CN113429369A - Efficient cabazitaxel purification method - Google Patents
Efficient cabazitaxel purification method Download PDFInfo
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- CN113429369A CN113429369A CN202110836263.6A CN202110836263A CN113429369A CN 113429369 A CN113429369 A CN 113429369A CN 202110836263 A CN202110836263 A CN 202110836263A CN 113429369 A CN113429369 A CN 113429369A
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- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 title claims abstract description 154
- 229960001573 cabazitaxel Drugs 0.000 title claims abstract description 154
- 238000000746 purification Methods 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 130
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 84
- 239000012043 crude product Substances 0.000 claims abstract description 59
- 238000010438 heat treatment Methods 0.000 claims abstract description 30
- 238000001816 cooling Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 239000000047 product Substances 0.000 claims abstract description 20
- 238000010992 reflux Methods 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000000967 suction filtration Methods 0.000 claims abstract description 14
- 238000001953 recrystallisation Methods 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000001291 vacuum drying Methods 0.000 claims description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 238000013094 purity test Methods 0.000 description 9
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical group CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229940122255 Microtubule inhibitor Drugs 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 cabazitaxel acetic ether compound Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an efficient cabazitaxel purification method, which adopts the technical scheme that the method comprises the following steps: s1, primary recrystallization: dissolving cabazitaxel raw material by ethyl acetate, heating to reflux, slowly cooling, carrying out suction filtration, and drying to obtain a cabazitaxel crude product I; s2, secondary recrystallization: dissolving the cabazitaxel crude product I by acetonitrile, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding ethyl acetate for dissolving, heating to reflux, slowly cooling, and performing suction filtration to obtain a cabazitaxel crude product II. S3, third recrystallization: and dissolving the cabazitaxel crude product II by acetonitrile, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding ethyl acetate for dissolving, heating to reflux, slowly cooling, filtering, and drying to obtain a cabazitaxel finished product.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to an efficient cabazitaxel purification method.
Background
Cabazitaxel is a drug developed by Sanofi-aventis, seiforph, france, which was approved by the U.S. Food and Drug Administration (FDA) for marketing on 17/6/2010. The drug is a microtubule inhibitor and is suitable for being combined with prednisone to treat patients suffering from metastatic prostate cancer which is difficult to treat by hormone in the conventional polyene-containing paclitaxel treatment scheme. The methods for synthesizing cabazitaxel serving as a raw material medicament are reported more, and basically involve more complicated steps, and people in the industry know that side reactions are more in the cabazitaxel synthesis process, the purity of the primarily obtained cabazitaxel crude product is lower, and a product with high purity cannot be obtained through a simple purification mode, wherein the common mode is column chromatography purification.
At present, chinese patent publication No. CN104039771A discloses a method for purifying cabazitaxel using ethyl acetate/n-hexane as a mobile phase. But has problems: the highest purity is 99.79%, the lowest purity is 91.3%, most of the purities are concentrated around 97%, the purity distribution is unstable, and the content of the cabazitaxel obtained by the reaction is not high.
At present, there is a chinese patent with publication number CN110078686A, in which the content of crude cabazitaxel obtained is 74.1%, and higher purity can be achieved only by column chromatography purification and recrystallization. But has problems: the column chromatography purification needs more equipment support, such as supporting facilities of a chromatographic column, a concentration tank and the like, the equipment cost is high, more solvents are consumed, and the comprehensive production cost is high.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an efficient cabazitaxel purification method, which has the advantages of greatly improving the cabazitaxel purification effect, simplifying the purification operation and reducing the comprehensive production cost.
The technical purpose of the invention is realized by the following technical scheme:
an efficient cabazitaxel purification method is characterized by comprising the following steps:
s1, primary recrystallization: dissolving cabazitaxel raw material by ethyl acetate, heating to reflux, slowly cooling, carrying out suction filtration, and drying to obtain a cabazitaxel crude product I;
s2, secondary recrystallization: dissolving the cabazitaxel crude product I by acetonitrile, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding ethyl acetate for dissolving, heating to reflux, slowly cooling, and performing suction filtration to obtain a cabazitaxel crude product II;
s3, third recrystallization: and dissolving the cabazitaxel crude product II by acetonitrile, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding ethyl acetate for dissolving, heating to reflux, slowly cooling, filtering, and drying to obtain a cabazitaxel finished product.
Further, in step S1, the purity of cabazitaxel raw material is in the range of 34 to 70%.
Further, in step S1, the amount of ethyl acetate is 6 to 8 times (V/W) the amount of cabazitaxel raw material.
Further, in step S1, the final temperature range of the cooling is 0 to 20 ℃.
