CN113773282A - Preparation method of 10-acetyl paclitaxel - Google Patents
Preparation method of 10-acetyl paclitaxel Download PDFInfo
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- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 31
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 63
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 24
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
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- 239000002253 acid Substances 0.000 claims abstract description 8
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- 238000000967 suction filtration Methods 0.000 claims description 30
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000002339 acetoacetyl group Chemical group O=C([*])C([H])([H])C(=O)C([H])([H])[H] 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 239000000758 substrate Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
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- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241001149649 Taxus wallichiana var. chinensis Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 229940041181 antineoplastic drug Drugs 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
- LLCSWKVOHICRDD-UHFFFAOYSA-N buta-1,3-diyne Chemical group C#CC#C LLCSWKVOHICRDD-UHFFFAOYSA-N 0.000 description 1
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- 125000004432 carbon atom Chemical group C* 0.000 description 1
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- 239000004359 castor oil Substances 0.000 description 1
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- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
- 229930002995 diterpene alkaloid Natural products 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
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- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
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- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of 10-acetyl paclitaxel, which adopts the technical scheme that: s1: dissolving 10-DAB with dichloromethane and pyridine, dropwise adding chloroformic acid-2, 2, 2-trichloroethyl ester, quenching reaction, and processing to obtain IMJ-1; s2: dissolving IMJ-1 in toluene, adding paclitaxel side chain acid and 4-dimethylaminopyridine, adding N, N' -dicyclohexylcarbodiimide, quenching reaction, and processing to obtain IMJ-2; s3: dissolving IMJ-2 in methanol and acetic acid, adding zinc powder, stirring for reaction, adding dilute hydrochloric acid into the filtrate, stirring for reaction, extracting with dichloromethane, adding n-heptane, and crystallizing to obtain IMJ-3; s4: dissolving IMJ-3 in N, N-dimethylformamide, adding 2-methylimidazole and triethylchlorosilane, stirring for reaction, and processing to obtain IMJ-4; s5: dissolving IMJ-4 in tetrahydrofuran, adding sodium carbonate and diketene, concentrating the filtrate, pulping with methyl tert-butyl ether, and vacuum filtering to obtain IMJ-5; s6: IMJ-5 is dissolved and cleaned by acetonitrile, hydrochloric acid is added, dichloromethane and saturated sodium bicarbonate solution are added for extraction, and the target product is obtained by concentration.
Description
Technical Field
The invention relates to the field of taxane natural products, in particular to a preparation method of 10-acetyl paclitaxel.
Background
Paclitaxel, a natural anticancer drug, has been widely used clinically in the treatment of breast cancer, ovarian cancer, and some head and neck and lung cancers. Paclitaxel is taken as diterpene alkaloid compound with anticancer activity, has novel and complex chemical structure, wide and remarkable biological activity, completely new and unique action mechanism and scarce natural resources, is greatly favored by phytologists, chemists, pharmacologists and molecular biologists, and becomes an anticancer star which draws attention in the next half of the 20 th century and research focus.
The structure of paclitaxel is shown in formula 1, and the structure of 10-acetyl paclitaxel is shown in formula 2, and the difference between the two is mainly that the 10-position groups are different, the former is common acetyl, and the latter is acetoacetyl. The data show that the properties of paclitaxel and 10-acetyl paclitaxel are similar, the retention time of the two in liquid phase is very close, and it can be concluded that the activity of 10-acetyl paclitaxel is similar to that of paclitaxel. Paclitaxel has a significant disadvantage of poor water solubility, so that polyoxyethylene castor oil is used in a first-generation paclitaxel preparation, namely paclitaxel injection, to increase the solubility of paclitaxel, which of course also brings about a strong side effect to paclitaxel injection. This subtle structural distinction between 10-acetylpaclitaxel and paclitaxel gives 10-acetylpaclitaxel the potential to improve this physical property.
Through search, the method has no literature report on a synthetic method taking accessible compounds as raw materials, so that the development of a preparation method with feasibility has very important significance.
