CN115073328A - Preparation method of cabazitaxel impurity - Google Patents
Preparation method of cabazitaxel impurity Download PDFInfo
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- CN115073328A CN115073328A CN202210839858.1A CN202210839858A CN115073328A CN 115073328 A CN115073328 A CN 115073328A CN 202210839858 A CN202210839858 A CN 202210839858A CN 115073328 A CN115073328 A CN 115073328A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
Abstract
The invention discloses a cabazitaxel impurity K and a preparation method thereof, and the technical scheme comprises the following steps: s1, dissolving Cab-3 in dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, and adding trimethyl oxonium tetrafluoroborate while stirring. After the reaction is completed, adding water to quench the reaction, extracting and separating liquid, concentrating an organic phase until no solvent is evaporated, dissolving and cleaning a concentrate by using methanol, adding purified water to crystallize, performing suction filtration and drying to obtain an impurity K intermediate; s2, dissolving the intermediate K impurity with methanol, adding 1mol/L dilute hydrochloric acid, stirring for reaction, adding purified water after the reaction is completed, separating out a large amount of solid, performing suction filtration, and drying a filter cake; s3, heating and dissolving the filter cake with ethyl acetate, cooling, performing suction filtration, collecting and concentrating filtrate, and performing column chromatography purification and drying to obtain a target product; the method has the advantages of improving the impurity conversion rate by controlling the reaction conditions, along with higher overall yield and simple operation.
Description
Technical Field
The invention relates to the technical field of preparation of anti-cancer drugs, in particular to a preparation method of cabazitaxel impurities.
Background
Cabazitaxel (Cabazitaxel, XRP-6258, trade name Jevtana) is a drug developed by Sanofi-aventis, Senoffel, France, which was approved by the U.S. Food and Drug Administration (FDA) for marketing on 17/6.2010. The medicine is an injection, and is mainly used for treating advanced, hormone refractory, and prostate cancer aggravated during or after docetaxel treatment.
Cabazitaxel has many impurities, and the impurities are very different according to different synthesis processes. The key step of the cabazitaxel process is methylation, and because the active sites of a cabazitaxel mother nucleus are more, impurities with excessive methylation are easily obtained, for example, 1-bit hydroxyl group is excessively methylated to obtain impurities with the following structure (formula 1), and each large impurity is sold by manufacturers and is one of the characteristic impurities of cabazitaxel.
In actual research and development experiments, it is found that, for example, besides the impurities with the structure, cabazitaxel can also undergo a four-membered ring opening reaction, so that an impurity K (formula 2) is obtained, and the impurity K is a very characteristic impurity in certain cabazitaxel preparation processes, so that the preparation of the impurity K is very important for quality control and quality research of cabazitaxel bulk drugs. In the conventional cabazitaxel preparation process, the impurity K is a reaction byproduct, not only the yield is low, but also the separation is very difficult, so a mature preparation method for the impurity K is needed.
Disclosure of Invention
In view of the above-mentioned disadvantages of the prior art, the present invention provides a method for preparing cabazitaxel impurity, which has the advantages of strictly and precisely designing and controlling the methylation reaction conditions, increasing the generation ratio of the target impurity product, and increasing the yield of the target product.
The technical purpose of the invention is realized by the following technical scheme:
step S1, preparing a cabazitaxel impurity K intermediate, which comprises the following steps:
the first process step is as follows: dissolving Cabazitaxel raw material Cab-3 with dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, and adding trimethyloxonium tetrafluoroborate to react under stirring;
the second step is as follows: after the reaction is completed, adding water into the reaction product to quench the reaction, extracting and separating liquid, concentrating an organic phase until no solvent is evaporated, dissolving the concentrate with methanol, adding purified water to crystallize, filtering, and drying to obtain an impurity K intermediate;
step S2, opening the intermediate of the impurity K:
dissolving the intermediate of the impurity K with methanol, adding dilute hydrochloric acid, stirring for reaction, adding purified water after the reaction is completed, separating out a large amount of solids, performing suction filtration, and drying a filter cake to obtain a filter cake containing the impurity K;
step S3, purifying impurity K:
heating and dissolving the crude product of the impurity K by ethyl acetate, cooling, performing suction filtration, collecting filtrate, concentrating, purifying by column chromatography, and drying to obtain a target product;
the reaction route of the preparation process is as follows:
further, in the first step of step S1, the ratio of the amount of 1, 8-bis-dimethylaminonaphthalene to cabazitaxel raw material Cab-3 is 2.3 to 3.4 (W/W).
