CN111018770A - Preparation method of bazedoxifene oxide - Google Patents
Preparation method of bazedoxifene oxide Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of bazedoxifene oxide, which comprises the following steps: dissolving bazedoxifene free base serving as a raw material in a first benign solvent, adding an organic base, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain an intermediate 1; dissolving the intermediate 1 in a second benign solvent, adding an oxidant, and oxidizing to obtain an intermediate 2; and dissolving the intermediate 2 in a third benign solvent, and adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide. The preparation method of bazedoxifene oxide provided by the invention provides a preparation method of 1- [4- [2- (azepane-1-yl) ethoxy ] benzyl ] -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5-phenol-N-oxide, and has important significance for effectively controlling the quality of bazedoxifene.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of bazedoxifene oxide.
Background
Bazedoxifene Acetate (Bazedoxifene Acetate) was purchased from hewlett-packard, later by fevered, as a small molecule drug, approved by the european drug administration to be marketed in italy and spain at 4 months 2009 under the trade name Conbriza, primarily for the treatment of postmenopausal osteoporosis. The existence of bazedoxifene acetate impurities not only affects the purity of bazedoxifene acetate, but also can bring toxic and side effects. Therefore, in the actual drug production process, the comparison with clear and definite impurities is an indispensable link in the drug production, and is a necessary means for effectively controlling the drug components and ensuring the drug safety.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a preparation method of bazedoxifene oxide, synthesizes bazedoxifene oxide 1- [4- [2- (azepane-1-yl) ethoxy ] benzyl ] -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5-phenol-N-oxide, and can solve the problem of monitoring the quality of bazedoxifene in the existing production process.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of bazedoxifene oxide, which comprises the following steps:
dissolving bazedoxifene free base serving as a raw material in a first benign solvent, adding an organic base, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain an intermediate 1;
dissolving the intermediate 1 in a second benign solvent, adding an oxidant, and oxidizing to obtain an intermediate 2;
dissolving the intermediate 2 in a third benign solvent, adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide, wherein the bazedoxifene oxide is 1- [4- [2- (azepane-1-yl) ethoxy ] benzyl ] -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5-phenol-N-oxide.
In one embodiment, the bazedoxifene has the structural formula:
the structural formula of the intermediate 1 is as follows:
the structural formula of the intermediate 2 is as follows:
the structural formula of the bazedoxifene oxide is as follows:
in one embodiment, the first benign solvent comprises at least one of dichloromethane, chloroform, tetrahydrofuran, dioxane, and ethyl acetate;
and/or, the second benign solvent comprises at least one of dichloromethane, trichloromethane, ethyl acetate, and tetrahydrofuran;
and/or the third benign solvent comprises at least one of methanol, ethanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether.
In one embodiment, the silane protecting group comprises at least one of trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane, triisopropylchlorosilane, ethyldimethylchlorosilane, phenyldimethylchlorosilane, methyldiphenylchlorosilane, and t-butyldiethylchlorosilane.
In one embodiment, the organic base comprises at least one of triethylamine, diisopropylethylamine.
In one embodiment, the oxidant comprises at least one of hydrogen peroxide and m-chloroperoxybenzoic acid.
In one embodiment, the deprotecting reagent comprises at least one of hydrochloric acid, acetic acid, hydrogen fluoride, tetrabutylammonium fluoride.
In one embodiment, the molar ratio of bazedoxifene free base to silane protecting groups is from 1.0:2.0 to 1.0: 6.0.
In one embodiment, the molar ratio of the intermediate 1 to the oxidant is 1.0:1.0 to 1.0: 2.0.
In one embodiment, the reaction temperature for adding the silane protecting group is-10 ℃ to 40 ℃, and the reaction time is 2 to 8 hours;
and/or the temperature of the oxidation reaction for adding the oxidant is 20-50 ℃, and the reaction time is 4-12 hours;
and/or adding the protecting group removing reagent at the reaction temperature of 10-60 ℃ for 0.5-5 hours.
