CN113603660B - Preparation method of 10-carbonyl docetaxel - Google Patents
Preparation method of 10-carbonyl docetaxel Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
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- 238000000034 method Methods 0.000 claims description 13
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- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 5
- ZUKDFIXDKRLHRB-UHFFFAOYSA-K cobalt(3+);triacetate Chemical compound [Co+3].CC([O-])=O.CC([O-])=O.CC([O-])=O ZUKDFIXDKRLHRB-UHFFFAOYSA-K 0.000 claims description 5
- 229940116318 copper carbonate Drugs 0.000 claims description 5
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- 229910001958 silver carbonate Inorganic materials 0.000 claims description 5
- -1 copper carbonate Chemical class 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZDZOTLJHXYCWBA-MQOKZWAMSA-N 7-epidocetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-MQOKZWAMSA-N 0.000 description 1
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- AHSBSUVHXDIAEY-UHFFFAOYSA-K manganese(iii) acetate Chemical compound [Mn+3].CC([O-])=O.CC([O-])=O.CC([O-])=O AHSBSUVHXDIAEY-UHFFFAOYSA-K 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention discloses a preparation method of 10-carbonyl docetaxel, which comprises the following steps: s1: dissolving docetaxel with a solvent, adding heavy metal salt, stirring for reaction, filtering after the reaction is completed, and concentrating an organic phase to obtain a degradation mixture; s2: the degradation mixture is subjected to column chromatography purification, the mobile phase is dichloromethane, methanol and acetic acid, the product is collected and concentrated, cyclohexane is used for pulping, and the 10-carbonyl docetaxel is obtained by suction filtration and drying.
Description
Technical Field
The invention relates to the field of anticancer drugs, in particular to a preparation method of 10-carbonyl docetaxel.
Background
Docetaxel, which is a taxane drug, has pharmacological effects of inhibiting mitosis and proliferation of cancer cells by promoting assembly of microtubule dimer into a microtubule, stabilizing the microtubule by preventing the process of deglycomerization, and blocking cells in G2 and M phases.
One degradation product of docetaxel is 10-carbonyl docetaxel, which is recorded as impurity B by the European Pharmacopoeia (EP). In order to better follow the international route, intensive studies on the impurities are also required in the quality study of docetaxel, and thus it is necessary to prepare 10-carbonyl docetaxel with high purity. The preparation of 10-carbonyl docetaxel is mainly achieved by degradation, which is always accompanied by 7-epi-10-carbonyl docetaxel (docetaxel impurity D). The 10-carbonyl docetaxel has special properties, is very easy to be further degraded into 7-epi-10-carbonyl docetaxel after higher purity, and thus the preparation of the high-purity 10-carbonyl docetaxel is difficult to realize by a conventional separation method.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 10-carbonyl docetaxel, which has the advantages of high yield, simple operation and good product purity through efficient degradation and ingenious purification design.
The technical aim of the invention is realized by the following technical scheme:
a method for preparing 10-carbonyl docetaxel, comprising the following steps:
s1: dissolving docetaxel with a solvent, adding heavy metal salt, stirring for reaction, filtering after the reaction is completed, and concentrating an organic phase to obtain a degradation mixture;
s2: purifying the degradation mixture by column chromatography, wherein the mobile phase is dichloromethane, methanol and acetic acid, collecting the product, concentrating, pulping with cyclohexane, and vacuum filtering and drying to obtain 10-carbonyl docetaxel;
the reaction route of the preparation process is as follows:
further, in step S1, the solvent is one or more of methanol, ethanol, and N, N-dimethylformamide.
Further, in step S1, the heavy metal salt is one of copper acetate, copper carbonate, manganese (III) acetate, cobalt (III) acetate, and silver carbonate.
Further, in the step S1, the reaction temperature is 65-80 ℃ and the reaction time is 3-8 hours.
In step S2, methylene chloride is frozen in advance, and the temperature condition of methylene chloride is 0 ℃ or lower.
Further, in step S2, the volume ratio of dichloromethane, methanol and acetic acid is 100:1:0.1.
Further, in step S1, docetaxel was dissolved in methanol, and then copper acetate was added thereto, and the mixture was heated to 65 ℃ and reacted under reflux with stirring for 8 hours.
Further, in step S1, docetaxel was dissolved in N, N-dimethylformamide, copper carbonate was added thereto, and the mixture was heated to 80℃and reacted under reflux with stirring for 3 hours.
Further, docetaxel is dissolved in ethanol, and then heavy metal salt, namely cobalt (III) acetate, is added, and the temperature is raised to 78 ℃ and the mixture is stirred for reflux reaction for 8 hours.
