Idecalciferol preparation impurity and preparation method thereof
By preparing and monitoring new impurities in the estigalisol synthesis process, the problem of impurities generated during A-ring construction in synthesis was solved, the synthesis process was improved, and the product quality and purity were improved.
Patent Information
- Application Number
- CN202311849680.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-29
- Publication Date
- 2025-07-01
AI Technical Summary
In the synthesis process of estigalisol, new impurities will be generated when constructing the A ring of key intermediates, affecting the quality and efficiency of the synthesis process.
The compounds of formulas (I) and (III) are prepared by a series of compound reaction steps including reduction, iodination, substitution reaction, phosphate, selective deprotection and TBS protection, and the compounds described in formulas (I) and (III) are monitored and compared to improve synthesis process and quality control.
Through monitoring and comparison of these impurities, the synthesis process of estigalisol can be improved, the quality and purity of the product can be improved, and the stability and efficiency of the synthesis process can be ensured.
Smart Images
Figure CN120230141A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of chemical drug analysis and drug synthesis, and particularly relates to an impurity in the preparation process of eldecalcitol and a preparation method thereof. Technical Background
[0002] Eldecalcitol ((1R,2R,3R,5Z,7E)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-trien-1,3,25-triol) is the active pharmaceutical ingredient (API) of the osteoporosis therapeutic agent Edirol, and its structure is shown below. It is a vitamin D drug jointly developed by Chugai Pharmaceutical of Japan and CPPC Pharmaceutical, used for the treatment of osteoporosis, and was first launched in Japan in 2011 under the trade name Edirol. Eldecalcitol is a new active vitamin D3 derivative for the treatment of osteoporosis following alfacalcidol. Phase III clinical data from a 3-year study involving 1054 osteoporosis patients showed that eldecalcitol was more effective than alfacalcidol and had similar safety, indicating good application prospects.
[0003]
[0004] Currently, one of the important synthesis processes of eldecalcitol is the coupling of the A-ring part and the CD-ring part of the key intermediate. In particular, the stereospecific construction of the A-ring of the key intermediate is particularly important.
[0005]
[0006] During the synthesis and storage of the A-ring of the key intermediate, various impurities will be generated. Discovering the various impurities that may be generated in the above process and comparing and monitoring them during the synthesis and storage process is of great significance for improving and enhancing the synthesis process of eldecalcitol and improving quality control. Summary of the Invention
[0007] The present invention has discovered new impurities in the process of synthesizing eldecalcitol when constructing the A-ring of the key intermediate. The impurities have the structure shown in formula (I):
[0008]
[0009] On the one hand, the present invention provides the compounds as described in formulas (I) and (III).
[0010] On the other hand, the present invention provides a preparation method for the compounds as described in formulas (I) and (III). The process of the method is shown as follows:
[0011]
[0012] It includes the following steps:
[0013] (1) Compound (VI) is reduced and iodized to obtain compound (V);
[0014] (2) Compound (V) undergoes a substitution reaction to obtain compound (IV);
[0015] (3) Compound (IV) undergoes a substitution reaction with diphenylphosphine to obtain compound (III);
[0016] (4) Compound (III) is selectively deprotected to obtain compound (II);
[0017] (5) Compound (II) reacts with a TBS protecting group reagent to obtain compound (I).
[0018] Preferably, the reduction reaction in step (1) is the Red-Al reaction.
[0019] Preferably, the substitution reaction reagent in step (2) is NCS.
[0020] Preferably, in step (3), the substitution reaction is completed by oxidation with hydrogen peroxide in the presence of n-butyllithium.
[0021] Preferably, in step (4), the selective deprotection reagent is TBAF and HOAc.
[0022] Preferably, in step (5), the TBS protecting group reagent is TBSOTF.
[0023] The beneficial effects of the present invention are as follows:
[0024] The present invention has for the first time discovered the compound of formula (I), which is an impurity generated during the synthesis process of eldecalcitol, especially during the construction of the A ring of the key intermediate. By comparing and monitoring this impurity, it is of great significance for improving and enhancing the synthesis process of eldecalcitol and perfecting quality control. Description of the Drawings
[0025] Figure 1 is the chromatogram of the compound of formula (V) in Example 1.
[0026] Figure 2 is the chromatogram of the compound of formula (IV) in Example 2.
[0027] Figure 3 is the chromatogram of the compound of formula (III) in Example 3.
[0028] Figure 4 is the chromatogram of the compound of formula (II) in Example 4.
[0029] Figure 5is the chromatogram of the compound of formula (I) in Example 5. DETAILED DESCRIPTION
[0030] The following embodiments can enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the embodiments.
[0031] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.
