A method for synthesizing an impurity of eldecalcitol

Abstract

The present application relates to a kind of synthesis method of impurity of eldecalcitol, is realized by oxidation-reduction in " one pot " without purification and separation of intermediate product.The method of the present application successfully synthesizes the phytosterol impurity of eldecalcitol, and the phytosterol impurity obtained is higher in purity, can be used as the reference substance of eldecalcitol related substance, for the content determination, impurity and related substance detection of eldecalcitol, is the necessary product of eldecalcitol quality control.The whole preparation method of the present application is simple, convenient, helps the quality improvement and control of eldecalcitol.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical organic chemical synthesis, specifically to a method for synthesizing idecalciferol impurities. Background Technology

[0002] On January 21, 2011, the Japanese Ministry of Health, Labour and Welfare approved the marketing of idecalciferol soft capsules, a drug for the treatment of osteoporosis. Idecalciferol, the active ingredient, is a new active vitamin D3 derivative for treating osteoporosis, following alfacalciferol. Data from a three-year Phase III clinical trial involving 1054 osteoporosis patients showed that idecalciferol was more effective than alfacalciferol, with a similar safety profile, indicating promising application prospects.

[0003] Impurity research is a crucial aspect of drug development, directly impacting drug quality control and safety. Controlling impurities in drug products ensures their quality and safety. Idemardol impurities refer to starting materials, intermediates, by-reaction products, residual impurities from raw materials, and degradation products introduced during the production of idecalciferol.

[0004] On page 5 of the registration document (IF file 9th edition) for idecalciferol published by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the tachysterol impurity ((1R,2R,3R,6E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5(10),6,8(9)-triene-1,3,25-triol) is listed as an impurity for idecalciferol. Specifically, by searching for information such as medical drug additive documents on PMDA (pmda.go.jp) and entering the Japanese name for idecalciferol: エルデカルシトール, this impurity is listed in its 9th edition. In addition, patent CN101721708A reported an ED-71 formulation. ED-71 is the development code name for Chugai Pharmaceutical Co., Ltd.'s original drug, idecalciferol. Idecalciferol belongs to the vitamin D food category and has a conjugated triene structure. It undergoes transformation under light or heating conditions, generating impurities.

[0005] The prerequisite for studying the types and sources of impurities in pharmaceuticals and how to control the generation of process impurities is obtaining the impurities themselves. Therefore, synthesizing idecalciferol tachysterol impurities is of great significance for effectively controlling the quality of idecalciferol raw materials and their preparations. However, there are currently no similar literature reports on the preparation methods of tachysterol impurities.

[0006] The tachysterol impurities of idecalciferol are degradation impurities of idecalciferol and are isomers of idecalciferol, making their synthesis difficult. High-temperature degradation results in low purity and makes them difficult to concentrate. Therefore, a simple method for synthesizing idecalciferol impurities with high purity and yield is of great significance. Summary of the Invention

[0007] To solve the above-mentioned technical problems, the inventors, through numerous attempts, have obtained a simple and efficient method for synthesizing paclitaxel impurities, as detailed below:

[0008] A method for synthesizing idecalciferol impurities, the synthetic route is as follows:

[0009]

[0010] Furthermore, the method for synthesizing the idecalciferol impurity includes the following steps:

[0011] (1) The compound of formula I is oxidized in the presence of an organic solvent and an oxidizing agent to produce the compound of formula II;

[0012] (2) Compound II of formula is reduced to idicalcitol impurity under the action of a reducing agent.

[0013] Further, in step (1), the organic solvent is selected from at least one of tetrahydrofuran, ethanol, isopropanol, acetone, ethyl acetate, and dichloromethane.

[0014] Preferably, the organic solvent is a mixture of tetrahydrofuran and dichloromethane in a volume ratio of 1-3:1-3, and most preferably a mixture of tetrahydrofuran and dichloromethane in a volume ratio of 1:1. The compound of Formula I is oxidized to prepare the intermediate of Formula II, and then reduced to obtain the final product, idecalciferol impurity. The difficulty lies in the numerous oxidation side reactions in step (1), which require improvement in both yield and purity. The inventors unexpectedly discovered that, using the aforementioned mixed solvent and the Desmartin reagent, they could simultaneously achieve higher yields and higher purity. The inventors had previously attempted to use a single solvent or other mixed solvents, or to change the oxidation system, but were unable to simultaneously achieve high yields and purity. This indicates that the catalyst, the Desmartin reagent, combined with the mixed solvent system, is the key to achieving both high yield and high purity in this invention.

