Paricalcitol 24-ene degradation impurity and synthesis method thereof
By adopting specific synthesis steps and reaction conditions in drug research and development, the problem of synthesis of impurities degraded by paritol 24-ene is successfully solved, providing high-purity standard products, reducing R&D costs, and meeting the needs of establishing drug quality standards.
Patent Information
- Application Number
- CN202311415429.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-30
- Publication Date
- 2025-05-02
AI Technical Summary
The prior art is difficult to effectively synthesize and provide high-purity pariscalcitol 24-ene degraded impurities, resulting in high cost and difficulty in establishing quality standards for raw materials.
By using pariscalcitol as the starting material, through the steps of up protection, elimination, and deprotection, and using specific reaction conditions and solvent combinations, the high-purity pariscalcitol 24-ene degraded impurities are successfully synthesized.
The synthesis of high-purity pariscalcitol 24-ene degraded impurities has been achieved, which reduces R&D costs and provides necessary standards for drug quality control.
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Figure CN119912375A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of medicines and relates to a paricalcitol 24-ene degradation impurity and a synthesis method thereof. Background Art
[0002] Paricalcitol was originally developed by Abbott Laboratories and was first approved for marketing in the United States on April 17, 1998. It is used to prevent and treat secondary hyperparathyroidism associated with chronic kidney disease. It has the effect of reducing parathyroid hormone (PTH) levels and has little effect on blood calcium and phosphorus levels. The drug was approved for marketing in EU countries in September 2002. Currently, the product has been marketed in more than 60 countries around the world.
[0003] Paricalcitol injection is a synthetic, selective, third-generation vitamin D receptor activator with a dual mechanism of action: it mainly acts on the vitamin D receptor (VDR) and also on the calcium-sensitive receptor (CaSR), which can increase the expression of VDR in the parathyroid glands, but not in the intestines, and can also increase the expression of CaSR in the parathyroid glands, thereby reducing PTH production, regulating calcium and phosphorus levels and bone health. Its structure is shown in Formula II:
[0004]
[0005] Impurity research is an important link in the drug development process. The establishment of quality standards requires a certain number of impurity standards. In order to obtain sufficient impurity standards, developing impurity-directed synthesis methods is an important task in drug development.
[0006] Paricalcitol 24-ene degradation impurities are specific impurities that must be studied for the establishment of the quality standard of Paricalcitol API. At present, there is no literature report on the synthesis method of Paricalcitol 24-ene degradation impurities; a small amount of this impurity is generated by strong degradation and destruction of Paricalcitol, and then separated by preparative liquid phase, so the preparation of impurity reference substances required for the quality standard research of Paricalcitol API is extremely difficult and costly.
[0007] The inventors have confirmed the structure of the degradation impurity of paricalcitol 24-ene through research and provided a synthesis method. The method is simple to operate and has high purity, and provides high-purity impurity samples and standards for process research and quality control of paricalcitol. Summary of the invention
[0008] In order to meet the need for paricalcitol 24-ene degradation impurities when establishing the quality standard of paricalcitol raw materials, the present invention discloses for the first time a method of obtaining high-purity paricalcitol 24-ene degradation impurities by using paricalcitol as a starting material through the steps of protection, elimination, deprotection, etc., which provides necessary standard products for drug research and development, and greatly reduces the research and development cost of preparing the impurities. The preparation method of paricalcitol 24-ene degradation impurities of the present invention comprises the following steps:
[0009]
[0010] Step 1: Paricalcitol D is dissolved in an organic base I, acetic anhydride is added and stirred, and the reaction is carried out at room temperature to obtain intermediate C;
[0011] Step 2: Dissolve the intermediate C in an organic base I, cool to 0±10°C, and add phosphorus oxychloride to react to obtain the intermediate B;
[0012] Step 3: intermediate B is dissolved in organic solvent I, and an inorganic base is added to react at room temperature to obtain paricalcitol degradation impurity A;
[0013] The organic base I is selected from: triethylamine, N,N-diisopropylethylamine, pyridine, methylpyridine, etc.; the organic solvent I is selected from: one or a mixed solvent of two or more of methanol, ethanol, isopropanol, etc.; the inorganic base is selected from: sodium carbonate, potassium carbonate, cesium carbonate.