The preparation method of bazedoxifene oxide provided by the invention comprises the steps of dissolving bazedoxifene free base serving as a raw material in a first benign solvent, adding an organic base, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain an intermediate 1; dissolving the intermediate 1 in a second benign solvent, adding an oxidant, and oxidizing to obtain an intermediate 2; and dissolving the intermediate 2 in a third benign solvent, and adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide. The preparation method provides a preparation method of 1- [4- [2- (azepan-1-yl) ethoxy ] benzyl ] -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5-phenol-N-oxide, and has important significance for effectively controlling the quality of bazedoxifene.
Drawings
FIG. 1 is a route to the preparation of bazedoxifene oxide in the present invention;
FIG. 2 is a mass spectrum of bazedoxifene oxide of example 1 of the invention;
figure 3 is an HPLC profile of bazedoxifene oxide of example 1 of the invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a preparation method of bazedoxifene oxide, which comprises the following steps:
step S11, dissolving bazedoxifene free alkali serving as a raw material in a first benign solvent, adding an organic alkali, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain an intermediate 1;
step S12, dissolving the intermediate 1 in a second benign solvent, adding an oxidant, and oxidizing to obtain an intermediate 2;
and step S13, dissolving the intermediate 2 in a third benign solvent, and adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide.
Further, in step S11, the first benign solvent includes at least one of dichloromethane, chloroform, tetrahydrofuran, dioxane and ethyl acetate; the silane protecting group comprises at least one of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, ethyldimethylchlorosilane, phenyldimethylchlorosilane, methyldiphenylchlorosilane and tert-butyldiethylchlorosilane; the organic base comprises at least one of triethylamine and diisopropylethylamine.
The molar ratio of bazedoxifene free base to silane protecting group is 1.0:2.0 to 1.0:6.0, and may be, for example, 1.0:2.0, 1.0:2.1, 1.0:2.2, 1.0:2.3, 1.0:2.4, 1.0:2.5, 1.0:3.0, 1.0:3.5, 1.0:4.0, 1.0:4.5, 1.0:5.0, 1.0:5.5, 1.0:6.0, and the like, and preferably 1.0:4.0 to 1.0:5.0, and when the molar ratio of bazedoxifene free base to silane protecting group is relatively low, the reaction is incomplete, and when the molar ratio of bazedoxifene free base to silane protecting group is relatively high, the cost increases.
The temperature of the silane protecting group solution to be added is-10 ℃ to 40 ℃, and may be, for example, -10 ℃, -9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃ and the like, preferably 0 ℃ to 5 ℃, and when the temperature of the reaction is too low, the reaction is not easily performed, and when the temperature of the reaction is too high, other by-products are generated, and the reaction yield is lowered. The reaction time is 2 to 8 hours, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, etc., preferably 3 to 5 hours, and when the reaction time is too short, the reaction is insufficient, and when the reaction time is too long, impurities are easily generated.
Further, in step S12, the second benign solvent includes at least one of dichloromethane, chloroform, ethyl acetate and tetrahydrofuran; the oxidant comprises at least one of hydrogen peroxide and m-chloroperoxybenzoic acid.
The molar ratio of the intermediate 1 to the oxidizing agent is 1.0:1.0 to 1.0:2.0, and may be, for example, 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, 1.0:2.0, and the like, and preferably 1.0:1.2, and when the molar ratio of the intermediate 1 to the oxidizing agent is low, the reaction is incomplete, and when the molar ratio of the intermediate 1 to the oxidizing agent is high, a large potential safety hazard exists.
The temperature of the oxidation reaction by adding the oxidizing agent is 20 to 50 ℃, for example, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃ and the like, preferably 36 to 42 ℃; the reaction time is 4-12 h, for example, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h and the like, preferably 5-8 h; when the reaction temperature is low and the reaction time is short, the reaction is incomplete, and when the reaction temperature is high and the reaction time is long, potential safety hazards exist, and by-product impurities are easily generated.
Further, in step S12, the third benign solvent includes at least one of methanol, ethanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, diethyl ether, isopropyl ether, and methyl tert-butyl ether; the protective group removing reagent comprises at least one of hydrochloric acid, acetic acid, hydrogen fluoride and tetrabutylammonium fluoride.
Wherein the reaction temperature for adding the protecting group removing reagent is 10-60 ℃, for example, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃ and the like, preferably 20-35 ℃; the reaction time is 0.5 to 5 hours, for example, 0.5 hour, 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours and the like, preferably 1 to 2 hours; when the reaction temperature is low and the reaction time is short, the reaction is incomplete, and when the reaction temperature is high and the reaction time is long, potential safety hazards exist, and by-product impurities are easily generated.