Disclosure of Invention
In view of the above-mentioned disadvantages of the prior art, the present invention provides a method for preparing 10-acetylpaclitaxel, which has the advantages of accessibility of the starting materials, mild reaction conditions, high purity of the target product, and suitability for mass production.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of 10-acetyl paclitaxel comprises the following steps:
s1: dissolving 10-DAB with dichloromethane and pyridine, dropwise adding chloroformic acid-2, 2, 2-trichloroethyl ester, stirring for reaction, adding water after the reaction is finished to quench the reaction, washing with hydrochloric acid and salt water respectively, collecting and concentrating an organic phase, and pulping with toluene to obtain IMJ-1;
s2: dissolving IMJ-1 in toluene, adding paclitaxel side chain acid and 4-dimethylaminopyridine, dropwise adding N, N' -dicyclohexylcarbodiimide, stirring for reaction, adding water for quenching reaction after the reaction is finished, performing suction filtration, adding ethyl acetate into filtrate, extracting with saline solution, concentrating an organic phase, and recrystallizing with ethyl acetate and N-heptane to obtain IMJ-2;
s3: dissolving IMJ-2 in methanol and acetic acid, adding zinc powder, stirring for reaction, after the reaction is finished, performing suction filtration, adding dilute hydrochloric acid into filtrate, stirring for reaction, extracting the reaction solution with dichloromethane to obtain an organic phase, washing the organic phase with water, collecting the organic phase, concentrating the organic phase to a small amount, and adding n-heptane for crystallization to obtain IMJ-3;
s4: dissolving IMJ-3 in N, N-dimethylformamide, adding 2-methylimidazole, dropwise adding triethylchlorosilane, stirring for reaction, adding water to separate out a solid after the reaction is finished, and performing suction filtration and drying to obtain IMJ-4;
s5: dissolving IMJ-4 in tetrahydrofuran, adding sodium carbonate, dropwise adding diketene, stirring for reaction, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate, pulping with methyl tert-butyl ether, and carrying out suction filtration to obtain IMJ-5;
s6: dissolving IMJ-5 in acetonitrile, adding hydrochloric acid, stirring at room temperature for reaction, adding dichloromethane and saturated sodium bicarbonate solution for extraction after the reaction is finished, concentrating an organic phase, passing through a column, and drying to obtain 10-acetyltaxol;
the reaction route of the preparation process is as follows:
further, in step S1, the weight ratio of chloroformic acid-2, 2, 2-trichloroethyl ester to 10-DAB is 1.2 to 1.3; the weight ratio of the dichloromethane to the 10-DAB is 13-26; the weight ratio of the pyridine to the 10-DAB is 4.9-5.2.
Further, in step S1, the reaction temperature of the quenching reaction is in the range of 0-10 ℃ and the reaction time is in the range of 0.5-2 h.
Further, in step S2, the weight ratio of the paclitaxel side chain acid to the IMJ-1 is 0.4-0.5; the weight ratio of the 4-dimethylaminopyridine to the IMJ-1 is 0.06-0.08; the weight ratio of the N, N' -dicyclohexylcarbodiimide to the IMJ-1 is 0.4-0.5; the weight ratio of the toluene to the IMJ-1 is 9-10, the reaction temperature ranges from 0 ℃ to 10 ℃, and the reaction time ranges from 0.5h to 2 h.
Further, in the step S3, the weight ratio of the zinc powder to the IMJ-2 is 1.0-1.2; the weight ratio of the methanol to the IMJ-2 is 9-10; the weight ratio of the acetic acid to the IMJ-2 is 3-4; the concentration of the dilute hydrochloric acid is 1mol/L, and the weight ratio of the dilute hydrochloric acid to the IMJ-2 is 2-3; the reaction temperature is 0-10 ℃, and the reaction time is 2-3 h.
Further, in step S4, the weight ratio of 2-methylimidazole to IMJ-3 is 0.3 to 0.4; the weight ratio of the triethylchlorosilane to the IMJ-3 is 0.46-0.52; the weight ratio of the N, N-dimethylformamide to the IMJ-3 is 5-8.