Further, in step S2, the amount of acetonitrile is 30-40 times V/W of the cabazitaxel crude product i, and the amount of ethyl acetate is 6-8 times V/W of the cabazitaxel crude product i.
Further, in step S2, the final temperature range of the cooling is 0 to 20 ℃.
Further, in step S3, the amount of acetonitrile is 30-40 times V/W of the cabazitaxel crude product ii, and the amount of ethyl acetate is 5-7 times V/W of the cabazitaxel crude product ii.
Further, in step S3, the final temperature of the cooling is 0-20 ℃.
Further, in step S1, the drying condition is vacuum drying at 50 ℃.
Further, in step S3, the drying condition is vacuum drying at 50 ℃.
In conclusion, the invention has the following beneficial effects:
1. the traditional crystallization mode realizes purification through different solubilities of different substances, and the two common methods are a positive and negative solvent method and a high-temperature dissolution cooling crystallization method, so that in the traditional crystallization system, low-content cabazitaxel is difficult to form crystals to precipitate, but oily substances are easy to form, namely, a large amount of impurities and cabazitaxel are simultaneously precipitated to form the oily substances.
The crystallization principle of the invention is different from the conventional method, the invention utilizes the characteristic that cabazitaxel forms ethyl acetate solvate specifically and other impurities can not form, and utilizes the characteristic that cabazitaxel has functional group-COOR which forms ester solvate, particularly the solvate has low solubility in ethyl acetate, thus cabazitaxel can be separated out in solvent, and a large amount of impurities are still dissolved in ethyl acetate, thereby achieving the purification purpose and solving the problem that the conventional recrystallization method can not realize recrystallization of low-purity cabazitaxel basically.
2. In the subsequent crystallization step, acetonitrile and other organic solvents are used, so that the state of the cabazitaxel acetic ether compound is converted into a free state, the cabazitaxel is matched with ethyl acetate to form an ester again, and the ester is crystallized and purified again, so that the purity of the cabazitaxel is greatly improved.
3. The second crystallization uses crude cabazitaxel II which is not dried, the drying process is reduced, and the second crystallization mode is basically repeated to ensure that all impurities are effectively reduced to be below 0.1 percent.
4. In the prior art, about 98% of cabazitaxel is crystallized, and the application can crystallize 34-70% of the purity raw material, so that the application range is greatly expanded; the purity of the cabazitaxel finished product is about 99.5%, the purification method is simple, complex purification equipment is not needed, and the cabazitaxel purification cost is greatly reduced.
Drawings
Fig. 1 is an HPLC profile of cabazitaxel starting material used in example 1.
FIG. 2 is an HPLC chromatogram of crude Cabazitaxel I obtained in example 1.
FIG. 3 is an HPLC chromatogram of crude Cabazitaxel II obtained in example 1.
FIG. 4 is an HPLC chromatogram of the final cabazitaxel product obtained in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the present invention is provided 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 is to be noted that the drawings are in a very simplified form and are all used in a non-precise scale for the purpose of facilitating and distinctly aiding in the description of the embodiments of the present invention.
It should be understood that the structures, ratios, sizes, and the like shown in the drawings and described in the specification are only used for matching with the disclosure of the specification, so as to be understood and read by those skilled in the art, and are not used to limit the implementation conditions of the present invention, so that the present invention has no technical significance, and any structural modification, ratio relationship change or size adjustment should still fall within the scope of the present invention without affecting the efficacy and the achievable purpose of the present invention.
Example 1:
a high-efficiency cabazitaxel purification method comprises the following steps:
s1, first crystallization: 96g of cabazitaxel starting material (purity 64.099%, HPLC pattern shown in FIG. 1) was dissolved in 580ml of ethyl acetate, which was 6.04 times the amount of cabazitaxel starting material (V/W). Heating to reflux, slowly cooling to room temperature of 20 deg.C, vacuum filtering, and vacuum drying at 50 deg.C to obtain 48g of crude Cabazitaxel I product with purity of 96.419%, and HPLC chromatogram shown in FIG. 2.
S2, second crystallization: dissolving the cabazitaxel crude product I by 1.5L of acetonitrile, wherein the using amount of the acetonitrile is 31.25 times of that of the cabazitaxel crude product I, heating to be clear, concentrating under reduced pressure until no solvent is evaporated out, adding 288ml of ethyl acetate for dissolving, wherein the ethyl acetate is 6 times (V/W) of that of the cabazitaxel crude product I, heating to reflux, slowly cooling to 0 ℃, and performing suction filtration to obtain 43.9g of cabazitaxel crude product II, wherein the purity is 99.418%, and an HPLC (high performance liquid chromatography) spectrum is shown in figure 3.