[0015] Furthermore, in step (1), the volume ratio of the organic solvent to the mass ratio of compound I is 10-40 mL: 1 g, preferably 20-30 mL: 1 g.

[0016] Further, in step (1), the oxidant is a Desmartin reagent. Even further, the amount of Desmartin reagent used is 1-2 times the molar amount of the compound of formula I, preferably 1.3-1.8 times, for example 1.3 times, 1.4 times, 1.5 times, 1.6 times, or 1.7 times.

[0017] Furthermore, in step (1), the reaction conditions are 10-30℃ and the reaction time is 2-4h.

[0018] Further, in step (2), the reducing agent is at least one of sodium borohydride and potassium borohydride; the amount of reducing agent used is 8-12 times the molar amount of the compound of formula I.

[0019] Furthermore, in step (2), the reaction conditions are 10-30℃ and the reaction time is 10-20h.

[0020] Furthermore, after step (2), there is also a purification step (3), such as purification by column chromatography, with the mobile phase being a mixed solvent of acetonitrile and water in a volume ratio of 1-5:1-5.

[0021] The oxidation-reduction process of this invention is achieved in a one-pot reaction, eliminating the need for purification and separation of intermediate product II; simply adding excess reducing agent is sufficient for the reaction. This method successfully synthesizes tachysterol impurities of idecalciferol with high purity, making them suitable as reference standards for idecalciferol content determination, impurity and related substance detection, and essential for idecalciferol quality control. The entire preparation method of this invention is simple and convenient, contributing to the improvement and control of idecalciferol quality. Attached Figure Description

[0022] Figure 1 It is the tachysterol impurity compound prepared in Example 1. 1 H-NMR spectrum;

[0023] Figure 2 This is a high-resolution mass spectrum of the tachysterol impurity compound prepared in Example 1;

[0024] Figure 3 This is a high-performance liquid chromatogram of the tachysterol impurity compound prepared in Example 1. Detailed Implementation

[0025] The present invention will be further described below with reference to embodiments.

[0026] Example 1

[0027] The synthetic route for the preparation of tachysterol impurities is as follows:

[0028]

[0029] (1) Add compound (I) (1.0g, 2.04mmol, 1.0eq) to a 100mL single-necked flask, dissolve it in tetrahydrofuran (10mL), add dichloromethane (10mL), add Desmartin reagent (1.38g, 2.04mmol, 1.6eq), react at 10-30℃ for 3h, and then directly proceed to the next step of the reaction.

[0030] (2) Sodium borohydride (0.77 g, 20.38 mmol, 10.0 eq) was slowly added to the reaction solution, and the reaction was carried out at 10-30℃ for 3 h. The reaction solution was then added to ammonium chloride aqueous solution (40 mL), and dichloromethane (20 mL) was added for extraction and separation. The organic phase was washed once with sodium chloride aqueous solution (30 mL), dried and concentrated to obtain crude phytosterol.

[0031] (3) The crude sterol was prepared by liquid chromatography with a mobile phase ratio of acetonitrile:water = 48:52. After concentration under reduced pressure, extraction with dichloromethane, and concentration of the organic phase, idecalciferol impurity was obtained with a purity of 98.25%. According to calculation, based on the compound of formula I, the yield of idecalciferol impurity in Example 1 was 72.8%.

[0032] Figure 1 It is the idecalciferol impurity compound prepared in Example 1. 1 H-NMR spectrum; Figure 2 This is a high-resolution mass spectrometry of the idicalcitol impurity compound prepared in Example 1; Figure 3 This is a high-performance liquid chromatogram of the idecalciferol impurity compound prepared in Example 1.

[0033] The results of high performance liquid chromatography are shown in Table 1 and Figure 3 .

[0034] Table 1. HPLC results of the products

[0035] Serial Number Retention time / min Peak area Peak Area percentage (%) 1 5.8033 0.0328 0.2417 0.0257 2 6.2800 0.0191 0.1290 0.0150 3 6.9267 0.0186 0.0983 0.0146 4 7.3067 0.0222 0.1122 0.0174 5 9.1167 0.2234 0.9943 0.1751 6 9.4867 0.2627 1.1186 0.2059 7 10.3367 0.0374 0.1610 0.0293 8 10.8333 0.2085 0.7724 0.1635 9 11.3467 0.1002 0.3446 0.0785 10 11.8900 0.1454 0.4477 0.1140 11 13.6300 0.0478 0.0699 0.0374 12 16.5900 0.0921 0.1537 0.0722 13 20.5300 0.0304 0.0528 0.0238 14 21.8700 0.1204 0.2537 0.0943 15 23.3233 126.0831 260.8469 98.8343 16 25.4267 0.0792 0.1201 0.0621 17 45.2900 0.0471 0.0657 0.0369 18 - 127.570 265.982 100.00