Further, in step S4, the reaction temperature is in the range of 0 to 5 ℃ and the reaction time is in the range of 0.5 to 1 hour.
Further, in step S5, the weight ratio of diketene to IMJ-4 is 0.4-0.6; the weight ratio of the sodium carbonate to the IMJ-4 is 1.0-1.5; the weight ratio of the tetrahydrofuran to the IMJ-4 is 8-10, and the weight ratio of the methyl tert-butyl ether to the IMJ-4 is 3-3.5.
Further, in step S5, the reaction temperature ranges from 60 to 66 ℃ and the reaction time ranges from 8 to 18 hours.
Further, in step S6, the weight ratio of the hydrochloric acid to the IMJ-5 is 1.5 to 1.6; the weight ratio of the acetonitrile to the IMJ-5 is 8-10, and the concentration of hydrochloric acid is 3-6 mol/L.
In conclusion, the invention has the following beneficial effects:
1. the starting material 10-DAB is a natural extraction product, has higher content in branches and leaves of the taxus chinensis, is a variety with the maximum yield in the taxane natural extraction products, and has lower cost compared with a route taking paclitaxel or other taxane products as the starting material; meanwhile, the yield of 10-DAB is larger, the accessibility is better, and the method is beneficial to large-batch industrial production.
2. The invention ensures that main reactions of all steps are clear through cross protection, basically no obvious side reaction exists, and the product point is easy to judge.
3. The specificity of removing the acetyl at the 10-position is not strong, the side chain can be removed, the yield is low, the route of the invention avoids removing the acetyl at the 10-position and then replacing the acetyl, and the problem can not be caused.
4. Some of the structural intermediates appearing in comparative example 1 failed to remove the acetyl group at position 10, resulting in failure to obtain the final product. Therefore, the substitution of the acetoacetyl is carried out by adopting the diacetylene, the advantages are obvious, the yield is high, and no obvious side reaction exists. In addition, since acetoacetic acid is unstable, the substitution of acetoacetyl group cannot be completed by condensation of carboxylic acid with hydroxyl group, and ethyl acetoacetate/methyl acetoacetate, which is slightly more stable, requires transesterification form for the substitution of acetoacetyl group, and it can be seen from the results of comparative example 2 that the target product is not substantially produced because the activity of 10-hydroxyl group as a substrate is not strong.
Drawings
FIG. 1 is an HPLC chromatogram of 10-acetyltaxol prepared in example 1.
FIG. 2 is the MS spectrum (positive ion mode) of 10-acetyltaxol in example 1.
FIG. 3 is a drawing showing the preparation of 10-acetyltaxol in example 11H NMR spectrum.
FIG. 4 shows the preparation of 10-acetyltaxol in example 113C NMR spectrum.
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. To make the objects, features and advantages of the present invention comprehensible, reference is made to the accompanying drawings. 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:
s1: 10g of precursor 10-deacylated baccatin III (10-DAB), subsequently replacing with 10-DAB, dissolving 10-DAB with 130g of dichloromethane and 49g of pyridine, dropwise adding 12g of chloroformic acid-2, 2, 2-trichloroethyl ester, stirring and reacting for 2 hours at ice bath (0 ℃), adding water to quench the reaction after the reaction is finished, washing with hydrochloric acid and salt water respectively, collecting and concentrating an organic phase, adding 15g of toluene, pulping, filtering and drying to obtain 15.1g of IMJ-1;
