is the HPLC spectrum of the synthetic product Atorvastatin impurity J. The analysis results of each peak in the HPLC spectrum are shown in the table below. It can be seen that the purity of the synthetic product Atorvastatin impurity J is 98.81%.

[0033] Peak RetTime Area Height Area % 1 0.705 9.7622 1.7888 0.1077 2 0.968 11.7267 4.3495 0.1294 3 1.084 11.5539 1.3783 0.1275 4 1.744 30.8318 3.9500 0.3400 5 2.700 28.5254 5.2547 0.3147 6 2.910 8956.4531 1358.9043 98.8072 7 3.541 15.7241 2.1693 0.1735 sum 9064.5772 1377.7895 100.0000

[0034] Furthermore, it should be noted that the volume ratio of the 40% concentrated sulfuric acid solution used in step S1 to the mass ratio of atorvastatin calcium 1 is 20-30:1.

[0035] Furthermore, the heating method in step S1 is 130° C. oil bath heating.

[0036] Furthermore, the second base in step S2 includes at least any one of lithium hydroxide, sodium hydroxide and potassium hydroxide, and the molar ratio of the second base to compound 2 is 1.0 to 3.0:1.

[0037] In summary, the present invention adopts the above-mentioned technical scheme to make up for the shortcomings of the prior art, has reasonable design, convenient operation, and has the advantages of cheap and readily available raw materials, simple operation, short preparation cycle, easy purification, high yield and low production cost. The prepared atorvastatin calcium impurity J has high purity and no obvious impurity points, meets the requirements of impurity reference substances, can be used as an atorvastatin calcium impurity J standard product, and is applied to the qualitative and quantitative research and detection of atorvastatin calcium impurity J, which has certain significance for the quality control of atorvastatin calcium raw materials and related preparations.

[0038] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing atorvastatin calcium impurity J, characterized in that: The following steps are involved: S1: heating atorvastatin calcium 1 in formula I under strong acid conditions to reflux to obtain compound 2 and atorvastatin calcium impurity H; S2: hydrolyzing the atorvastatin calcium impurity J with the compound 2 in formula II under the action of a second base.

2. The method for preparing atorvastatin calcium impurity J according to claim 1, characterized in that: The solvent used in step S1 is a 40% concentrated sulfuric acid solution, and the volume ratio of the solvent to the mass ratio of atorvastatin calcium 1 is 20-30:

1.

3. The method for preparing atorvastatin calcium impurity J according to claim 1, characterized in that: The heating method in step S1 is 130° C. oil bath heating.

4. The method for preparing atorvastatin calcium impurity J according to claim 1, characterized in that: The second base in step S2 includes at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide, and the molar ratio of the second base to compound 2 is 1.0-3.0:

1.

5. The method for preparing atorvastatin calcium impurity J according to claim 1, characterized in that: The solvent used in step S2 is a mixed solvent consisting of tetrahydrofuran and water, and the volume ratio of the two is 1:1.

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