Further, in the first step of step S1, the ratio of the amount of trimethyloxonium tetrafluoroborate to cabazitaxel raw material Cab-3 is 1.6 to 2.4 (W/W).
Further, in the first step of step S1, the ratio of the amount of dichloromethane used to the amount of the raw material Cab-3 is 18 to 23 (V/W).
Further, in the first step of step S1, the reaction temperature is in the range of 30 to 40 ℃, and the reaction time is in the range of 5 to 10 hours.
Further, in step S2, the concentration of the dilute hydrochloric acid is 1mol/L, and the ratio of the dilute hydrochloric acid to the intermediate of the impurity K is 2.12-2.50 (W/W).
Further, in step S2, the reaction temperature ranges from 0 to 10 ℃ and the reaction time ranges from 2 to 3 hours.
Further, in step S3, the ratio of the amount of ethyl acetate to the filter cake is 8-10 (V/W).
Further, in step S3, the temperature is raised to reflux, the reflux temperature is 73-81 ℃, and the temperature is lowered to 25 +/-3 ℃.
Further, in step S3, the column chromatography purification uses ethyl acetate and n-heptane as mobile phases.
In conclusion, the invention has the following beneficial effects:
1. a methylation reaction is formulated by using cabazitaxel raw materials Cab-3, 1, 8-bis-dimethylamino naphthalene and trimethyloxonium tetrafluoroborate, and an intermediate of a target impurity with the closest molecular structure is obtained by strictly controlling the methylation reaction conditions, so that the generation ratio and the yield of the target product are improved as much as possible.
2. The reaction temperature of methylation is 0-10 ℃, the reaction time is 2-3 h, the reaction conditions are easy to achieve, and the preparation difficulty is reduced.
3. The target product is obtained by carrying out ring-opening reaction on the dilute hydrochloric acid and the intermediate solute, the related reactant is easy to obtain, the ring-opening reaction is direct and accurate, and the related byproducts are few.
4. The main product is separated out by adopting an ethyl acetate crystallization mode, the target impurities exist in the crystallization mother liquor, and the target impurities are quickly enriched, so that the purification in subsequent operation is facilitated.
The conventional common flow combination cannot realize effective separation of the impurity K from other products, so that the impurity K is effectively separated from other byproducts by using ethyl acetate and n-heptane as the mobile phase.
Drawings
Fig. 1 is an HPLC profile of cabazitaxel impurity K obtained in example 1 of the present invention.
Fig. 2 is an MS spectrum of cabazitaxel impurity K obtained in example 1 of the present invention.
FIG. 3 is a 1H NMR spectrum of Cabazitaxel impurity K obtained in example 1 of the present invention.
FIG. 4 is a 13C NMR spectrum of Cabazitaxel impurity K obtained in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the embodiments of the present invention will be described in detail with reference to the accompanying drawings and the following 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.
Example 1:
step S1: dissolving 10g of cabazitaxel raw material Cab-3 in 200ml of dichloromethane, adding 23g of 1, 8-bis-dimethylamino-naphthalene, stirring to dissolve, adding 16g of trimethyloxonium tetrafluoroborate, and reacting for 5 hours in an oil bath at 40 ℃ (reflux). Wherein the dosage ratio of the 1, 8-bis-dimethylamino naphthalene to the cabazitaxel raw material Cab-3 is 2.3 (W/W); the dosage ratio of the dichloromethane to the cabazitaxel raw material Cab-3 is 20 (V/W); the ratio of the amount of trimethyloxonium tetrafluoroborate to the amount of Cab-3, a cabazitaxel starting material, was 1.6 (W/W).