s2: dissolving 15.1g of IMJ-1 in 150g of toluene, adding 6.0g of paclitaxel side chain acid and 0.91g of 4-dimethylaminopyridine, dropwise adding 6.0g N, N' -dicyclohexylcarbodiimide (diluted by a small amount of toluene), stirring and reacting for 2 hours at room temperature of about 20 ℃, adding water to quench the reaction after the reaction is finished, carrying out suction filtration, adding ethyl acetate into the filtrate, extracting with saline solution, concentrating the organic phase, dissolving with 30ml of ethyl acetate, dropwise adding 60ml of N-heptane to recrystallize, carrying out suction filtration and drying to obtain 19.4g of IMJ-2;
s3: dissolving 19.4g of IMJ-2 in 174.6g of methanol and 58.2g of acetic acid, adding 19.4g of zinc powder, stirring and reacting for 3 hours in an ice bath (at 0 ℃), filtering after the reaction is finished, adding 38.8g of 1mol/L diluted hydrochloric acid into the filtrate, stirring and reacting for 6 hours, extracting the reaction solution by using dichloromethane, washing the organic phase by using water, collecting the organic phase, concentrating to a small amount, adding 50ml of n-heptane for crystallization, filtering and drying to obtain 12.2g of IMJ-3;
s4: dissolving 12.2g of IMJ-3 in 61g N, N-dimethylformamide, adding 3.7g of 2-methylimidazole, dropwise adding 5.7g of triethylchlorosilane, stirring in an ice bath (at 0 ℃) for reacting for 40min, adding 300ml of water to precipitate a solid after the reaction is finished, and performing suction filtration and drying to obtain 14.9g of IMJ-4;
s5: dissolving 14.9g of IMJ-4 with 145g of tetrahydrofuran, adding 22.3g of sodium carbonate, dropwise adding 6g of diketene, refluxing (about 66 ℃) and stirring for reacting for 8 hours, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate, pulping with 45g of methyl tert-butyl ether, and carrying out suction filtration to obtain 14.1g of IMJ-5;
s6: 14.1g of IMJ-5 is dissolved by 140g of acetonitrile, 21.2g of 3mol/L hydrochloric acid is added, the mixture is stirred and reacted for 6 hours at room temperature (about 20 ℃), after the reaction is finished, dichloromethane and saturated sodium bicarbonate solution are added for extraction, 9.3g of 10-acetyl paclitaxel is obtained by concentrating an organic phase, passing through a column and drying, the HPLC purity is 98.8%, the total yield is 56.5%, and the liquid phase chromatogram is shown in figure 1. (ii) a
As shown in FIG. 2, the MS spectrum of 10-acetyltaxol in this example is shown, wherein the mass-to-charge ratio M/z is 918.3[ M + Na []+So that its molecular formula is C49H53NO15。
As shown in FIG. 3, this example shows the preparation of 10-acetyltaxol1A HNMR map wherein,1H NMR(500 MHz,CDCl3)δ:7.35～8.14(15H,ArH),6.98(1H,d,J＝8.4Hz,-NH),6.32 (1H,s,H10),6.23(1H,t,J＝8.6Hz,H13),5.79(1H,d,J＝8.1Hz,H34),5.68 (1H,d,J＝6.8Hz,H2),4.94(1H,d,J＝8.9Hz,H5),4.79(1H,s,H33),4.39 (1H,dd,J＝10.3Hz,6.8Hz,H7),4.30(1H,d,J＝8.3Hz,H20),4.20(1H,d, J＝8.4Hz,H20),3.79(1H,d,J＝6.8Hz,H3),3.61(2H,s,H29),2.55(1H, m,H6),2.38(8H,m,2H14 overlapped with 3H27 and 3H31),1.90(1H,m, H6),1.82(3H,s,H18),1.69(3H,s,H19),1.23(3H,s,H16/H17),1.12(3H, s,H16/H17). The carbon atom numbering refers to the following structural formula:
as shown in FIG. 4, the 13C NMR spectrum of this example 10-acetyltaxol is shown in FIG. 4, wherein 13C NMR (125MHz, CDCl3) delta: 203.173,199.66,172.741,170.402,167.165, 167.119,166.989,142.576,137.993,133.727,133.68,132.778,131.98, 130.227,129.189,129.055,128.718,128.396,127.052,84.36,81.153, 78.997,76.513,76.361,74.929,73.172,72.357,72.064,58.68,55.049, 49.907,45.704,43.143,35.766,31.865,30.175,28.989,26.836,22.663, 22.614,21.82,14.802,14.065, 9.619.
