A preparation process of paclitaxel palmitate

Abstract

The invention discloses a preparation process of paclitaxel palmitate, comprising the following steps: (1) adding paclitaxel into a reaction vessel, dissolving the paclitaxel in anhydrous acetone, and then adding 4-dimethylaminopyridine to obtain a paclitaxel reaction solution; (2) dissolving palmitic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in anhydrous acetone to obtain a palmitic acid reaction solution; (3) under the protection of an inert atmosphere, stirring and heating the paclitaxel reaction solution in the reaction vessel, spraying the palmitic acid reaction solution into the paclitaxel reaction solution, and after stirring and spraying, continuing to heat the reaction to obtain a crude reaction product. The preparation process of the invention can improve the preparation efficiency of paclitaxel palmitate, and improve product purity and yield.

Description

Technical Field

[0001] The invention relates to a preparation process of paclitaxel palmitate, and belongs to the technical field of pharmaceutical chemical industry. Background Art

[0002] Paclitaxel, also known as Taxol, Purple, Special, chemical name: 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxane-11-ene-9-one-4,10-diacetate-2-benzoate-13[(2'R,3'S)-N-benzoyl-3-phenylisoserine ester], is a highly effective, low-toxic, broad-spectrum natural anticancer drug. Currently, it is also one of the best natural anti-tumor drugs on the market. Paclitaxel is a white crystalline powder, odorless, tasteless, insoluble in water, and poorly lipophilic. It is almost not absorbed orally, which limits the development and application of clinical preparations. Therefore, in recent years, the research on paclitaxel drugs has mainly focused on structural modification, designing prodrugs and new dosage forms. For example, paclitaxel fatty acid ester prodrugs with good lipophilicity are obtained by esterification of fatty acids with hydroxyl groups in the paclitaxel structure. However, the synthesis time of existing fatty acids and paclitaxel is relatively long and the purity is still relatively low. Summary of the invention

[0003] In order to solve at least one problem existing in the above-mentioned prior art, the present invention provides a process for preparing paclitaxel palmitate, which can improve the preparation efficiency of paclitaxel palmitate and improve the purity and yield of the product.

[0004] In order to achieve the above object, the present invention adopts the following technical scheme: a preparation process of paclitaxel palmitate, comprising the following steps:

[0005] (1) adding paclitaxel into a reaction container, dissolving the paclitaxel in anhydrous acetone, and then adding 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0006] (2) dissolving palmitic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in anhydrous acetone to obtain a palmitic acid reaction solution;

[0007] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container is stirred and heated to 40-50° C., and the palmitic acid reaction solution is sprayed into the paclitaxel reaction solution. After the stirring and spraying is completed, the reaction is continued at 40-50° C. for 1-2 hours;

[0008] (4) Acetone is then removed by rotary evaporation under reduced pressure, and then diluted hydrochloric acid and saturated brine are added in sequence for washing, and the washing is repeated 2 to 3 times to obtain a crude reaction product.

[0009] Preferably, the method further comprises separation and purification of the crude reaction product: separation and purification of the crude reaction product is performed by silica gel column chromatography, and the solvent is removed by rotary evaporation to obtain paclitaxel palmitate.

[0010] Preferably, the crude reaction product is subjected to column chromatography using a gradient elution with a methanol-ethyl acetate mixture having a volume ratio of 15:85, 35:65, and 80:20.

[0011] Preferably, the spraying rate of the palmitic acid reaction solution is 0.2-0.4 mL / min. A high spraying rate will reduce the paclitaxel palmitate; a low spraying rate will extend the spraying time, reduce the efficiency, and increase the energy consumption.

[0012] Preferably, the molar ratio of paclitaxel to 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and palmitic acid is 1:1.15-1.25:1.15-1.25:1.05-1.15; preferably, the molar ratio of paclitaxel to 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and palmitic acid is 1:1.2:1.2:1.1, so that paclitaxel has a better conversion rate and reduces the cost of raw materials.

[0013] Preferably, the concentration of paclitaxel in the paclitaxel reaction solution is 40 to 50 mmol / L.

[0014] Preferably, the concentration of palmitic acid in the palmitic acid reaction solution is 50 to 62.5 mmol / L.