[0014] The advantages of the present invention are: for the first time, the specific structure of the degradation impurity of paricalcitol 24-ene is confirmed by nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum; and a synthesis method of the degradation impurity of paricalcitol 24-ene is disclosed. The synthesis method has mild reaction conditions, is environmentally friendly, and has a high yield, with a total yield of 76.6%, which greatly reduces the research and development cost of preparing the impurity. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Figure 1 :H-NMR spectrum of compound A
[0016] Figure 2 :NMR carbon spectrum of compound A
[0017] Figure 3 : Mass spectrum of compound A DETAILED DESCRIPTION
[0018] In order to enable those skilled in the art to better understand the present invention, the technical solution of the present invention is further described below through specific embodiments. It should be understood that the following embodiments are only given to better illustrate the present invention and are not intended to limit the content of the present invention.
[0019] Embodiment 1:
[0020] A method for synthesizing paricalcitol 24-ene degradation impurities comprises the following steps:
[0021] Step 1: Weigh 3.0 g of paricalcitol, 30 mL of pyridine, and 10 mL of acetic anhydride into a reaction flask, stir at ambient temperature for 16 h, add 150 mL of ethyl acetate and 100 mL of water to separate, wash the organic phase with 50 mL of 3 mol / L HCl aqueous solution, 150 mL of water, and 100 mL of saturated NaHCO3 aqueous solution, concentrate under reduced pressure, and purify by column chromatography to obtain 3.58 g of off-white solid compound C.
[0022] Step 2: Weigh 3.58g of compound C and 40mL of pyridine, stir and dissolve, cool to an internal temperature of 0±10°C, add 3mL of trichlorophosphine, control the internal temperature at 0±10°C and react for 5h; add 50mL of saturated NaHCO3 aqueous solution to quench the reaction, add 100mL of ethyl acetate to extract and separate the liquids, wash the organic phase with 50mL of 3mol / LHCl aqueous solution, wash with 100mL of water, wash with 100mL of saturated NaHCO3 aqueous solution, concentrate under reduced pressure and purify by column chromatography to obtain 2.5g of compound B as an off-white solid.
[0023] Step 3: Weigh 2.5 g of compound B and 35 mL of methanol, stir and dissolve, add 3.0 g of sodium carbonate, heat to 40±10°C and stir for 16 h, and the reaction solution is directly concentrated under reduced pressure and purified by column chromatography to obtain 2.2 g of an off-white solid (molar yield: 76.6%). 1 H NMR (400MHz, CDCl3)δ 1 H NMR (400MHz, CDCl3) δ6.42(d,J=15.4Hz,1H),6.31(d,J=11.2Hz,1H),5.85(d,J=11.3Hz,1H),5.42(dd,J=15.4,8 .8Hz,1H),4.16~4.08(m,1H),4.04(tt,J=8.1,4.0Hz,1H),2.80(dd,J=12.1,4.1Hz,1H),2.73(dd,J=13.2,3.8Hz, 1H),2.48(dd,J=13.3,3.4Hz,1H),2.27~2.09(m,3H),1.97(dt,J=10.1,7.7Hz,3H),1.80(s,3H),1.77(s,3H),1. 73(d,J=1.0Hz,3H),1.72~1.62(m,3H),1.62~1.46(m,5H),1.45~1.22(m,4H),1.07(d,J=6.6Hz,3H),0.58(s,3H). 13C NMR (100MHz, CDCl3) δ142.99,134.55,131.15,128.52,126.86,126.11,123.82,115.31,67.41,67.20,56.58,56.40 ,45.78,44.66,42.18,40.99,40.38,37.19,28.92,27.92,23.48,22.23,21.62,21.10,20.22,14.46,12.36.MS: m / z 399.20[M+H] + .
[0024] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.
Claims
1. A degradation impurity of paricalcitol 24-ene, whose chemical name is: 4-[2-[(3R,5R)-dihydroxy]cyclohexylidene]ethylidene]octahydro-7a-methyl-1[(1R,2E,4S)-1,4,5-trimethyl-2,4-hexadien-1-yl]-(1R,3aS,7aR)-1H-indene, having the following structure:
2. A method for preparing the degraded impurity according to claim 1, characterized in that: The reaction formula is as follows: The following routes are included: Step 1: Paricalcitol D is dissolved in an organic base I, acetic anhydride is added and stirred, and the reaction is carried out at room temperature to obtain intermediate C; Step 2: Dissolve the intermediate C in an organic base I, cool to 0±10°C, and add phosphorus oxychloride to react to obtain the intermediate B; Step 3: intermediate B is dissolved in an organic solvent I, and an inorganic base is added to react at room temperature to obtain paricalcitol degradation impurity A; The organic base I is selected from: triethylamine, N,N-diisopropylethylamine, pyridine, methylpyridine, etc.; the organic solvent I is selected from: one or a mixed solvent of two or more of methanol, ethanol, isopropanol, etc.; the inorganic base is selected from: sodium carbonate, potassium carbonate, cesium carbonate.