Example 2:
s1: dissolving 10g of 10-DAB with 180g of dichloromethane and 50g of pyridine, dropwise adding 12g of chloroformic acid-2, 2, 2-trichloroethyl, stirring at room temperature (about 5 ℃) for reaction for 1 hour, adding water after the reaction is finished to quench the reaction, washing with hydrochloric acid and salt water respectively, collecting and concentrating an organic phase, adding 15g of toluene for pulping, and performing suction filtration and drying to obtain 14.8g of IMJ-1;
s2: dissolving 14.8g of IMJ-1 in 135g of toluene, adding 7.4g of paclitaxel side chain acid and 0.90g of 4-dimethylaminopyridine, dropwise adding 7.4g N, N' -dicyclohexylcarbodiimide (diluted by a small amount of toluene), stirring and reacting for 4 hours at the room temperature of about 23 ℃, adding water to quench the reaction after the reaction is finished, carrying out suction filtration, adding ethyl acetate into the filtrate, extracting with saline solution, concentrating the organic phase, dissolving with 30ml of ethyl acetate, dropwise adding 60ml of N-heptane to recrystallize, carrying out suction filtration and drying to obtain 19.0g of IMJ-2;
s3: dissolving 19g of IMJ-2 in 190g of methanol and 76g of acetic acid, adding 21g of zinc powder, stirring and reacting for 2h at room temperature (about 5 ℃), after the reaction is finished, carrying out suction filtration, adding 57g of 1mol/L diluted hydrochloric acid into the filtrate, stirring and reacting for 3h, extracting the reaction solution with dichloromethane, washing the organic phase with water, collecting the organic phase, concentrating to a small amount, adding 50ml of n-heptane for crystallization, carrying out suction filtration and drying to obtain 11.3g of IMJ-3;
s4: dissolving 11.3g of IMJ-3 in 90g N, N-dimethylformamide, adding 4.5g of 2-methylimidazole, dropwise adding 5.7g of triethylchlorosilane, stirring in an ice bath (at 0 ℃) for reacting for 45min, adding 300ml of water to precipitate a solid after the reaction is finished, and performing suction filtration and drying to obtain 13.5g of IMJ-4;
s5: dissolving 13.5g of IMJ-4 in 110g of tetrahydrofuran, adding 13.5g of sodium carbonate, dropwise adding 8.1g of diketene, heating (about 60 ℃), stirring and reacting for 18 hours, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate, pulping with 45g of methyl tert-butyl ether, and carrying out suction filtration to obtain 13.2g of IMJ-5;
s6: 13.2g of IMJ-5 is dissolved by 106g of acetonitrile, 20g of 4mol/L hydrochloric acid is added, the mixture is stirred and reacted for 4 hours at room temperature (about 22 ℃), after the reaction is finished, dichloromethane and saturated sodium bicarbonate solution are added for extraction, 8.3g of 10-acetyltaxol is obtained by concentrating an organic phase, passing through a column and drying, the HPLC purity is 98.3%, and the total yield is 50.4%.