[0015] The invention has the following beneficial effects: 1) the invention uses paclitaxel and palmitic acid as reaction raw materials, uses 4-dimethylaminopyridine as a catalyst, and uses 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as an activator, and optimizes the conditions of the esterification reaction, so that the reaction can improve the yield of paclitaxel palmitate and shorten the reaction time; 2) the invention uses acetone as a solvent, thereby reducing the use of chloroalkane solvents with relatively high toxicity in the prior art; 3) the invention adopts a column chromatography method with gradient elution, so as to further improve the purity of paclitaxel palmitate, and the purity of the prepared paclitaxel palmitate is relatively stable; 4) the preparation method of the invention is simple, easy to operate, and has high production yield and efficiency, which helps to reduce the cost of industrial production. DETAILED DESCRIPTION

[0016] The following is a clear and complete description of the technical solutions in the implementation of the present invention. The described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work are within the scope of protection of the present invention. If the specific conditions are not specified in the embodiments, they are carried out according to the normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents, instruments, and components used, they are all conventional products that can be purchased commercially.

[0017] Example 1

[0018] A preparation process of paclitaxel palmitate comprises the following steps:

[0019] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 25 ml of anhydrous acetone, and then add 1.15 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0020] (2) dissolving 1.05 mmol of palmitic acid and 1.15 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 21 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0021] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 40° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.4 mL / min. After the stirring and spraying was completed, the reaction was continued at 40° C. for 1.5 h;

[0022] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing twice to obtain a crude reaction product;

[0023] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC to calculate the yield (based on paclitaxel).

[0024] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 97.98% by HPLC analysis, thereby determining the comprehensive yield to be 95.46%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature. Specifically, ESI-MS (m / z) was 1092.48 [M+H] + ; 1H-NMR (600MHz, DMSO-d6) δ: 9.19(d,1H), 7.97(d,2H), 7.85(d,2H), 7.73(t,1H), 7.66(t,2H), 7.55(t,1H), 7.49(t ,2H), 7.43~7.48(m,4H), 7.17~7.19(m,1H), 6.29(s,1H), 5.80(t,1H), 5.53(t,1H), 5.41(d,1H), 5.35(d,1H), 4.91 (t,2H), 4.62(s,1H), 4.09~4.12(m,1H), 3.98~4.03(m,2H), 3.57(d,1H), 2.29~2.41(m,3H), 2.25(s,3H), 2.09(s,3 H), 1.76~1.81(m,4H), 1.64(t,1H), 1.46~1.51(m,6H), 1.13~1.26(m,24H), 1.04(s,3H), 1.01(s,3H), 0.85(t,3H).

[0025] Example 2

[0026] A preparation process of paclitaxel palmitate comprises the following steps:

[0027] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 25 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0028] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 22 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0029] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 40° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.4 mL / min. After the stirring and spraying was completed, the reaction was continued at 40° C. for 1.5 h;

[0030] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing twice to obtain a crude reaction product;

[0031] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC to calculate the yield (based on paclitaxel).

[0032] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 98.76% as analyzed by HPLC, thereby determining the comprehensive yield to be 96.58%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0033] Example 3

[0034] A preparation process of paclitaxel palmitate comprises the following steps:

[0035] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 25 ml of anhydrous acetone, and then add 1.25 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0036] (2) dissolving 1.15 mmol of palmitic acid and 1.25 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 23 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0037] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 40° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.4 mL / min. After the stirring and spraying was completed, the reaction was continued at 40° C. for 1.5 h;

[0038] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing twice to obtain a crude reaction product;

[0039] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC to calculate the yield (based on paclitaxel).

[0040] The paclitaxel palmitate obtained after separation and purification is a white solid powder. The purity of the paclitaxel palmitate is 98.23% as analyzed by HPLC, and the comprehensive yield is determined to be 95.14%. The structure of the compound is confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance are consistent with those reported in the literature.

[0041] Example 4

[0042] A preparation process of paclitaxel palmitate comprises the following steps:

[0043] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 20 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0044] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 20 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0045] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 45° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.3 mL / min. After the stirring and spraying was completed, the reaction was continued at 45° C. for 1.5 h;

[0046] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing three times to obtain a crude reaction product;

[0047] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC to calculate the yield (based on paclitaxel).