After the reaction is completed, water is added to quench the reaction, liquid is separated by extraction, an organic phase is concentrated until no solvent is evaporated, the concentrate is dissolved and cleared by methanol, purified water is added to crystallize, and 11.3g of impurity K intermediate is obtained by drying after suction filtration.
S2: 11.3g of the impurity K intermediate was dissolved in 100ml of methanol, 24g of 1mol/L diluted hydrochloric acid was added, and the reaction was stirred at 0 ℃ for 3 hours. Wherein the ratio of the dilute hydrochloric acid to the intermediate of impurity K is 2.12 (W/W).
After the reaction is completed, 200ml of purified water is added, a large amount of solid is separated out, the filtration is carried out, and 8.0g of a product containing the impurity K is obtained after a filter cake is dried.
S3: mixing the filter cake with 80ml of ethyl acetate, wherein the ratio of the amount of the ethyl acetate to the filter cake is 10(V/W), heating to reflux, specifically at 77 ℃, dissolving, cooling to room temperature, performing suction filtration, collecting filtrate, concentrating, purifying by column chromatography (ethyl acetate and n-heptane are mobile phases), and performing vacuum drying at 45 ℃ to obtain 0.8g of cabazitaxel impurity K, wherein the purity is 99.074%, the total yield is 8.5%, and the liquid phase diagram is shown in figure 1.
The reaction route of the preparation process is shown as formula 3:
as shown in fig. 2, the MS spectrum of cabazitaxel impurity K in this example, wherein the mass/charge ratio M/z is 890.4[ M + Na ] +, the molecular weight is 867, which is consistent with the target compound.
As shown in fig. 3, which is a 1H NMR spectrum of cabazitaxel impurity K of the present example, 1H NMR (500MHz, CDCl3) δ: 7.29 to 8.07(10H, ArH),5.91(1H, t, H) 13 ),5.57(1H,d,J＝6.6Hz,H 2 ),5.51(1H,d,-NH),5.21(2H,H 5 overlapped with H 3’ ),4.84(1H,s,H 10 ),4.48(1H,s,H 2’ ),3.62(1H,m,H 7 ),3.56(3H,s,10-OMe),3.53(1H,m,H 3 ),3.31(1H,d,J＝9.7Hz,H 20 ),3.27(3H,s,7-OMe),3.19(1H,d,J＝9.8Hz,H 20 ),2.91(1H,m,H 14 ),2.14(4H,3H 27 overlapped with H 6 ),1.88(3H,s,H 18 ),1.75(1H,m,H 6 ),1.40(12H,3H 19 overlapped with-tBu),1.05(3H,s,3H 16 /3H 17 ),0.96(3H,s,3H 16 /3H 17 )。
As shown in fig. 4, 13C NMR spectrum of cabazitaxel impurity K of this example, wherein 13C NMR (125MHz, CDCl3) δ: 204.303,169.822,166.345,155.218,133.175,130.252,129.827,128.652,128.569,127.868,126.811,81.652,78.911,78.405,77.255,77.001,76.746,74.585,74.132,72.895,71.95,70.772,68.981,59.639,58.634,57.541,56.759,45.208,35.392,28.591,28.218,27.402,24.73,21.204,11.45,11.328.
Example 2:
step S1: dissolving 4.4g of cabazitaxel raw material Cab-3 in 100ml of dichloromethane, adding 14.9g of 1, 8-bis-dimethylamino-naphthalene, stirring to dissolve, adding 10.5g of trimethyloxonium tetrafluoroborate, and reacting in an oil bath at 30 ℃ for 10 hours. Wherein the dosage ratio of the 1, 8-bis-dimethylamino naphthalene to the cabazitaxel raw material Cab-3 is 3.4 (W/W); the dosage ratio of the dichloromethane to the cabazitaxel raw material Cab-3 is 22.7 (V/W); the ratio of the amount of trimethyloxonium tetrafluoroborate to the amount of Cab-3, a cabazitaxel starting material, was 2.4 (W/W).