S3, third crystallization: dissolving the cabazitaxel crude product II by 1.5L of acetonitrile, wherein the using amount of the acetonitrile is 34.2 times (V/W) of that of the cabazitaxel crude product II, heating to dissolve the cabazitaxel crude product II, concentrating under reduced pressure until no solvent is evaporated out, adding 240ml of ethyl acetate for dissolving, wherein the using amount of the ethyl acetate is 5.47 times (V/W) of that of the cabazitaxel crude product II, heating to reflux, slowly cooling to 0 ℃, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 40.6g of cabazitaxel finished products, wherein the purity is 99.768%, and an HPLC (high performance liquid chromatography) spectrum is shown in figure 4.
In the crystallization process, workers record the appearances of the cabazitaxel crude product I and the cabazitaxel crude product II in a related manner.
The purity test results of the above materials are shown in Table 1 below.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 64.099％ | 96.419％ | 99.418％ | 99.768％ |
| Impurity D | 5.883％ | 2.034％ | 0.509％ | 0.093％ |
| Other maximum single hetero | 4.728％ | 0.252％ | 0.073％ | 0.073％ |
TABLE 1
Example 2:
a high-efficiency cabazitaxel purification method comprises the following steps:
s1, first crystallization: dissolving 100g of cabazitaxel raw material (with the purity of 54.487%) in 800ml of ethyl acetate, wherein the dosage of the ethyl acetate is 8 times (V/W) of the dosage of the cabazitaxel raw material, heating to reflux, slowly cooling to 0 ℃, carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain 48g of cabazitaxel crude product I.
S2, second crystallization: dissolving the crude cabazitaxel I with 1.7L of acetonitrile, wherein the using amount of the acetonitrile is 35.41 times of that of the crude cabazitaxel I, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding 380ml of ethyl acetate for dissolving, wherein the ethyl acetate is 6.91 times (V/W) of that of the crude cabazitaxel I, heating to reflux, slowly cooling to 15 ℃, and performing suction filtration to obtain 43.3g of crude cabazitaxel II.
S3, third crystallization: dissolving the cabazitaxel crude product II by 1.7L of acetonitrile, wherein the consumption of the acetonitrile is 39.3 times (V/W) of that of the cabazitaxel crude product II, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding 303ml of ethyl acetate for dissolving, wherein the consumption of the ethyl acetate is 7 times (V/W) of that of the cabazitaxel crude product II, heating to reflux, slowly cooling to room temperature of 20 ℃, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 39.8g of cabazitaxel finished product with the purity of 99.847%.
The purity test results of the above materials are shown in Table 2 below.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 54.487％ | 96.648％ | 99.40％ | 99.847％ |
| Impurity D | 1.622％ | 0.513％ | 0.133％ | 0.039％ |
| Other maximum single hetero | 18.178％ | 1.527％ | 0.180％ | 0.074％ |
TABLE 2
Example 3:
a high-efficiency cabazitaxel purification method comprises the following steps:
s1, first crystallization: dissolving 20g of cabazitaxel raw material (with the purity of 34.599%) in 140ml of ethyl acetate, wherein the dosage of the ethyl acetate is 7 times (V/W) of the dosage of the cabazitaxel raw material, heating to reflux, slowly cooling to the room temperature of 15 ℃, carrying out suction filtration, and carrying out vacuum drying at the temperature of 50 ℃ to obtain 10.3g of cabazitaxel crude product I.
S2, second crystallization: dissolving the cabazitaxel crude product I by 410ml of acetonitrile, wherein the consumption of the acetonitrile is 39.8 times of that of the cabazitaxel crude product I, heating to be clear, concentrating under reduced pressure until no solvent is evaporated out, adding 72ml of ethyl acetate for dissolving, wherein the ethyl acetate is 6.99 times (V/W) of that of the cabazitaxel crude product I, heating to reflux, slowly cooling to 20 ℃, and performing suction filtration to obtain 9.5g of cabazitaxel crude product II.
S3, third crystallization: dissolving the cabazitaxel crude product II by 410ml of acetonitrile, wherein the consumption of the acetonitrile is 43.2 times (V/W) of that of the cabazitaxel crude product II, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding 60ml of ethyl acetate for dissolving, wherein the consumption of the ethyl acetate is 6.32 times (V/W) of that of the cabazitaxel crude product II, heating to reflux, slowly cooling to 0 ℃, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 8.0g of cabazitaxel finished product with the purity of 99.736%.
