CN115215820A - Preparation method of cabazitaxel impurity F - Google Patents
Preparation method of cabazitaxel impurity F Download PDFInfo
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- CN115215820A CN115215820A CN202210985131.4A CN202210985131A CN115215820A CN 115215820 A CN115215820 A CN 115215820A CN 202210985131 A CN202210985131 A CN 202210985131A CN 115215820 A CN115215820 A CN 115215820A
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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Abstract
The invention discloses a preparation method of cabazitaxel impurity F, which adopts the technical scheme that the preparation method comprises the following steps: step S1, tabulation: dissolving raw material Cab-3 with N, N-dimethylformamide, adding silver carbonate, stirring for reaction, performing suction filtration, extracting, separating liquid, concentrating an organic phase, and performing column chromatography purification to obtain impurity F intermediate-1; step S2, methylation: dissolving the impurity F intermediate-1 by using dichloromethane, adding 1,8-bis-dimethylamino-naphthalene and trimethyloxonium tetrafluoroborate, stirring for reaction, carrying out suction filtration on a reaction solution, concentrating a filtrate, adding methanol clear solution, dropwise adding hydrochloric acid, adjusting to be neutral, adding purified water, precipitating a solid, and drying after suction filtration to obtain an impurity F intermediate-2; step S3, opening the ring: dissolving the intermediate-2 of the impurity F in methanol, adding p-toluenesulfonic acid, stirring for reaction, adding purified water, separating out a solid, filtering the solid, purifying a filter cake by column chromatography, and drying to obtain the cabazitaxel impurity F.
Description
Technical Field
The invention relates to the technical field of preparation of anti-cancer drugs, in particular to a preparation method of a cabazitaxel impurity F.
Background
Cabazitaxel (Cabazitaxel, XRP-6258, trade name Jevtana) is a drug developed by Sainuffy-Anvats, france, which was approved for marketing by the U.S. Food and Drug Administration (FDA) on 17 th month 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. Cabazitaxel is generally synthesized by taking 10-DAB as a starting material, the 7-position and the 10-position of the 10-DAB are two hydroxyl groups, and in the process, if chiral inversion occurs at the 7-position and methylation is only carried out at the 10-position, a cabazitaxel characteristic impurity F (formula 1) can be obtained, wherein the conversion process is shown as a formula 2. The cabazitaxel impurity F is generated under harsh conditions, and materials with high content are difficult to obtain through a normal process approach.
However, the impurity F is a very characteristic impurity in the cabazitaxel process, so that the directional preparation of the impurity F is very important for quality control and quality research of cabazitaxel bulk drug, and a large-scale industrial preparation method of the impurity is not reported in related documents.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention aims to provide a method for preparing cabazitaxel impurity F, which has the advantages of simple and direct reaction route design, low reaction requirement conditions, reduction of related side reactions, corresponding reduction of reaction byproducts, substantial improvement of the conversion rate of target products, and high overall reaction yield.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of cabazitaxel impurity F is characterized by comprising the following steps:
step S1, tabulation: dissolving raw material Cab-3 with N, N-dimethylformamide, adding silver carbonate, heating, stirring for reaction, filtering the reaction solution after the stirring reaction is completely finished, adding water and ethyl acetate into the reaction solution for extraction and liquid separation, concentrating an organic phase until no solvent is evaporated, and purifying by column chromatography to obtain impurity F intermediate-1;
step S2, methylation: dissolving the impurity F intermediate-1 by using dichloromethane, adding 1,8-bis-dimethylamino-naphthalene and trimethyloxonium tetrafluoroborate, stirring for reaction, after the reaction is completed, carrying out suction filtration on a reaction solution, concentrating a filtrate to dryness, adding methanol clear solution into a concentrate, dropwise adding hydrochloric acid, adjusting to neutrality, adding purified water, precipitating a solid, and drying after suction filtration to obtain an impurity F intermediate-2;
step S3, opening the ring: dissolving the intermediate-2 of the impurity F by using methanol, adding p-toluenesulfonic acid, stirring for reaction, adding purified water into a reaction solution, separating out a solid, filtering the solid, and purifying and drying a filter cake by using column chromatography to obtain a cabazitaxel impurity F;
the reaction route of the preparation process is as follows:
further, in step S1, the ratio of N, N-dimethylformamide to the starting material Cab-3 is 5 to 10 (V/W).
