Idecalciferol preparation process impurity and preparation method thereof
By preparing and monitoring impurity compounds in the A-ring process in the methyl calcitol synthesis process, the problem of impurities affecting quality control is solved, and the purity and reliability of the synthesis process are improved.
Patent Information
- Application Number
- CN202311852909.5
- 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 are generated in the construction of the A-ring of the key intermediates, which affects the quality control and purity of the synthesis process.
Compounds of formula (I) and (I') are prepared by a series of chemical reaction steps including reduction, substitution, phosphorus substitution, selective deprotection and TBS protecting group reaction, and these impurities are monitored and compared to improve the synthesis process.
The quality control of the synthesis process of estigalisol has been achieved, the purity and impurity monitoring capabilities have been improved, and the reliability of the synthesis process has been improved.
Smart Images
Figure CN120230143A_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, and is used for the treatment of osteoporosis. It 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 after 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 various impurities that may be generated in the above process and comparing and monitoring them during the synthesis and storage process are of great significance for improving and enhancing the synthesis process of eldecalcitol and improving quality control. Summary of the Invention
[0007] The present invention discovers new impurities in the process of constructing the A-ring of the eldecalcitol synthesis process. The impurities have the structure shown in formula (I):
[0008]
[0009] On the one hand, the present invention provides the compounds shown in formula (I) and (I’).
[0010] On the other hand, the present invention provides a preparation method of the compound shown in formula (I). The process of the method is shown as follows:
[0011]
[0012] It includes the following steps:
[0013] (1) Compound (VI) is reduced 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] On the other hand, the present invention provides a method for preparing the compound represented by formula (I’), and the process of the method is as follows:
[0019]
[0020] It includes the following steps:
[0021] (1) Compound (VI) is reduced to obtain compound (V’);
[0022] (2) Compound (V’) undergoes a substitution reaction to obtain compound (IV’);
[0023] (3) Compound (IV’) undergoes a substitution reaction with diphenylphosphine to obtain compound (III’);
[0024] (4) Compound (III’) is selectively deprotected to obtain compound (II’);
[0025] (5) Compound (II’) reacts with a TBS protecting group reagent to obtain compound (I’).
[0026] Preferably, the reduction reaction in step (1) is the Red-Al reaction.
[0027] Preferably, the substitution reaction reagent in step (2) is NCS.
[0028] Preferably, in step (3), the substitution reaction is completed by oxidation with hydrogen peroxide in the presence of n-butyllithium.
[0029] Preferably, in step (4), the reagent for selective deprotection is TBAF and HOAc.
[0030] Preferably, in step (5), the TBS protecting group reagent is TBSOTF.
[0031] The beneficial effects of the present invention are:
[0032] The present invention has first discovered the compounds of formula (I) and formula (I'), which are impurities 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 the quality control. Description of the Drawings
[0033] Figure 1a It is the chromatogram of the compound of formula (V') in Example 1.
[0034] Figure 1b It is the chromatogram of the compound of formula (V) in Example 1.
[0035] Figure 2a It is the chromatogram of the compound of formula (IV) in Example 2.
[0036] Figure 2b It is the chromatogram of the compound of formula (IV') in Example 2.
[0037] Figure 3a It is the chromatogram of the compound of formula (III) in Example 3.
[0038] Figure 3b It is the chromatogram of the compound of formula (III') in Example 3.
[0039] Figure 4 It is the chromatogram of the compound of formula (II) in Example 4.
[0040] Figure 5a It is the chromatogram of the compound of formula (I) in Example 5.
[0041] Figure 5b It is the chromatogram of the compound of formula (I') in Example 5. Detailed Description of the Invention
[0042] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention within the scope of the described examples.
[0043] The reagents used in the present invention can all be purchased from the market or can be prepared by the methods described in the present invention.
[0044] Example 1: Synthesis of the compound of formula (V) / (V'):
[0045]
[0046] 1.5 g of the compound of formula (IV) was added to a 100 ml three-necked flask, 18 ml of methylcyclopentyl ether was added, and 1.7 g of Red-Al (70% / 3.5 M) was added dropwise. The reaction was carried out at 5 - 10 °C for 16 h. The reaction solution was added dropwise to 50 ml of saturated potassium sodium tartrate solution, extracted twice with 40 ml of EA*2, separated, concentrated under reduced pressure to obtain a crude product, and purified by column chromatography to obtain 630 mg of the E-configured compound of formula (V') with a purity of 95.7%, and 180 mg of the Z-configured compound of formula (V) with a purity of 95.6%. The chromatogram of the E-configured compound of formula (V') is shown in Figure 1a , and the chromatogram of the Z-configured compound of formula (V) is shown in Figure 1b .
[0047] Example 2: Synthesis of the compound of formula (IV) / (IV'):
[0048]
[0049]
[0050] 180 mg of the compound of formula (V) was added to a 100 ml single-necked flask, 99 mg of PPh3 was added, dissolved in 5 ml of DCM, and 41 mg of NCS dissolved in 1 ml of DCM was added dropwise, and the mixture was stirred for 2 h. 20 ml of water was added to the reaction solution, extracted with 20 ml of DCM, separated, concentrated under reduced pressure to obtain 200 mg of a colorless oily compound of formula (IV) with a purity of 98.82%. The chromatogram is shown in Figure 2a .
