CN112661727A - Purification method of 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel - Google Patents
Purification method of 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel Download PDFInfo
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- CN112661727A CN112661727A CN202011586979.7A CN202011586979A CN112661727A CN 112661727 A CN112661727 A CN 112661727A CN 202011586979 A CN202011586979 A CN 202011586979A CN 112661727 A CN112661727 A CN 112661727A
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- trichloroethyloxycarbonyl
- paclitaxel
- taxol
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Abstract
A method for purifying 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel, comprising the following steps: 1) adding the taxol intermediate crude product into an alcohol solvent, and heating to 30-60 ℃ to dissolve; 2) dripping water, stirring, cooling to 0-20 deg.C, and crystallizing to obtain wet crystal; 3) adding wet crystals into an alcohol solvent, heating to 30-60 ℃, and pulping, wherein the mass volume ratio of the wet crystals to the alcohol solvent is 1: 4-10; 4) cooling to 0-20 deg.C, and crystallizing to obtain 7- (2,2, 2-trichloroethyloxycarbonyl) taxol. The method has the advantages of simple operation, low purification cost and high yield, can effectively purify and obtain the high-purity 7- (2,2, 2-trichloroethyloxycarbonyl) taxol, and effectively meets the production requirements of enterprises.
Description
Technical Field
The invention relates to the field of medicine synthesis, and in particular relates to a method for purifying 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel.
Background
Paclitaxel is an ideal anticancer drug with the best international anticancer effect, strong broad spectrum, small side effect and brand new action mechanism. Is mainly suitable for ovarian cancer and breast cancer, and also has certain curative effects on lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma and cerebroma.
At present, the semi-synthesis method of paclitaxel is mainly divided into three types, namely a straight chain synthesis method, a four-membered ring side chain method and a five-membered ring side chain method. In the five-membered ring side chain method, 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel is an important intermediate in the synthesis process, however, in the current synthesis technology, the intermediate is not purified.
Patent CN101863862B teaches the synthesis of paclitaxel by a 4-step method using a five-membered ring side chain method, which does not describe the 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel intermediate, and paclitaxel is synthesized directly by a one-pot method.
Patent CN103130753B discloses a method for synthesizing paclitaxel by 5-step method using five-membered ring side chain method, which obtains 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel intermediate crude product by formic acid ring opening, and directly synthesizes paclitaxel without purification.
Some of the patents in the literature adopt the following method to synthesize paclitaxel intermediate 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel, and the synthesis process is accompanied by the generation of p-methoxybenzaldehyde, which is a byproduct. The reaction formula is as follows:
according to the reaction condition, p-methoxybenzaldehyde exists in the product, so that 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel is difficult to crystallize and separate out, and the existing process is basically impure and directly enters a downstream process. Therefore, the purification difficulty of the paclitaxel is increased, the yield of the paclitaxel is low, the column passing difficulty is increased, and the production cost of the paclitaxel is increased.
Disclosure of Invention
The invention aims to provide a method for purifying 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel, which is simple to operate, low in purification cost and high in yield, can effectively purify and obtain high-purity 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel, and effectively meets the production requirements of enterprises.
The technical scheme of the invention is as follows: a method for purifying 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel, comprising the following steps:
1) adding the taxol intermediate crude product into an alcohol solvent, and heating to 30-60 ℃ to dissolve;
2) dripping water, stirring, cooling to 0-20 deg.C, and crystallizing to obtain wet crystal;
3) adding wet crystals into an alcohol solvent, heating to 30-60 ℃, and pulping, wherein the mass volume ratio of the wet crystals to the alcohol solvent is 1: 4-10;
4) cooling to 0-20 deg.C, and crystallizing to obtain 7- (2,2, 2-trichloroethyloxycarbonyl) taxol.
Further, the taxol intermediate crude product in the step 1) contains p-methoxybenzaldehyde, and the content of the p-methoxybenzaldehyde is 25% -30%.
Preferably, the alcohol solvent in step 1) is any one or a mixture of methanol, ethanol and isopropanol.
Preferably, the mass-to-volume ratio of the paclitaxel intermediate crude product in the step 1) to the alcoholic solvent is 1: 10-20.