The purity test results of the above materials are shown in Table 3 below.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 34.599％ | 95.944％ | 99.067％ | 99.736％ |
| Impurity D | 11.328％ | 2.373％ | 0.693％ | 0.058％ |
| Other maximum single hetero | 11.726％ | 0.339％ | 0.171％ | 0.091％ |
TABLE 3
Comparative example 1:
the point different from example 1 is that ethyl acetate may be replaced with methyl acetate in step S1.
The purity test results of the above materials are shown in Table 4 below.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 64.099％ | / | / | / |
| Impurity D | 5.883％ | / | / | / |
| Other maximum single hetero | 4.728％ | / | / | / |
TABLE 4
Purification using methyl acetate in step S1 resulted in an oil that could not be passed on to subsequent purification steps.
Comparative example 2:
the point different from example 1 is that ethyl acetate is replaced with butyl acetate in step S1.
The purity test results of the above materials are shown in Table 5.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| CabazitaxelPurity of | 64.099％ | / | / | / |
| Impurity D | 5.883％ | / | / | / |
| Other maximum single hetero | 4.728％ | / | / | / |
TABLE 5
Purification using butyl acetate in step S1 gave an oil which could not be passed on to the subsequent purification step.
Comparative example 3:
the point different from example 1 is that acetonitrile was substituted for methanol in steps S2 and S3.
The purity test results of the above materials are shown in Table 6 below.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 64.099％ | 90.056％ | 95.188％ | 95.629％ |
| Impurity D | 5.883％ | 3.734％ | 2.321％ | 2.183％ |
| Other maximum single hetero | 4.728％ | 1.951％ | 0.262％ | 0.154％ |
TABLE 6
Comparative example 4:
the point different from example 1 is that acetonitrile was substituted for ethanol in steps S2 and S3.
The purity test results of the above materials are shown in Table 7.
TABLE 7
Comparative example 5:
the point different from example 1 is that acetonitrile is substituted for tetrahydrofuran in steps S2 and S3.
The purity test results of the above materials are shown in Table 8 below.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 64.099％ | 96.337％ | 97.417％ | 97.417％ |
| Impurity D | 5.883％ | 1.993％ | 1.471％ | 1.053％ |
| Other maximum single hetero | 4.728％ | 0.568％ | 0.215％ | 0.200％ |
TABLE 8
Comparative example 6:
the point different from example 1 is that acetonitrile was substituted for dichloromethane in steps S2 and S3.
The purity test results of the above materials are shown in Table 9.
| Detecting items | Cabazitaxel raw material | Cabazitaxel crude product I | Cabazitaxel crude product II | Cabazitaxel finished product |
| Cabazitaxel purity | 64.099％ | 96.329％ | 97.341％ | 97.751％ |
| Impurity D | 5.883％ | 2.034％ | 1.576％ | 0.849％ |
| Other maximum single hetero | 4.728％ | 1.232％ | 0.339％ | 0.220％ |
TABLE 9
Conclusion analysis:
1. the purity of the cabazitaxel finished product is about 99.5 percent, the method is simple, complex purification equipment is not needed, and the cabazitaxel purification cost is greatly reduced.
2. In examples 1-3, both crude cabazitaxel i and crude cabazitaxel ii were non-oily, indicating that a large amount of impurities did not precipitate with cabazitaxel from the side.
3. Comparing comparative examples 1 and 2 with examples 1-3, the first purification step using other similar materials to ethyl acetate instead of ethyl acetate all yielded oils that were not amenable to subsequent purification work, further indicating that ethyl acetate had good purification performance and no substitutability.
3. Comparing the comparative examples 3-5 with the examples 1-3, and performing the second-step purification by using other substances similar to acetonitrile instead of ethyl acetate, wherein the purity of the final product of the comparative example is about 97%, and is about two% different from that of the final products of the examples 1-3, further showing that the method greatly improves the purification effect of cabazitaxel.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. An efficient cabazitaxel purification method is characterized by comprising the following steps:
s1, primary recrystallization: dissolving cabazitaxel raw material by ethyl acetate, heating to reflux, slowly cooling, carrying out suction filtration, and drying to obtain a cabazitaxel crude product I;
s2, secondary recrystallization: dissolving the cabazitaxel crude product I by acetonitrile, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding ethyl acetate for dissolving, heating to reflux, slowly cooling, and performing suction filtration to obtain a cabazitaxel crude product II;
s3, third recrystallization: and dissolving the cabazitaxel crude product II by acetonitrile, heating to clear, concentrating under reduced pressure until no solvent is evaporated out, adding ethyl acetate for dissolving, heating to reflux, slowly cooling, filtering, and drying to obtain a cabazitaxel finished product.
2. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S1, the purity of cabazitaxel raw material is in the range of 34-70%.
3. The method for purifying cabazitaxel with high efficiency according to claim 2, wherein: in step S1, the amount of ethyl acetate is 6-8 times V/W of the amount of cabazitaxel raw material.
4. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S1, the final temperature range of the temperature reduction is 0-20 ℃.
5. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S2, the amount of acetonitrile is 30-40 times V/W of the cabazitaxel crude product I, and the amount of ethyl acetate is 6-8 times V/W of the cabazitaxel crude product I.
6. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S2, the final temperature range of the temperature reduction is 0-20 ℃.
7. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S3, the amount of acetonitrile is 30-40 times V/W of the cabazitaxel crude product II, and the amount of ethyl acetate is 5-7 times V/W of the cabazitaxel crude product II.
8. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S3, the final temperature of the cooling is 0-20 ℃.
9. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S1, the drying condition is vacuum drying at 50 ℃.
10. The method for purifying cabazitaxel with high efficiency according to claim 1, wherein: in step S3, the drying condition is vacuum drying at 50 ℃.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746258A (en) * | 2012-07-25 | 2012-10-24 | 重庆泰濠制药有限公司 | Crystal forms of cabazitaxel and preparation method thereof |
| CN102898406A (en) * | 2012-11-02 | 2013-01-30 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| EP2743264A1 (en) * | 2012-12-13 | 2014-06-18 | INDENA S.p.A. | New crystalline form of cabazitaxel, process for the preparation and pharmaceutical compositions thereof |
| WO2014128728A2 (en) * | 2013-02-25 | 2014-08-28 | Laurus Labs Private Limited | Solid forms of cabazitaxel and processes for preparation thereof |
| US20140343133A1 (en) * | 2011-12-13 | 2014-11-20 | Aventis Pharma Sa | Crystalline form of cabazitaxel and process for preparing the same |
| CN104650011A (en) * | 2013-11-18 | 2015-05-27 | 苏州雷纳药物研发有限公司 | Method of purifying taxane-type derivative |
| CN105085443A (en) * | 2015-09-21 | 2015-11-25 | 四川农业大学 | Method for using Taxus media branches and leaves as raw material to prepare high-purity 10-deacetyl baccatin III |
| CN108409691A (en) * | 2018-02-12 | 2018-08-17 | 江苏红豆杉药业有限公司 | A kind of Cabazitaxel crystal form HDC-1 and preparation method thereof |
| CN110078686A (en) * | 2019-04-28 | 2019-08-02 | 云南汉德生物技术有限公司 | The method of 10- deacetylate Bakating III synthesis Cabazitaxel |
| CN110305080A (en) * | 2019-08-12 | 2019-10-08 | 新乡双鹭药业有限公司 | A kind of purification process of docetaxel |
-
2021
- 2021-07-23 CN CN202110836263.6A patent/CN113429369B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140343133A1 (en) * | 2011-12-13 | 2014-11-20 | Aventis Pharma Sa | Crystalline form of cabazitaxel and process for preparing the same |
| CN102746258A (en) * | 2012-07-25 | 2012-10-24 | 重庆泰濠制药有限公司 | Crystal forms of cabazitaxel and preparation method thereof |
| CN102898406A (en) * | 2012-11-02 | 2013-01-30 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| EP2743264A1 (en) * | 2012-12-13 | 2014-06-18 | INDENA S.p.A. | New crystalline form of cabazitaxel, process for the preparation and pharmaceutical compositions thereof |
| WO2014128728A2 (en) * | 2013-02-25 | 2014-08-28 | Laurus Labs Private Limited | Solid forms of cabazitaxel and processes for preparation thereof |
| CN104650011A (en) * | 2013-11-18 | 2015-05-27 | 苏州雷纳药物研发有限公司 | Method of purifying taxane-type derivative |
| CN105085443A (en) * | 2015-09-21 | 2015-11-25 | 四川农业大学 | Method for using Taxus media branches and leaves as raw material to prepare high-purity 10-deacetyl baccatin III |
| CN108409691A (en) * | 2018-02-12 | 2018-08-17 | 江苏红豆杉药业有限公司 | A kind of Cabazitaxel crystal form HDC-1 and preparation method thereof |
| CN110078686A (en) * | 2019-04-28 | 2019-08-02 | 云南汉德生物技术有限公司 | The method of 10- deacetylate Bakating III synthesis Cabazitaxel |
| CN110305080A (en) * | 2019-08-12 | 2019-10-08 | 新乡双鹭药业有限公司 | A kind of purification process of docetaxel |
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