[0051] 630 mg of the compound of formula (V') was added to a 100 ml single-necked flask, 348 mg of PPh3 was added, dissolved in 10 ml of DCM, and 144 mg of NCS dissolved in 2 ml of DCM was added dropwise, and the mixture was stirred for 2 h. 20 ml of water was added to the system, extracted with 20 ml of DCM, separated, concentrated under reduced pressure to obtain 720 mg of a colorless oily compound of formula (IV) with a purity of 99.2%. The chromatogram is shown in Figure 2b .
[0052] Example 3: Synthesis of the compound of formula (III) / (III'):
[0053]
[0054] 107 mg of PHPh2 was added to a 100 ml single-necked flask, dissolved in 3 ml of THF, 0.21 ml of N-BuLi was added dropwise, stirred at 0 - 5 °C for 2 h, 200 mg of the compound of formula (IV) dissolved in 2 ml of THF was added dropwise, and the reaction was continued for 1 h. The reaction solution was quenched with 5 ml of aqueous NH4Cl solution, extracted with 3 ml of THF, and concentrated under reduced pressure to obtain an oily substance. It was dissolved in 5 ml of CHCl3, 0.16 ml of H2O2 was added dropwise, and stirred at room temperature for 30 min. Quenched with saturated aqueous sodium thiosulfate solution, extracted with DCM, and concentrated under reduced pressure to obtain 400 mg of an oily substance. Purified by TLC to obtain 120 mg of a colorless transparent liquid of the compound of formula (III) with a purity of 97.4%. See the chromatogram Figure 3a 。
[0055] 367 mg of PHPh2 was added to a 100 ml single-necked flask, dissolved in 8 ml of THF, 0.71 ml of N-BuLi was added dropwise, stirred at 0 - 5 °C for 2 h, 720 mg of the compound of formula (IV’) dissolved in 2 ml of THF was added dropwise, and the reaction was continued for 1 h. The reaction solution was quenched with 20 ml of aqueous NH4Cl solution, extracted with 10 ml of THF, and concentrated under reduced pressure to obtain an oily substance. It was dissolved in 20 ml of CHCl3, 0.536 ml of H2O2 was added dropwise, and stirred at room temperature for 30 min. Quenched with saturated aqueous sodium thiosulfate solution, extracted with DCM, and concentrated under reduced pressure to obtain 1.0 g of an oily substance. Purified by column chromatography to obtain 500 mg of an oily substance with a purity of 96.3%. See the chromatogram Figure 3b 。
[0056] Example 4: Synthesis of the compound of formula (II) / (II’):
[0057]
[0058] 90 mg of the compound of formula (III) was added to a 25 ml single-necked flask, dissolved in 2 ml of THF, 11 mg of HOAC was added, 0.18 ml of TBAF was added dropwise, and stirred at room temperature for 16 h. 30 ml of water was added, extracted three times with EA (50 ml * 3), the organic phases were combined, and concentrated under reduced pressure to obtain 90 mg of an oily substance. Purified by TLC to obtain 55 mg of a colorless transparent liquid of the compound of formula (II) with a purity of 96.5%. See the chromatogram Figure 4 。
[0059] 400 mg of the compound of formula (III’) was added to a 25 ml single-necked flask, dissolved in 5 ml of THF, 48 mg of HOAC was added, 0.8 ml of TBAF was added dropwise, and stirred at room temperature for 1 h. 30 ml of water was added, extracted three times with EA (20 ml * 3), the organic phases were combined, and concentrated under reduced pressure to obtain 207 mg of an oily substance.
[0060] Example 5: Synthesis of the compound of formula (I) / (I’):
[0061]
[0062] In a 50 ml single-necked flask, add 55 mg of the compound of formula (II), dissolve it in 2 ml of DCM, add 53 mmol of 2,6-lutidine, dropwise add 38 mmol of TBSOTF, and stir at room temperature for 2 h. Add 40 ml of DCM, wash twice with 4 ml * 2 of 1M HCl, concentrate the organic phase under reduced pressure to obtain a crude product, and purify by TLC to obtain 30 mg of a colorless transparent liquid with a purity of 98.5%. See the chromatogram Figure 5a .
[0063] In a 50 ml single-necked flask, add 207 mg of the compound of formula (II'), dissolve it in 5 ml of DCM, add 202 mg of 2,6-lutidine, dropwise add 183 mg of TBSOTF, and stir at room temperature for 2 h. Add 60 ml of DCM, wash twice with 6 ml * 2 of 1M HCl, concentrate the organic phase under reduced pressure to obtain a crude product, and purify by TLC to obtain 200 mg of a colorless transparent liquid with a purity of 98.6%. See the chromatogram Figure 5b .
[0064] The above shows and describes the specific embodiments of the present invention and the advantages of the present invention. 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 structure of formula (I) or (I'):
2. The preparation method of the compound of formula (I) as described in claim 1, and the process of the method is as follows: It includes the following steps: (1) Compound (VI) is reduced 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 preparation method of the compound of formula (I') according to claim 1, and the process of the method is as follows: It includes the following steps: (1) Compound (VI) is reduced 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').
4. The method according to claim 1 or 2, characterized in that, The reduction reaction in step (1) is a Red-Al reaction.
5. The method according to claim 1 or 2, characterized in that, The substitution reaction reagent in step (2) is NCS.
6. The method according to claim 1 or 2, characterized in that, The substitution reaction in step (3) is completed by oxidation with hydrogen peroxide in the presence of n-butyllithium.
7. The method according to claim 1 or 2, characterized in that, The reagent for selective deprotection in step (4) is TBAF and HOAc.
8. The method according to claim 1 or 2, characterized in that, The TBS protecting group reagent in step (5) is TBSOTF.