[0048] The paclitaxel palmitate obtained after separation and purification is a white solid powder, and its purity is 98.92% as analyzed by HPLC, thereby determining the comprehensive yield to be 96.86%. The structure of the compound is confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance are consistent with those reported in the literature.

[0049] Example 5

[0050] A preparation process of paclitaxel palmitate comprises the following steps:

[0051] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 22.5 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0052] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 17.6 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0053] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 40° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.2 mL / min. After the stirring and spraying was completed, the reaction was continued at 40° C. for 1.5 h;

[0054] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing three times to obtain a crude reaction product;

[0055] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC, and the yield was calculated to be 98% (based on paclitaxel).

[0056] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 98.53% as analyzed by HPLC, thereby determining the comprehensive yield to be 95.98%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0057] Example 6

[0058] A preparation process of paclitaxel palmitate comprises the following steps:

[0059] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 20 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0060] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 17.6 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0061] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 45° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.3 mL / min. After the stirring and spraying was completed, the reaction was continued at 45° C. for 2 h;

[0062] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing twice to obtain a crude reaction product;

[0063] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC to calculate the yield (based on paclitaxel).

[0064] The paclitaxel palmitate obtained after separation and purification is a white solid powder. The purity of the paclitaxel palmitate is 98.62% as analyzed by HPLC, and the comprehensive yield is determined to be 96.13%. The structure of the compound is confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance are consistent with those reported in the literature.

[0065] Example 7

[0066] A preparation process of paclitaxel palmitate comprises the following steps:

[0067] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 25 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0068] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 17.6 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0069] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 55° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.3 mL / min. After the stirring and spraying was completed, the reaction was continued at 55° C. for 1 hour;

[0070] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing twice to obtain a crude reaction product;

[0071] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC to calculate the yield (based on paclitaxel).

[0072] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 98.43% as analyzed by HPLC, thereby determining the comprehensive yield to be 96.06%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0073] Example 8

[0074] A preparation process of paclitaxel palmitate comprises the following steps:

[0075] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 22.5 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0076] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 16.8 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0077] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 40° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.2 mL / min. After the stirring and spraying was completed, the reaction was continued at 40° C. for 1.5 h;

[0078] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing three times to obtain a crude reaction product;

[0079] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC, and the yield was calculated to be 98% (based on paclitaxel).

[0080] The paclitaxel palmitate obtained after separation and purification is a white solid powder, and its purity is 98.05% as analyzed by HPLC, thereby determining the comprehensive yield to be 95.81%. The structure of the compound is confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance are consistent with those reported in the literature.

[0081] Example 9

[0082] A preparation process of paclitaxel palmitate comprises the following steps:

[0083] (1) Add 1 mmol of paclitaxel to a reaction container, dissolve it in 22.5 ml of anhydrous acetone, and then add 1.2 mmol of 4-dimethylaminopyridine to obtain a paclitaxel reaction solution;

[0084] (2) dissolving 1.1 mmol of palmitic acid and 1.2 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 18.4 ml of anhydrous acetone to obtain a palmitic acid reaction solution;

[0085] (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container was stirred and heated to 40° C., and the palmitic acid reaction solution was sprayed into the paclitaxel reaction solution at a rate of 0.2 mL / min. After the stirring and spraying was completed, the reaction was continued at 40° C. for 1.5 h;

[0086] (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing three times to obtain a crude reaction product;

[0087] (5) The crude product was subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20 by silica gel column chromatography, and the solvent was then removed by rotary evaporation to obtain paclitaxel palmitate. The structure was confirmed by ESI-MS and 1H-NMR, and the purity was determined by HPLC, and the yield was calculated to be 98% (based on paclitaxel).

[0088] The paclitaxel palmitate obtained after separation and purification is a white solid powder, and its purity is 98.34% as analyzed by HPLC, thereby determining the comprehensive yield to be 95.15%. The structure of the compound is confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance are consistent with those reported in the literature.