Example 3:
s1: dissolving 100g of 10-DAB with 2600g of dichloromethane and 500g of pyridine, dropwise adding 125g of chloroformic acid-2, 2, 2-trichloroethyl, stirring at 0-10 ℃ for reacting for 0.5h, adding water after the reaction is finished to quench the reaction, washing with hydrochloric acid and salt water respectively, collecting and concentrating an organic phase, adding 150g of toluene for pulping, and performing suction filtration and drying to obtain 149.1g of IMJ-1;
s2: dissolving 148g of IMJ-1 in 1480g of toluene, adding 68g of paclitaxel side chain acid and 11.8g of 4-dimethylaminopyridine, dropwise adding 74g N, N' -dicyclohexylcarbodiimide (diluted by a small amount of toluene), stirring at about 23 ℃ for reaction for 3.5h, after the reaction is finished, adding water for quenching reaction, carrying out suction filtration, adding ethyl acetate into filtrate, extracting by using saline solution, concentrating an organic phase, dissolving by using 300ml of ethyl acetate, dropwise adding 600ml of N-heptane for recrystallization, carrying out suction filtration and drying to obtain 187g of IMJ-2;
s3: dissolving 187g of IMJ-2 in 1870g of methanol and 710g of acetic acid, adding 224g of zinc powder, stirring and reacting for 2h at 0-10 ℃, after the reaction is finished, performing suction filtration, adding 560g of 1mol/L diluted hydrochloric acid into the filtrate, stirring and reacting for 3h, extracting the reaction solution with dichloromethane, washing the organic phase with water, collecting the organic phase, concentrating to a small amount, adding 500ml of n-heptane for crystallization, performing suction filtration and drying to obtain 108g of IMJ-3;
s4: dissolving 108g of IMJ-3 in 750g N N-dimethylformamide, adding 41g of 2-methylimidazole, dropwise adding 53g of triethylchlorosilane, stirring at 0-5 ℃ for reaction for 50min, adding 3000ml of water to separate out a solid after the reaction is finished, and performing suction filtration and drying to obtain 125g of IMJ-4;
s5: dissolving 125g of IMJ-4 with 1250g of tetrahydrofuran, adding 125g of sodium carbonate, dropwise adding 50g of diketene, refluxing (about 66 ℃), stirring and reacting for 10 hours, filtering the reaction solution after the reaction is finished, concentrating the filtrate, pulping with 400g of methyl tert-butyl ether, and filtering to obtain 120g of IMJ-5;
s6: dissolving 120g of IMJ-5 with 1080g of acetonitrile, adding 180g of 6mol/L hydrochloric acid, stirring and reacting at 20-25 ℃ for 6h, after the reaction is finished, adding dichloromethane and saturated sodium bicarbonate solution for extraction, concentrating an organic phase, passing through a column, and drying to obtain 77.1g of 10-acetyltaxol, wherein the HPLC purity is 98.5%, and the total yield is 46.9%.
Comparative example 1:
the preparation of 10-acetyl paclitaxel by using paclitaxel as a raw material is tried, and the route is short.
S1: a100 ml reaction flask was charged with 2.0810g of paclitaxel and 2.0153g of 2-methylimidazole, and the mixture was dissolved in 10ml of DMF. Replacing air in the reaction bottle with nitrogen, adding 3ml of triethylchlorosilane, and stirring for reaction for 2 hours. Adding water into the reaction solution, separating out solids, performing suction filtration, dissolving and cleaning a filter cake by using dichloromethane, then adding water for washing, collecting and concentrating an organic phase to obtain IMJ-1'.
S2: dissolving the IMJ-1' in 20ml of ethanol, adding 2ml of hydrazine hydrate, monitoring by TLC after 2 hours, wherein the polarity of the product is higher, and the product is 7-Tes-10-DAB through analysis, so that subsequent experiments cannot be carried out, and the route is abandoned;
comparative example 2:
methyl acetoacetate was tried as an acetylation agent, and IMJ-4 was used in the same manner as described in the present invention.
Dissolving 1g of IMJ-4 in 10ml of tetrahydrofuran, adding 2.5g of ferric triacetylacetonate and 2ml of methyl acetoacetate, stirring and reacting under reflux (about 66 ℃), and monitoring for 8h and 24h to ensure that no new product is generated. Acetylation of the hydroxyacetyl group at position 10 of the IMJ-4 substrate of the present invention cannot be achieved using methyl acetoacetate.