Further, docetaxel is dissolved by N, N-dimethylformamide, and then heavy metal salt, namely silver carbonate, is added, and reflux reaction is carried out for 3 hours under stirring after the temperature is raised to 80 ℃.
In summary, the invention has the following beneficial effects:
1. the 10-carbonyl docetaxel can be obtained by selectively oxidizing 10-hydroxyl through screening several heavy metal salts, and only 10-carbonyl docetaxel and 7-epi-10-carbonyl docetaxel are used as main products in the reaction, so that the raw materials are completely degraded, the variety of the products is few, the industrial production is facilitated, and the method has important significance for the quality research of docetaxel.
2. The method avoids the simultaneous oxidation of the hydroxyl at the 7-position and the hydroxyl at the 2' -position of the side chain caused by the traditional strong oxidant, and the increase of products occurs to influence the final yield.
Drawings
FIG. 1 is an HPLC chart of 10-carbonyl docetaxel obtained in example 1 of the present invention.
FIG. 2 is an MS spectrum of 10-carbonyl docetaxel obtained in example 1 of the present invention.
FIG. 3 is a 1H NMR spectrum of 10-carbonyl docetaxel obtained in example 1 of the present invention.
FIG. 4 is a 13C NMR spectrum of 10-carbonyl docetaxel obtained in example 1 of the present invention.
FIG. 5 is an HPLC chart of 10-carbonyl docetaxel obtained in comparative example 3 of the present invention
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following more detailed description of the device according to the present invention is given with reference to the accompanying drawings and the detailed description. The advantages and features of the present invention will become more apparent from the following description. It should be understood that the drawings are merely for understanding and reading of the disclosure, and are not intended to limit the scope of the invention, and any structural modifications, proportional changes or size adjustments should fall within the scope of the disclosure without affecting the efficacy and achievement of the invention.
Example 1:
step S1: 10g of docetaxel was dissolved in 200ml of methanol, 2g of copper acetate was added thereto, and the mixture was heated to 65℃and reacted under reflux with stirring for 8 hours. After the reaction is completed, the reaction liquid is filtered by suction, and the filtrate is concentrated to obtain a degradation mixture.
S2: the degradation mixture is dissolved with a small amount of dichloromethane, then is sampled by a wet method, is subjected to column chromatography purification (common 200-300 mesh silica gel), and has a mobile phase of dichloromethane, methanol and acetic acid (volume ratio is 100:1:0.1), wherein the dichloromethane is pre-frozen (below 0 ℃), a product section is collected and concentrated, a small amount of cyclohexane is added for beating, 3.4g of 10-carbonyl docetaxel is obtained after suction filtration and drying, the purity is 97.366%, and a liquid phase diagram is shown in figure 1.
The structure of the 10-carbonyl docetaxel is shown as a formula I:
as shown in FIG. 2, the MS spectrum of 10-carbonyl docetaxel in this example, in which the mass-to-charge ratio m/z=828.3 [ M+Na ] +, was found to have a molecular weight of 805, which was consistent with the target compound.
As shown in FIG. 3, the 1H NMR spectrum of 10-carbonyl docetaxel of this example, 1H NMR (500 MHz, CDCl 3) δ:7.31 to 8.12 (10H, arh), 6.22 (1H, t, j=8.9 hz, H13), 5.81 (1H, d, j=6.8 hz, H35), 5.39 (1H, H30), 5.26 (1H, H2), 4.90 (1H, d, j=8.6 hz, H5), 4.63 (1H, s, H9), 4.31 (1H, d, j=8.5 hz, H20 a), 4.18 (1H, d, j=8.5 hz, H20 b), 4.02 (1H, dd, j=10.5 hz,7.1hz, H7), 3.62 (1H, d, j=6.7 hz, H3), 2.56 (1H, m, H6 a), 2.37 (5H,3H27 overlapped with 2H14), 1.92 (3H, s, H18), 1.85 (1H, m, H73, H9), 1.37 (1H, H37, H9), 4.02 (1H, d, H37, H38), 1.37 (1H, H35, H9, H43, H) and (1/3H);
as shown in FIG. 4, the 13C NMR spectrum of 10-carbonyl docetaxel of the present example, wherein 13C NMR (125 MHz, CDCl 3) was δ:206.116,193.962,172.753,170.167,166.972,155.468,146.996,141.655,138.233,133.874,130.207,128.937,128.896,128.771,128.148,126.754,84.231,80.661,80.344,79.264,76.153,74.66,73.521,72.105,68.705,58.392,56.315,45.35,40.912,35.578,35.403,28.178,26.898 (Solvent Cyclohexane), 23.887,22.493,14.186,8.362.