Further, in step S1, the ratio of silver carbonate to the raw material Cab-3 is 0.2 to 0.3 (W/W).
Further, in step S1, the reaction temperature of the stirring reaction is controlled to be 50-60 ℃, and the reaction time is controlled to be 13-29 h.
Further, in step S2, the ratio of 1,8-bis-dimethylaminonaphthalene to the impurity F intermediate-1 is 0.7 to 1.6 (W/W).
Further, in step S2, the ratio of trimethyloxonium tetrafluoroborate to the impurity F intermediate-1 is 0.4 to 0.5 (W/W).
Further, in the step S2, the stirring reaction temperature ranges from 10 ℃ to 20 ℃, and the reaction time ranges from 5 h to 8h.
Further, in step S3, the ratio of methanol to the impurity F, intermediate-2, is 20 to 25 (V/W).
Further, in step S3, the ratio of p-toluenesulfonic acid to the impurity F, intermediate-2, is 0.4 to 0.5 (W/W).
Further, in step S3, the stirring reaction temperature is 15-25 ℃, and the reaction time is 1-3 h.
In conclusion, the invention has the following beneficial effects:
1. the method adopts a reaction route of methylation-ring opening, the reaction route is direct and simple, side reactions are few in the intermediate reaction process, reaction byproducts are further reduced, and the yield of the target product is improved.
2. The method comprises the steps of specifically externalizing a raw material Cab-3 by matching N, N-dimethylformamide and silver carbonate with specific reaction conditions, namely, carrying out chiral inversion, improving the conversion rate of an impurity F intermediate-1, carrying out extraction and liquid separation by using the impurity F intermediate-1 and other products with different solubilities in ethyl acetate, and purifying to obtain the high-purity impurity F intermediate-1 to the maximum extent.
3. By selecting 1,8-bis (dimethylamino) naphthalene and trimethyloxonium tetrafluoroborate for reaction and strictly controlling the proportion of substances participating in the reaction and related reaction conditions, the intermediate-1 of the impurity F is accurately methylated.
4. The ring-opening reaction is carried out by methanol and toluenesulfonic acid, and the proportion of substances and reaction conditions are also strictly limited to ensure that the ring-opening reaction is carried out in the forward direction.
5. The related substances participating in the reaction have good stability in a natural state, the related range conditions are all carried out at room temperature or low temperature, and the preparation conditions are easy to achieve.
Drawings
Fig. 1 is a schematic view of the steps of the preparation method of cabazitaxel.
Fig. 2 is an HPLC profile of cabazitaxel impurity K obtained in example 1 of the present invention.
Fig. 3 is an MS spectrum of cabazitaxel impurity K obtained in example 1 of the present invention.
FIG. 4 is a 1H NMR spectrum of Cabazitaxel impurity K obtained in example 1 of the present invention.
FIG. 5 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.
Example 1
A preparation method of cabazitaxel impurity F, as shown in fig. 1, comprises the following steps:
step S1: 5.0g of Cab-3 as a raw material is weighed into a reaction bottle, 40mL of DMF (N, N-dimethylformamide clearsolution) is added, the solution is stirred and clearsolution is added, 1.48g of silver carbonate is added, the temperature is raised to 50 ℃, and the reaction is carried out for 29h. And (3) carrying out suction filtration on the reaction solution, adding 500mL of purified water and 200mL of ethyl acetate for extraction, washing an organic phase with a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography purification to obtain 2.3g of an impurity F intermediate-1.