After the reaction is completed, water is added to quench the reaction, liquid is separated by extraction, an organic phase is concentrated until no solvent is evaporated, the concentrate is dissolved and cleared by methanol, purified water is added to crystallize, and 5g of impurity K intermediate is obtained by drying after suction filtration.
S2: dissolving 5g of the impurity K intermediate in 100ml of methanol, adding 12.5g of 1mol/L diluted hydrochloric acid, and stirring and reacting for 2 hours in an ice-water bath (with an internal temperature of 5-10 ℃). Wherein the ratio of the dilute hydrochloric acid to the intermediate of the impurity K is 2.5 (W/W).
After the reaction is completed, 100ml of purified water is added, a large amount of solid is separated out, suction filtration is carried out, and 4.3g of product containing impurity K is obtained after a filter cake is dried.
S3: mixing the filter cake with 43ml of ethyl acetate, wherein the ratio of the amount of the ethyl acetate to the filter cake is 10(V/W), heating to reflux, specifically 75 ℃, dissolving, cooling to room temperature, performing suction filtration, collecting filtrate, concentrating, purifying by column chromatography (ethyl acetate and n-heptane are mobile phases), and performing vacuum drying at 45 ℃ to obtain 0.42g of cabazitaxel impurity K, wherein the purity is 98.4%, and the total yield is 10.2%.
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. A preparation method of cabazitaxel impurities is characterized by comprising the following steps:
step S1, preparing a cabazitaxel impurity K intermediate, which comprises the following steps:
the first process step is as follows: dissolving Cabazitaxel raw material Cab-3 with dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, and adding trimethyloxonium tetrafluoroborate to react under stirring;
the second step is as follows: after the reaction is completed, adding water into the reaction product to quench the reaction, extracting and separating liquid, concentrating an organic phase until no solvent is evaporated, dissolving the concentrate with methanol, adding purified water to crystallize, filtering, and drying to obtain an impurity K intermediate;
step S2, opening the intermediate of the impurity K:
dissolving the intermediate of the impurity K with methanol, adding dilute hydrochloric acid, stirring for reaction, adding purified water after the reaction is completed, separating out a large amount of solids, performing suction filtration, and drying a filter cake to obtain a filter cake containing the impurity K;
step S3, purifying impurity K:
heating and dissolving the crude product of the impurity K by ethyl acetate, cooling, performing suction filtration, collecting filtrate, concentrating, purifying by column chromatography, and drying to obtain a target product;
the reaction route of the preparation process is as follows:
2. the method for preparing cabazitaxel impurity according to claim 1, wherein: in the first step of step S1, the ratio of the amount of 1, 8-bis-dimethylamino naphthalene to the cabazitaxel raw material Cab-3 is 2.3 to 3.4 (W/W).
3. The method for preparing cabazitaxel impurity according to claim 2, wherein: in the first step of step S1, the ratio of the amount of trimethyloxonium tetrafluoroborate to the cabazitaxel raw material Cab-3 is 1.6 to 2.4 (W/W).
4. The method for preparing cabazitaxel impurity according to claim 3, wherein: in the first step of step S1, the ratio of the amount of dichloromethane to the amount of the raw material Cab-3 is 18 to 23 (V/W).
5. The method for preparing cabazitaxel impurity according to claim 4, wherein: in the first step of step S1, the reaction temperature is 30-40 ℃ and the reaction time is 5-10 h.
6. The method for preparing cabazitaxel impurity according to claim 1, wherein: in step S2, the concentration of the dilute hydrochloric acid is 1mol/L, and the ratio of the dilute hydrochloric acid to the intermediate of the impurity K is 2.12-2.50 (W/W).