Example 2:
step S1: 10g of docetaxel was dissolved in 200ml of N, N-dimethylformamide, 2g of copper carbonate was added thereto, and the mixture was heated to 80℃and reacted under reflux with stirring for 3 hours. After the reaction is completed, the reaction liquid is filtered by suction, and the filtrate is concentrated to obtain a degradation mixture.
S2: the degradation mixture is dissolved with a small amount of dichloromethane, then is sampled by a wet method, and is subjected to column chromatography purification, wherein the mobile phase is dichloromethane, methanol and acetic acid (the volume ratio is 100:1:0.1), the dichloromethane is pre-frozen (below 0 ℃), the product is collected and concentrated, a small amount of cyclohexane is added for beating, and the product is dried after suction filtration, so that 2.8g of 10-carbonyl docetaxel with the purity of 96.8% and the total yield of 28% is obtained.
Example 3:
step S1: 10g of docetaxel was dissolved in 200ml of ethanol, 2g of cobalt (III) acetate was added thereto, and the mixture was heated to 78℃and reacted under reflux with stirring for 8 hours. After the reaction is completed, the reaction liquid is filtered by suction, and the filtrate is concentrated to obtain a degradation mixture.
S2: the degradation mixture is dissolved with a small amount of dichloromethane, is sampled by a wet method, is subjected to column chromatography purification (common 200-300 mesh silica gel), and has a mobile phase of dichloromethane, methanol and acetic acid (volume ratio is 100:1:0.1), wherein the dichloromethane is pre-frozen (below 0 ℃), a product section is collected and concentrated, a small amount of cyclohexane is added for beating, 3.8g of 10-carbonyl docetaxel is obtained after suction filtration and drying, the purity is 97.8%, the total yield is 34%, and the total yield is 38%.
Example 4:
step S1: 10g of docetaxel was dissolved in 200ml of N, N-dimethylformamide, 2g of silver carbonate was added thereto, and the mixture was heated to 80℃and reacted under reflux with stirring for 3 hours. After the reaction is completed, the reaction liquid is filtered by suction, and the filtrate is concentrated to obtain a degradation mixture.
S2: the degradation mixture is dissolved with a small amount of dichloromethane, then is sampled by a wet method, and is subjected to column chromatography purification, wherein the mobile phase is dichloromethane, methanol and acetic acid (the volume ratio is 100:1:0.1), the dichloromethane is pre-frozen (below 0 ℃), the product is collected and concentrated, a small amount of cyclohexane is added for beating, and the 10-carbonyl docetaxel with the purity of 95.3% is obtained after suction filtration and drying. The yield is lower, and the main product of the reaction is 7-epi docetaxel.
Comparative example 1 (using hydrogen peroxide as the oxidizing agent):
2g of docetaxel is dissolved in 40ml of methanol, 2ml of 30% hydrogen peroxide is added, and the mixture is heated to 65 ℃ and stirred for reflux reaction for 3 hours. The product obtained after the reaction of the raw materials is mainly a side chain hydrolysis product, and the target 10-carbonyl docetaxel is not observed basically.
Comparative example 2 (using manganese dioxide as the oxidant):
2g of docetaxel was dissolved in 40ml of methanol, 0.5g of manganese dioxide was added thereto, and the mixture was heated to 65℃and reacted under reflux with stirring for 3 hours. The number of the products obtained after the raw materials are reacted is approximately 7, and the 10-carbonyl docetaxel occupies less space and is difficult to separate.
Comparative example 3 (using lead dioxide as the oxidizing agent):
2g of docetaxel was dissolved in 40ml of N, N-dimethylformamide, and 0.5g of lead dioxide was added thereto, and the mixture was heated to 65℃and reacted under reflux with stirring for 3 hours. The products obtained after the raw materials are reacted are approximately 7, and the 10-carbonyl docetaxel accounts for a small proportion.
Comparative example 4 (using cobalt trifluoride oxidant):
2g of docetaxel was dissolved in 40ml of N, N-dimethylformamide, and 0.5g of cobalt trifluoride was added thereto, and the mixture was heated to 65℃and reacted under reflux with stirring for 3 hours. The products obtained after the reaction of the raw materials are complex, more than ten products are available, and 10-carbonyl docetaxel is not found.
Comparative example 5 (purification of liquid phase prepared using conventional means column chromatography complex):
step S1: 10g of docetaxel was dissolved in 200ml of methanol, 2g of copper acetate was added thereto, and the mixture was heated to 65℃and reacted under reflux with stirring for 8 hours. After the reaction is completed, pumping and filtering the reaction liquid, and concentrating the filtrate to obtain a degradation mixture;
s2: the degradation mixture is dissolved with a small amount of dichloromethane and then is sampled by a wet method, column chromatography purification (common 200-300 mesh silica gel) is carried out, the mobile phase is dichloromethane and methanol (volume ratio is 100:1), after 7-epi-10-carbonyl docetaxel is eluted in the column chromatography process, the mixture is all the intersection of 10-carbonyl docetaxel and 7-epi-10-carbonyl docetaxel, and the 10-carbonyl docetaxel with lower purity is obtained by collecting and concentrating.