Step S2: 2.3g of the impurity F, intermediate-1, was charged into a reaction flask, 46mL of methylene chloride was added, and stirred to dissolve it, 3.7g of 1, 8-bisdimethylaminonaphthalene was added, 2.2g of trimethyloxonium tetrafluoroborate was added, and the mixture was stirred at room temperature (19 ℃ C.) and reacted for 6 hours. And (3) carrying out suction filtration on the reaction solution, concentrating the filtrate to dryness, adding methanol, dropwise adding 6mL of 10% hydrochloric acid, adjusting to be neutral, adding 200mL of purified water, precipitating a large amount of solid, and drying after suction filtration to obtain 1.65g of impurity F intermediate-2.
And step S3: 1.59g of intermediate-2 as impurity F was weighed out into a reaction flask, dissolved in 40mL of methanol, added with 0.76g of p-toluenesulfonic acid and stirred at room temperature for 1 hour. 150mL of purified water is added into the reaction solution, a large amount of solid is separated out, 320mg of cabazitaxel impurity F is obtained by one-time normal phase column chromatography purification and one-time preparation liquid phase purification of the filter cake, the purity is 99.9%, the liquid phase spectrum is shown in figure 2, and the yield is 7.2%.
The reaction route of the preparation process is shown as formula 3:
as shown in FIG. 3, the MS spectrum of cabazitaxel impurity F in this example, wherein the mass to charge ratio m/z =844.35, [ M ] +Na ] +, can be inferred to be 821, consistent with the target compound.
As shown in FIG. 4, which is a 1H NMR spectrum of Cabazitaxel impurity F in the example, 1 H NMR(500MHz,CDCl 3 )δ:7.30～8.14(10H,ArH),6.29(1H,m,H 13 ),5.74(1H,d,J＝7.3Hz,-NH),5.37(1H,d,J＝9.2Hz,H 5 ),5.29(1H,H 2 ),5.22(1H,s,H 10 ),4.90(1H,m,H 7 ),4.63(2H,H 30 overlapped with-OH),4.37(2H,s,H 20 ),3.91(1H,d,J＝7.2Hz,H 31 ),3.70(1H,d,J＝6.8Hz,H 3 ),3.44(3H,s,-OMe),2.47(3H,s,H 27 ),2.31(4H,m,2H 14 overlapped with 2H 6 ),1.82(3H,s,H 18 ),1.66(3H,s,H 19 ),1.32(9H,s,t-Bu),1.21(3H,s,H 16 /H 17 ),1.16(3H,s,H 16 /H 17 )。
as shown in fig. 5, the 13C NMR spectrum of cabazitaxel impurity F of this example, wherein, 13 C NMR(125MHz,CDCl3)δ:209.939,172.874,172.197,167.194,155.35,138.494,138.237,134.78,133.613,130.205,129.405,128.882,128.735,128.055,126.659,85.584,82.722,82.378,80.223,79.212,77.744,75.861,75.497,73.728,72.406,57.706,56.742,56.115,42.703,40.415,35.892,35.459,28.162,25.857,22.581,20.746,16.496,14.423。
example 2:
step S1: weighing 10.0g of raw material Cab-3 into a reaction bottle, adding 50mL of DMF, stirring to dissolve, adding 2g of silver carbonate, heating to 60 ℃, and reacting for 13h. And (3) carrying out suction filtration on the reaction solution, adding 1000mL of purified water and 400mL of ethyl acetate for extraction, washing an organic phase with a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and carrying out column chromatography purification to obtain 5.8g of impurity F intermediate-1.
Step S2: 5.8g of the impurity F intermediate-1 is added into a reaction bottle, 60mL of dichloromethane is added, stirring and dissolving are carried out, 4g of 1, 8-bis-dimethylamino-naphthalene is added, 2.9g of trimethyloxonium tetrafluoroborate is added, and stirring and reaction are carried out for 8 hours at 10 ℃. And (3) carrying out suction filtration on the reaction solution, concentrating the filtrate to be dry, adding methanol, dropwise adding hydrochloric acid, adjusting to be neutral, adding 400mL of purified water, precipitating a large amount of solid, carrying out suction filtration, and drying to obtain 3.9g of impurity F intermediate-2.