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 10-acetyl paclitaxel is characterized by comprising the following steps:
s1: dissolving 10-DAB with dichloromethane and pyridine, dropwise adding chloroformic acid-2, 2, 2-trichloroethyl ester, stirring for reaction, adding water after the reaction is finished to quench the reaction, washing with hydrochloric acid and salt water respectively, collecting and concentrating an organic phase, and pulping with toluene to obtain IMJ-1;
s2: dissolving IMJ-1 in toluene, adding paclitaxel side chain acid and 4-dimethylaminopyridine, dropwise adding N, N' -dicyclohexylcarbodiimide, stirring for reaction, adding water for quenching reaction after the reaction is finished, performing suction filtration, adding ethyl acetate into filtrate, extracting with saline solution, concentrating an organic phase, and recrystallizing with ethyl acetate and N-heptane to obtain IMJ-2;
s3: dissolving IMJ-2 in methanol and acetic acid, adding zinc powder, stirring for reaction, after the reaction is finished, performing suction filtration, adding dilute hydrochloric acid into filtrate, stirring for reaction, extracting the reaction solution with dichloromethane to obtain an organic phase, washing the organic phase with water, collecting the organic phase, concentrating the organic phase to a small amount, and adding n-heptane for crystallization to obtain IMJ-3;
s4: dissolving IMJ-3 in N, N-dimethylformamide, adding 2-methylimidazole, dropwise adding triethylchlorosilane, stirring for reaction, adding water to separate out a solid after the reaction is finished, and performing suction filtration and drying to obtain IMJ-4;
s5: dissolving IMJ-4 in tetrahydrofuran, adding sodium carbonate, dropwise adding diketene, stirring for reaction, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate, pulping with methyl tert-butyl ether, and carrying out suction filtration to obtain IMJ-5;
s6: dissolving IMJ-5 in acetonitrile, adding hydrochloric acid, stirring at room temperature for reaction, adding dichloromethane and saturated sodium bicarbonate solution for extraction after the reaction is finished, concentrating an organic phase, passing through a column, and drying to obtain 10-acetyltaxol;
the reaction route of the preparation process is as follows:
2. the method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S1, the weight ratio of the chloroformic acid-2, 2, 2-trichloroethyl ester to the 10-DAB is 1.2-1.3; the weight ratio of the dichloromethane to the 10-DAB is 13-26; the weight ratio of the pyridine to the 10-DAB is 4.9-5.2.
3. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S1, the reaction temperature of the quenching reaction is in the range of 0-10 ℃ and the reaction time is in the range of 0.5-2 h.
4. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S2, the weight ratio of paclitaxel side chain acid to IMJ-1 is 0.4-0.5; the weight ratio of the 4-dimethylaminopyridine to the IMJ-1 is 0.06-0.08; the weight ratio of the N, N' -dicyclohexylcarbodiimide to the IMJ-1 is 0.4-0.5; the weight ratio of the toluene to the IMJ-1 is 9-10, the reaction temperature ranges from 0 ℃ to 10 ℃, and the reaction time ranges from 0.5h to 2 h.
5. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S3, the weight ratio of the zinc powder to the IMJ-2 is 1.0-1.2; the weight ratio of the methanol to the IMJ-2 is 9-10; the weight ratio of the acetic acid to the IMJ-2 is 3-4; the concentration of the dilute hydrochloric acid is 1mol/L, and the weight ratio of the dilute hydrochloric acid to the IMJ-2 is 2-3; the reaction temperature is 0-10 ℃, and the reaction time is 2-3 h.
6. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S4, the weight ratio of 2-methylimidazole to IMJ-3 is 0.3 to 0.4; the weight ratio of the triethylchlorosilane to the IMJ-3 is 0.46-0.52; the weight ratio of the N, N-dimethylformamide to the IMJ-3 is 5-8.
7. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S4, the reaction temperature is in the range of 0-5 ℃ and the reaction time is in the range of 0.5-1 h.
8. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S5, the weight ratio of diketene to IMJ-4 is 0.4-0.6; the weight ratio of the sodium carbonate to the IMJ-4 is 1.0-1.5; the weight ratio of the tetrahydrofuran to the IMJ-4 is 8-10, and the weight ratio of the methyl tert-butyl ether to the IMJ-4 is 3-3.5.
9. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S5, the reaction temperature is 60-66 ℃ and the reaction time is 8-18 h.
10. The method of claim 1, wherein the preparation of 10-acetylpaclitaxel comprises: in step S6, the weight ratio of hydrochloric acid to IMJ-5 is 1.5-1.6; the weight ratio of the acetonitrile to the IMJ-5 is 8-10, and the concentration of hydrochloric acid is 3-6 mol/L.
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