[0036] HPLC purity: 98.83%;

[0037] 1 H-NMR (400MHz, CDCl3) δppm:

[0038] 6.65(1H,d),6.10(1H,d),5.73(1H,s),4.23(2H,d),3.82(4H,qd),3.45(1H,m),2.46(2H,s),2.33(2H,s),2.24(2H,s), 1.99(2H,dd),1.91(3H,s),1.86(2H,dd),1.61(2H,s),1.40(8H,m),1.23(6H,d),1.07(1H,d),0.97(3H,d),0.68(3H,s).

[0039] Mass spectrometry (ESI): m / z 513.3582 [M+Na] + Theoretical value: 513.3658.

[0040] The above data demonstrate that the synthesis method of this invention successfully obtained the target product with high yield and purity, making it suitable for industrial production.

[0041] Toxicity studies were conducted on the impurities prepared in Example 1. Experimental animals: 6 six-week-old SD rats (male 140-170g, female 120-140g) were used in each dose group, with half males and half females. The impurities from Example 1 were administered via intravenous injection into the tail vein of mice using 10% DMSO PBS solution. Appropriate doses were selected based on survival rates within 3 days of administration. Animal survival time and mortality were observed, and the LD50 value was calculated. The LD50 of the impurities prepared in Example 1 was 1.7 μg / kg, while the LD50 of the active pharmaceutical ingredient idecalciferol was 12.6 μg / kg. This indicates that the impurities from Example 1 have significantly higher toxicity than idecalciferol, making quality control of them important.

[0042] Example 2

[0043] The other conditions were the same as in Example 1, except that in step (1), the organic solvent was replaced with 20 mL of tetrahydrofuran instead of 10 mL of tetrahydrofuran + 10 mL of dichloromethane. The final purity of idecalciferol was 96.72%, and the yield was 63.5%.

[0044] Example 3

[0045] The other conditions were the same as in Example 1, except that in step (1), the organic solvent was replaced with 20 mL of dichloromethane instead of 10 mL tetrahydrofuran + 10 mL dichloromethane. The final purity of idecalciferol was 97.58%, and the yield was 61.2%.

[0046] Example 4

[0047] The other conditions were the same as in Example 1, except that in step (1), the oxidant was replaced by an equimolar amount of pyridine dichromate instead of Desmartin reagent, and the final purity of idecalciferol was 93.80%, with a yield of 67.3%.

Claims

1. A method for synthesizing idecalciferol impurities, characterized in that, The synthesis route is as follows: ； The synthesis method includes the following steps: (1) The compound of formula I is oxidized in the presence of an organic solvent and an oxidizing agent to produce the compound of formula II; the oxidizing agent is a Desmartin reagent, and the amount of Desmartin reagent is 1-2 times the molar amount of the compound of formula I; (2) The compound of formula II is reduced to idecalciferol impurity under the action of a reducing agent; the reducing agent is at least one of sodium borohydride and potassium borohydride; the amount of reducing agent is 8-12 times the molar amount of the compound of formula I.

2. The synthesis method according to claim 1, characterized in that, In step (1), the organic solvent is selected from at least one of tetrahydrofuran, ethanol, isopropanol, acetone, ethyl acetate, and dichloromethane.

3. The synthesis method according to claim 2, characterized in that, The organic solvent is a mixture of tetrahydrofuran and dichloromethane in a volume ratio of 1-3:1-3.

4. The synthesis method according to claim 2, characterized in that, The organic solvent is a mixture of tetrahydrofuran and dichloromethane in a volume ratio of 1:

1.

5. The synthesis method according to claim 2 or 3, characterized in that, In step (1), the volume ratio of the organic solvent to the mass ratio of compound I is 10-40 mL: 1 g.

6. The synthesis method according to claim 4, characterized in that, The volume ratio of the organic solvent to the mass of compound I is 20-30 mL: 1 g.

7. The synthesis method according to claim 1, characterized in that, The amount of Desmartin reagent used is 1.3-1.8 times the molar amount of compound I.

8. The synthesis method according to claim 1, characterized in that, In step (1), the reaction conditions are 10-30℃ and the reaction time is 2-4h.

9. The synthesis method according to claim 1, characterized in that, In step (2), the reaction conditions are 10-30℃ and the reaction time is 10-20h.

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