And step S3: 3.9g of intermediate-2 as impurity F was weighed into a reaction flask, dissolved in 40mL of methanol, added with 1.56g of p-toluenesulfonic acid, and stirred at room temperature (about 20 ℃) for 3 hours. 300mL of purified water is added into the reaction solution, a large amount of solid is separated out, and 1.45g of cabazitaxel impurity F is obtained by one-time normal phase column chromatography purification and one-time preparation liquid phase purification of the filter cake, the purity is 98.2%, and the yield is 16.3%.
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 impurity F is characterized by comprising the following steps:
step S1, tabulation: dissolving raw material Cab-3 with N, N-dimethylformamide, adding silver carbonate, heating, stirring for reaction, filtering the reaction solution after the stirring reaction is completely finished, adding water and ethyl acetate into the reaction solution for extraction and liquid separation, concentrating an organic phase until no solvent is evaporated, and purifying by column chromatography to obtain impurity F intermediate-1;
step S2, methylation: dissolving the impurity F intermediate-1 by using dichloromethane, adding 1,8-bis-dimethylamino-naphthalene and trimethyloxonium tetrafluoroborate, stirring for reaction, after the reaction is completed, carrying out suction filtration on a reaction solution, concentrating a filtrate to dryness, adding methanol clear solution into a concentrate, dropwise adding hydrochloric acid, adjusting to neutrality, adding purified water, precipitating a solid, and drying after suction filtration to obtain an impurity F intermediate-2;
step S3, opening the loop: dissolving the intermediate-2 of the impurity F in methanol, adding p-toluenesulfonic acid, stirring for reaction, adding purified water into a reaction solution, separating out a solid, filtering the solid, and purifying and drying a filter cake by column chromatography to obtain a cabazitaxel impurity F;
the reaction route of the preparation process is as follows:
2. the method for preparing cabazitaxel impurity F according to claim 1, wherein: in step S1, the ratio of N, N-dimethylformamide to the starting material Cab-3 is 5 to 10 (V/W).
3. The method for preparing cabazitaxel impurity F according to claim 2, wherein: in step S1, the ratio of silver carbonate to the raw material Cab-3 is 0.2 to 0.3 (W/W).
4. The method for preparing cabazitaxel impurity F according to claim 3, characterized in that: in the step S1, the reaction temperature of the stirring reaction is controlled to be 50-60 ℃, and the reaction time is controlled to be 13-29 h.
5. The method for preparing cabazitaxel impurity F according to claim 1, wherein: in step S2, the ratio of 1,8-bis-dimethylaminonaphthalene to the impurity F intermediate-1 is 0.7 to 1.6 (W/W).
6. The method for preparing cabazitaxel impurity F according to claim 5, wherein: in step S2, the ratio of trimethyloxonium tetrafluoroborate to the impurity F intermediate-1 is from 0.4 to 0.5 (W/W).
7. The method for preparing cabazitaxel impurity F according to claim 6, wherein: in the step S2, the stirring reaction temperature ranges from 10 ℃ to 20 ℃, and the reaction time ranges from 5 h to 8h.
8. The method for preparing cabazitaxel impurity F according to claim 1, characterized in that: in step S3, the ratio of methanol to the impurity F, intermediate-2, is 20 to 25 (V/W).
9. The method for preparing cabazitaxel impurity F according to claim 8, wherein: in step S3, the ratio of p-toluenesulfonic acid to impurity F, intermediate-2, is 0.4 to 0.5 (W/W).
10. The method for preparing cabazitaxel impurity F according to claim 9, wherein: in step S3, the stirring reaction temperature is 15-25 ℃, and the reaction time is 1-3 h.
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| CN115850359A (en) * | 2022-12-14 | 2023-03-28 | 梯尔希（南京）药物研发有限公司 | Preparation method of gestodene impurity I |
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| CN115850359A (en) * | 2022-12-14 | 2023-03-28 | 梯尔希（南京）药物研发有限公司 | Preparation method of gestodene impurity I |
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