The preparation method of bazedoxifene oxide provided by the invention comprises the steps of dissolving bazedoxifene free base serving as a raw material in a first benign solvent, adding an organic base, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain an intermediate 1; dissolving the intermediate 1 in a second benign solvent, adding an oxidant, and oxidizing to obtain an intermediate 2; and dissolving the intermediate 2 in a third benign solvent, and adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide. The preparation method provides a preparation method of 1- [4- [2- (azepan-1-yl) ethoxy ] benzyl ] -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5-phenol-N-oxide, and has important significance for effectively controlling the quality of bazedoxifene.
The invention is described in further detail with reference to a number of tests performed in sequence, and a part of the test results are used as reference, and the following detailed description is given with reference to specific examples.
Example 1
Step S201, adding bazedoxifene free base (3.1g, 6.6mmol) and dichloromethane (15mL) into a reaction bottle, adding triethylamine (6.7g, 65.9mmol), cooling to 0 ℃ under the protection of nitrogen, slowly dropwise adding tert-butyldimethylsilyl chloride (5.0g, 32.9mmol) dissolved in dichloromethane (15mL), heating to room temperature after dropwise adding, and stirring for reaction for 4 hours; after completion of the reaction, the reaction solution was poured into 50mL of purified water, extracted with dichloromethane (30mL × 3), the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent dichloromethane: methanol ═ 5:95) to obtain 4.3g of intermediate 1 as a yellow oil in a yield of 93.48%.
Step S202, dissolving the intermediate 1(4.1g, 5.86mmol) obtained in S201 in dichloromethane (60mL), slowly dropwise adding hydrogen peroxide (30%, 60mL) under the condition of stirring at room temperature, heating to 40 ℃ after dropwise adding, and carrying out reflux stirring reaction for 6 hours; after completion of the reaction, the reaction mixture was allowed to stand for separation, the aqueous phase was extracted twice with methylene chloride (50 mL. times.3), and the organic phases were combined, washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3.4g of intermediate 2 as a pale yellow oil with a yield of 81.15%.
Step S203, adding the intermediate 2(2.5g, 3.50mmol) obtained in S202 and methanol (50mL) into a reaction bottle, slowly dropwise adding concentrated hydrochloric acid (37%, 5mL) under the condition of stirring at 0 ℃, and reacting for 1 hour under the condition of stirring at room temperature after dropwise adding; after completion of the reaction, concentration was carried out under reduced pressure, and the concentrate was purified by column chromatography (eluent dichloromethane: methanol 5:95) to obtain 1.2g of a yellow solid, bazedoxifene oxide, with a yield of 70.59%.
The electrospray mass spectrum is shown in figure 2: ESI-MS M/z 487.31[ M + H ]]+, the theoretical molecular formula of bazedoxifene oxide: c30H34N2O4Molecular weight: 486.61.
the purity of the target compound is detected in the following way: high performance liquid chromatography is carried out by taking Waters symmetry (4.6mm multiplied by 250mm, 5 mu m) as a chromatographic column, 220nm as a detection wavelength and 0.01mol/L potassium dihydrogen phosphate solution and acetonitrile as mobile phases, and a specific map is shown in figure 3.
Example 2
Step S301, adding bazedoxifene free base (5.0g, 10.6mmol) and dichloromethane (30mL) into a reaction bottle, adding triethylamine (6.5g, 63.7mmol), cooling to 0 ℃ under the protection of nitrogen, slowly dropwise adding a dichloromethane (30mL) solution of trimethylchlorosilane (5.8g, 53.1mmol), after dropwise adding, heating to room temperature, and stirring for reaction for 4 hours; after completion of the reaction, the reaction solution was poured into 100mL of purified water, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent dichloromethane: methanol ═ 5:95) to obtain 5.9g of intermediate 1 as a yellow oil in 90.30% yield.