7. The method for preparing cabazitaxel impurity according to claim 1, wherein: in step S2, the reaction temperature is in the range of 0-10 ℃ and the reaction time is in the range of 2-3 h.
8. The method for preparing cabazitaxel impurity according to claim 7, wherein: in step S3, the ratio of the amount of ethyl acetate to the filter cake is 8-10 (V/W).
9. The method for preparing cabazitaxel impurity according to claim 8, wherein: in step S3, the temperature is raised to the reflux temperature, the reflux temperature range is 73-77 ℃, and the temperature is lowered to 25 +/-3 ℃.
10. The method for preparing cabazitaxel impurity according to claim 9, wherein: in step S3, column chromatography purification uses ethyl acetate and n-heptane as mobile phases.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115521229A (en) * | 2022-10-09 | 2022-12-27 | 无锡紫杉药业股份有限公司 | Preparation method of docetaxel four-membered ring opening product |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887877A (en) * | 2012-11-05 | 2013-01-23 | 江苏红豆杉生物科技股份有限公司 | Method for purifying cabazitaxel |
| CN103217493A (en) * | 2013-03-30 | 2013-07-24 | 神威药业集团有限公司 | Method for measuring cabazitaxel related substances by using HPLC (High Performance Liquid Chromatography) method |
| CN103421036A (en) * | 2012-05-17 | 2013-12-04 | 上海希迈医药科技有限公司 | Cabazitaxel intermediate as well as preparation method and application thereof |
| CN103664837A (en) * | 2013-08-30 | 2014-03-26 | 北京阳光诺和药物研究有限公司 | Preparation method of high-purity cabazitaxel intermediate |
| US20180280295A1 (en) * | 2016-03-14 | 2018-10-04 | Song Lin | Single vial ready to use cabazitaxel formulations with increased stability and methods of preparations |
| CN109580811A (en) * | 2018-12-03 | 2019-04-05 | 河北神威药业有限公司 | A kind of detection method of the Cabazitaxel in relation to substance |
| CN113933441A (en) * | 2021-09-30 | 2022-01-14 | 无锡紫杉药业有限公司 | Method for measuring cabazitaxel and intermediate thereof |
-
2022
- 2022-07-18 CN CN202210839858.1A patent/CN115073328A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421036A (en) * | 2012-05-17 | 2013-12-04 | 上海希迈医药科技有限公司 | Cabazitaxel intermediate as well as preparation method and application thereof |
| CN102887877A (en) * | 2012-11-05 | 2013-01-23 | 江苏红豆杉生物科技股份有限公司 | Method for purifying cabazitaxel |
| CN103217493A (en) * | 2013-03-30 | 2013-07-24 | 神威药业集团有限公司 | Method for measuring cabazitaxel related substances by using HPLC (High Performance Liquid Chromatography) method |
| CN103664837A (en) * | 2013-08-30 | 2014-03-26 | 北京阳光诺和药物研究有限公司 | Preparation method of high-purity cabazitaxel intermediate |
| US20180280295A1 (en) * | 2016-03-14 | 2018-10-04 | Song Lin | Single vial ready to use cabazitaxel formulations with increased stability and methods of preparations |
| CN109580811A (en) * | 2018-12-03 | 2019-04-05 | 河北神威药业有限公司 | A kind of detection method of the Cabazitaxel in relation to substance |
| CN113933441A (en) * | 2021-09-30 | 2022-01-14 | 无锡紫杉药业有限公司 | Method for measuring cabazitaxel and intermediate thereof |
Non-Patent Citations (1)
| Title |
|---|
| 赵迎春等: "HPLC 法测定卡巴他赛的有关物质", 《辽宁化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115521229A (en) * | 2022-10-09 | 2022-12-27 | 无锡紫杉药业股份有限公司 | Preparation method of docetaxel four-membered ring opening product |
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