[0032] Example 1: Synthesis of compound of formula (V):
[0033]
[0034] 2.05g of the compound of formula (IV) was added to a 100ml three-necked flask, and 24.6ml of methyl cyclopentyl ether was added. The temperature was cooled to -5 to 0°C in an ice-salt bath, and 25ml of Red-Al was added dropwise. The temperature was kept at 5 to 10°C, and 350ml of ethyl acetate was added. A solution of 1.76g of I2 in 4ml of THF was added dropwise. The temperature was controlled to be below -65°C, and the reaction was stirred for 1.0h. 8.0ml of saturated NH4Cl solution and 8.0L of saturated Na2S2O3 solution were added. The temperature was returned to 5 to 10°C, and the mixture was stirred for 30min. The mixture was filtered, and the liquid was separated by standing. The aqueous phase was extracted with 10ml of EA, and the organic phases were combined and the solvent was removed to obtain a crude product, which was purified by PE / EA column chromatography. The product was collected and concentrated under reduced pressure to obtain 1.55g, with a molar yield of 70%. See the chromatogram. Figure 1 .
[0035] Example 2: Synthesis of compound of formula (IV):
[0036]
[0037] In a 100ml single-necked bottle, add 1.5g of compound (V), 657mg of PPh3, and 20ml of DCM, stir to dissolve, replace with N2 three times, dropwise add 250mg of NCS in 4ml of DCM solution, stir at 20-30℃ for 2h. Add 6ml of water, stir and separate, and concentrate the organic phase at 35℃ under reduced pressure to obtain a crude product, 1.21g of anhydrous oil, purity 51%. See the chromatogram for details. Figure 2 .
[0038] Example 3: Synthesis of compound of formula (III):
[0039]
[0040] In a 100 ml three-necked flask, add 405 mmol of PHPh2, dissolve it in 15 ml of THF, cool it to -5 to 0 °C in an ice-salt bath, dropwise add 842 mmol of N-BuLi, keep the temperature for reaction for 2 hours, dropwise add a 10 ml THF solution of the compound of formula (IV), continue the reaction for 1 hour, quench the reaction system with an aqueous NH4Cl solution, separate the layers, extract the aqueous phase twice with 10 ml of THF each time, combine the organic phases, and concentrate under reduced pressure at 35 °C to an oily substance. Dissolve it in 20 ml of CHCl3, cool it to below 10 °C, and dropwise add 635 mmol of H2O2, stir at room temperature for 30 min.
[0041] Quench the reaction solution with 10 ml of saturated aqueous sodium thiosulfate solution, separate the layers, extract the aqueous phase with 10 ml of DCM, combine the organic phases, concentrate under reduced pressure to obtain the crude product, purify it by column chromatography, collect the product spot, and concentrate under reduced pressure to obtain 700 mg of an oily substance. See the chromatogram in Figure 3 。
[0042] Example 4: Synthesis of the compound of formula (II):
[0043]
[0044] Add 430 mg of the compound of formula (III) to a 100 ml single-necked flask, stir and dissolve it in 5 ml of THF, under a N2 atmosphere, add 43 mmol of HOAC, cool it in an ice bath, dropwise add 756 mmol of TBAF, warm it to room temperature and stir for 16 h. Add 8 ml of water, extract it three times with EA (8 ml × 3), combine the organic phases, concentrate to obtain the crude product, purify it by TLC, and collect the product to obtain 240 mg with a purity of 96.8%. See the chromatogram in Figure 4 。
[0045] Example 5: Synthesis of the compound of formula (I):
[0046]
[0047] Add 260 mg of the compound of formula (II) to a 100 ml single-necked flask, dissolve it in 7.8 ml of DCM, add 212 mmol of 2,6-lutidine, cool it in an ice bath and dropwise add 153 mmol of TBSOTF, stir at room temperature for 2 h. Extract the reaction solution with 40 ml of DCM, separate the layers, concentrate under reduced pressure to obtain the crude product, and purify it by TLC to obtain 232 mg of a colorless transparent liquid with a purity of 98.3%. See the chromatogram in Figure 5 。
[0048] The specific embodiments of the present invention and the advantages of the present invention have been shown and described above. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention needs to be continuously changed and improved, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.
Claims
1. A compound having the structures represented by formula (I) and (III):
2. A method for preparing the compound according to claim 1, the process of the method is as follows: It includes the following steps: (1) Compound (VI) is reduced and iodinated to obtain compound (V); (2) Compound (V) undergoes a substitution reaction to obtain compound (IV); (3) Compound (IV) undergoes a substitution reaction with diphenylphosphine to obtain compound (III); (4) Compound (III) is selectively deprotected to obtain compound (II); (5) Compound (II) reacts with a TBS protecting group reagent to obtain compound (I).
3. The method according to claim 2, characterized in that, The reduction reaction in step (1) is a Red-Al reaction.
4. The method according to claim 2, wherein The substitution reaction reagent in step (2) is NCS.
5. The method according to claim 2, characterized in that The substitution reaction in step (3) is completed by oxidation with hydrogen peroxide in the presence of n-butyllithium.
6. The method according to claim 2, wherein The reagent for selective deprotection in step (4) is TBAF and HOAc.
7. The method according to claim 2, wherein The TBS protecting group reagent in step (5) is TBSOTF.