Step S302, dissolving the intermediate 1(5.0g, 8.1mmol) obtained in S301 in dichloromethane (60mL), slowly dropwise adding hydrogen peroxide (30%, 60mL) under the condition of stirring at room temperature, and after dropwise adding, heating to 40 ℃ for reflux stirring reaction for 6 hours; after completion of the reaction, the reaction mixture was allowed to stand for separation, and the aqueous phase was extracted twice with methylene chloride (50 mL. times.3), and the organic phases were combined, washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4.2g of intermediate 2 as a pale yellow oil with a yield of 81.87%.
Step S303, adding the intermediate 2(3.5g and 5.5mmol) obtained in S302 and methanol (50mL) into a reaction bottle, slowly dropwise adding concentrated hydrochloric acid (37 percent and 5mL) under the condition of stirring at 0 ℃, and after dropwise adding, stirring and reacting at room temperature for 1 hour; after completion of the reaction, concentration was carried out under reduced pressure, and the concentrate was purified by column chromatography (eluent dichloromethane: methanol 5:95) to obtain 1.7g of a yellow solid, which was bazedoxifene oxide, with a yield of 62.98%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A method of preparing bazedoxifene oxide, said method comprising:
dissolving bazedoxifene free base serving as a raw material in a first benign solvent, adding an organic base, and then adding a silane protecting group to protect two phenolic hydroxyl groups to obtain an intermediate 1;
dissolving the intermediate 1 in a second benign solvent, adding an oxidant, and oxidizing to obtain an intermediate 2;
and dissolving the intermediate 2 in a third benign solvent, and adding a protecting group removing reagent to remove two molecules of silane protecting groups to obtain bazedoxifene oxide, wherein the bazedoxifene oxide is 1- [4- [2- (azepane-1-yl) ethoxy ] benzyl ] -2- (4-hydroxyphenyl) -3-methyl-1H-indole-5-phenol-N-oxide.
2. The method of preparing bazedoxifene oxide according to claim 1, wherein said bazedoxifene has the formula:
the structural formula of the intermediate 1 is as follows:
the structural formula of the intermediate 2 is as follows:
the structural formula of the bazedoxifene oxide is as follows:
3. the method of preparing bazedoxifene oxide according to claim 1, wherein said first benign solvent comprises at least one of dichloromethane, chloroform, tetrahydrofuran, dioxane, and ethyl acetate;
and/or, the second benign solvent comprises at least one of dichloromethane, trichloromethane, ethyl acetate, and tetrahydrofuran;
and/or the third benign solvent comprises at least one of methanol, ethanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether.
4. The method of preparing bazedoxifene oxide according to claim 1, wherein said silane protecting group comprises at least one of trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane, triisopropylchlorosilane, ethyldimethylchlorosilane, phenyldimethylchlorosilane, methyldiphenylchlorosilane, and t-butyldiethylchlorosilane.
5. The method of preparing bazedoxifene oxide according to claim 1, wherein said organic base comprises at least one of triethylamine and diisopropylethylamine.
6. The method of preparing bazedoxifene oxide according to claim 1, wherein said oxidizing agent comprises at least one of hydrogen peroxide, m-chloroperoxybenzoic acid.
7. The process for preparing bazedoxifene oxide according to claim 1, wherein said deprotecting reagent comprises at least one of hydrochloric acid, acetic acid, hydrogen fluoride, tetrabutylammonium fluoride.
8. The method of preparing bazedoxifene oxide according to claim 1, wherein the molar ratio of bazedoxifene free base to silane protecting groups is from 1.0:2.0 to 1.0: 6.0.
9. The method of preparing bazedoxifene oxide according to claim 1, wherein the molar ratio of intermediate 1 to the oxidizing agent is from 1.0:1.0 to 1.0: 2.0.
10. The process for preparing bazedoxifene oxide according to any one of claims 1 to 9, wherein the silane protecting groups are added at a reaction temperature of-10 ℃ to 40 ℃ for 2 to 8 hours;
and/or the temperature of the oxidation reaction for adding the oxidant is 20-50 ℃, and the reaction time is 4-12 hours;
and/or adding the protecting group removing reagent at the reaction temperature of 10-60 ℃ for 0.5-5 hours.
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| CN111060619A (en) * | 2019-12-18 | 2020-04-24 | 北京鑫开元医药科技有限公司 | Method for detecting bazedoxifene acetate impurity |
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