After the 10-carbonyl docetaxel is dissolved with a small amount of acetonitrile, the solution is subjected to preparation liquid phase purification (the filling material is conventional C-18 reversed-phase filling material), 50% -70% acetonitrile is lifted, the eluent of the first main peak is collected (the elution is completed in 30 min), the solid is separated out after the eluent is concentrated, the 10-carbonyl docetaxel is obtained through suction filtration and drying, the purity is 28.261%, the graph is shown in figure 5, and most of target products are converted into degradation products 7-epi-10-carbonyl docetaxel.
From the comparative example, it can be seen that: 1. conventional oxidizing agents do not allow for a large proportion of docetaxel to be degraded to 10-carbonyl docetaxel; 2. performing silica gel column chromatography at normal temperature, wherein 10-carbonyl docetaxel is subjected to a large amount of further degradation in the eluting process to obtain 7-epi-10-carbonyl docetaxel; 3. the preparation of the liquid phase (C-18 reverse phase filler) liquid does not allow for efficient purification of 10-carbonyl docetaxel even though the overall process has a contact time of 10-carbonyl docetaxel with the filler of less than 30 minutes.
According to the invention, the degradation of 10-carbonyl docetaxel can be effectively inhibited by adding the stabilizer acetic acid into the mobile phase with lower temperature, so that the 10-carbonyl docetaxel with higher purity is finally obtained.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (1)
1. A method for preparing 10-carbonyl docetaxel, which is characterized by comprising the following steps:
s1: dissolving docetaxel with a solvent, adding heavy metal salt, wherein the heavy metal salt is one of copper acetate, copper carbonate, cobalt (III) acetate and silver carbonate, the weight ratio of docetaxel to the heavy metal salt is 3-8, stirring for reaction, the reaction temperature is 65-80 ℃, the reaction time is 3-8 hours, and after the reaction is complete, carrying out suction filtration and concentrating an organic phase to obtain a degradation mixture; in the step S1, the solvent is one or a combination of more of methanol, ethanol and N, N-dimethylformamide;
in the step S1, when docetaxel is dissolved in methanol, adding heavy metal salt, wherein the heavy metal salt is copper acetate, heating to 65 ℃, stirring and carrying out reflux reaction for 8 hours; in the step S1, docetaxel is dissolved by N, N-dimethylformamide, and then heavy metal salt, namely copper carbonate, is added, and the temperature is raised to 80 ℃ and the mixture is stirred for reflux reaction for 3 hours;
in the step S1, when docetaxel is dissolved in ethanol, adding heavy metal salt, wherein the heavy metal salt is cobalt (III) acetate, heating to 78 ℃, stirring and carrying out reflux reaction for 8 hours; in the step S1, docetaxel is dissolved by N, N-dimethylformamide, and then heavy metal salt, namely silver carbonate, is added, and the temperature is raised to 80 ℃ and the mixture is stirred for reflux reaction for 3 hours;
s2: purifying the degradation mixture by column chromatography, wherein the mobile phase is dichloromethane, methanol and acetic acid, collecting the product, concentrating, pulping with cyclohexane, and vacuum filtering and drying to obtain 10-carbonyl docetaxel; in the step S2, methylene dichloride is frozen in advance, and the temperature condition of the frozen methylene dichloride is below 0 ℃; in the step S2, the volume ratio of dichloromethane to methanol to acetic acid is 100:1:0.1;
the reaction route of the preparation process is as follows:
。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1995001969A1 (en) * | 1993-07-08 | 1995-01-19 | Rhone-Poulenc Rorer S.A. | Novel taxoids, preparation thereof and pharmaceutical compositions containing same |
| CN1218475A (en) * | 1996-05-10 | 1999-06-02 | 因迪纳有限公司 | Taxane derivatives preparation thereof and formulation containing them |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1995001969A1 (en) * | 1993-07-08 | 1995-01-19 | Rhone-Poulenc Rorer S.A. | Novel taxoids, preparation thereof and pharmaceutical compositions containing same |
| CN1218475A (en) * | 1996-05-10 | 1999-06-02 | 因迪纳有限公司 | Taxane derivatives preparation thereof and formulation containing them |
Non-Patent Citations (1)
| Title |
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| SYNTHESIS OF 7,9-NITROGEN-SUBSTITUTED PACLITAXEL DERIVATIVES;Appendino G et al.;《Tetrahedron letters》;19961231;第37卷(第43期);7837-7840 * |
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