[0089] Comparative Example 1

[0090] The difference from Example 1 is that: in step (3), under the protection of an inert atmosphere, the paclitaxel reaction solution and the palmitic acid reaction solution in the reaction container are stirred and heated to 40° C., and the reaction is continued at 40° C. for 5 hours; the rest is the same;

[0091] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 97.71% as analyzed by HPLC, thereby determining the comprehensive yield to be 91.45%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0092] Comparative Example 2

[0093] The difference from Example 1 is that: in step (3), under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container is stirred at room temperature, and the palmitic acid reaction solution is sprayed into the paclitaxel reaction solution at a rate of 2.5 mL / min. After the stirring and spraying is completed, the reaction is continued at room temperature for 6 hours; the rest is the same;

[0094] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 97.24% as analyzed by HPLC, thereby determining the comprehensive yield to be 90.18%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0095] Comparative Example 3

[0096] The difference from Example 1 is that: (1) 1 mmol of paclitaxel is added to a reaction container and dissolved in 25 ml of anhydrous acetone, and then 1.15 mmol of 4-dimethylaminopyridine and 1.15 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added to obtain a paclitaxel reaction solution;

[0097] (2) Dissolve 1.05 mmol of palmitic acid in 21 ml of anhydrous acetone to obtain a palmitic acid reaction solution; the rest is the same;

[0098] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 97.45% as analyzed by HPLC, thereby determining the comprehensive yield to be 92.87%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0099] Comparative Example 4

[0100] The difference from Example 1 is that: in step (5), the crude reaction product is subjected to gradient elution using a methanol-ethyl acetate mixture with a volume ratio of 55:45 by silica gel column chromatography, and then the solvent is removed by rotary evaporation to obtain paclitaxel palmitate; the rest is the same;

[0101] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 96.68% as analyzed by HPLC, thereby determining the comprehensive yield to be 95.95%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0102] Comparative Example 5

[0103] The difference from Example 1 is that: step (3) is sprayed at a rate of 0.5 mL / min, and the rest is the same;

[0104] The paclitaxel palmitate obtained after separation and purification was a white solid powder, and its purity was 98.12% as analyzed by HPLC, thereby determining the comprehensive yield to be 94.35%. The structure of the compound was confirmed by mass spectrometry and nuclear magnetic resonance, and the obtained mass spectrum and nuclear magnetic resonance were consistent with those reported in the literature.

[0105] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit and essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0106] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A process for preparing paclitaxel palmitate, characterized in that: The steps include: (1) Add paclitaxel into a reaction container, dissolve it in anhydrous acetone, and then add 4-dimethylaminopyridine to obtain a paclitaxel reaction solution; (2) dissolving palmitic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in anhydrous acetone to obtain a palmitic acid reaction solution; (3) Under the protection of an inert atmosphere, the paclitaxel reaction solution in the reaction container is stirred and heated to 40-50°C, and the palmitic acid reaction solution is sprayed into the paclitaxel reaction solution. After the stirring and spraying are completed, the reaction is continued at 40-50°C for 1-2 hours; (4) removing acetone by rotary evaporation under reduced pressure, and then washing with dilute hydrochloric acid and saturated brine in sequence, and repeating the washing 2 to 3 times to obtain a crude reaction product; The method also includes separation and purification of the crude reaction product: separation and purification of the crude reaction product by silica gel column chromatography, and removal of the solvent by rotary evaporation to obtain paclitaxel palmitate; column chromatography of the crude reaction product uses a gradient elution of a methanol-ethyl acetate mixture with a volume ratio of 15:85, 35:65, and 80:20; The spraying rate of the palmitic acid reaction solution is 0.2-0.4 mL / min; The molar ratio of paclitaxel to 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and palmitic acid is 1:1.15-1.25:1.15-1.25:1.05-1.

15.

2. The process for preparing paclitaxel palmitate according to claim 1, characterized in that: The molar ratio of paclitaxel to 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and palmitic acid is 1:1.2:1.2:1.

1.

3. The process for preparing paclitaxel palmitate according to claim 1, characterized in that: The concentration of paclitaxel in the paclitaxel reaction solution is 40-50 mmol / L.

4. The process for preparing paclitaxel palmitate according to claim 1, characterized in that: The concentration of palmitic acid in the palmitic acid reaction solution is 50-62.5 mmol / L.