Preferably, the mass-to-volume ratio of the paclitaxel intermediate crude product in the step 2) to water is 1: 10-20.
And 2) when water is added dropwise, keeping the temperature at 30-60 ℃, and stirring for 2 hours, wherein the crystallization time is 2 hours.
And 3) pulping for 2 hours.
The crystallization time of step 4) was 2 h.
Preferably, the alcohol solvent in step 3) is any one or a mixture of methanol, ethanol and isopropanol.
Drying the 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel obtained in the step 4) at the temperature of 50 ℃ to obtain a 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel product.
Adopt above-mentioned technical scheme to have following beneficial effect:
1. the purification method has the advantages of simple process route, mild purification conditions, safety, environmental protection, cheap and easily obtained used reagents, and is very suitable for industrial production.
2. The method comprises the steps of dissolving a taxol intermediate crude product in an alcohol solvent at 30-60 ℃, dropwise adding water under the heat preservation condition, separating out a product from a mixed system by utilizing the characteristic that the product is insoluble in water, carrying out primary crystallization, then cooling to 0-20 ℃, carrying out secondary crystallization by utilizing the influence of the temperature difference of the mixed system on the solubility of the product, wherein the wet crystal obtained by separation mainly comprises 7- (2,2, 2-trichloroethyloxycarbonyl) taxol, and the purity of the wet crystal is 94-96%. Adding the obtained wet crystal into an alcohol solvent again at the temperature of 30-60 ℃, pulping by utilizing the characteristic that the wet crystal obtained by the first alcohol and water crystallization has low solubility in the alcohol solvent and impurities are easy to dissolve in the alcohol solvent, then cooling to 0-20 ℃, and fully separating out the product by utilizing the influence of temperature difference on the solubility of the product, thereby obtaining the 7- (2,2, 2-trichloroethyloxycarbonyl) taxol with the purity of more than 99.1 percent.
3. The volume of the alcohol solvent is controlled to be 10-20 times of the mass of the taxol crude product, if the dosage of the alcohol solvent is too small, the removal effect on methoxybenzaldehyde is poor, the quality is influenced, and the yield is influenced due to too much alcohol solvent; by controlling the volume of the dropwise added water to be 10-20 times of the mass of the crude taxol product, if the using amount of the water is too small, part of the product cannot be separated out, and the water amount is too much, so that the waste of raw materials is caused.
4. The volume of the alcohol solvent is controlled to be 4-10 times of the wet crystal quality, if the alcohol solvent is too small in dosage, the impurity removal condition is poor, the purification of the product is not facilitated, the quality is influenced, and the yield is influenced due to too much alcohol solvent.
The applicant tests and verifies that the purity of the 7- (2,2, 2-trichloroethyloxycarbonyl) taxol purified by the purification method is more than 99.1 percent, the standard of medicine synthesis is met, the yield of the 7- (2,2, 2-trichloroethyloxycarbonyl) taxol is more than 91 percent, and the method is also suitable for large-scale industrial production.
The following is a further description with reference to specific examples.
Detailed Description
In the invention, the methanol is sourced from Chongqing Tuzhou chemical products limited company, and the batch number is 20200119 (the purity is more than or equal to 99 percent, and the water content is less than or equal to 0.1 percent). The ethanol used is from Chongqing Tuzhou chemical products Co., Ltd, and the batch number is 20200025 (the purity is more than or equal to 99 percent, and the water content is less than or equal to 0.1 percent). The isopropanol used was from the China Petroleum gas Limited, Inc., Kanzhou petrochemical company, lot number FG190156 (purity > 99%, moisture < 0.1%).
Example 1
Taking 50g of crude taxol intermediate flaky solid, adding into 1000ml of methanol, heating to 30-60 ℃, and stirring until the dissolution is finished. Preserving heat, dripping 1000ml of water, stirring for 2 hours after dripping is finished, then cooling to 0-20 ℃, continuously crystallizing for 2 hours, and filtering to obtain wet crystals.
Adding the wet crystals into 500ml of methanol, heating to 30-60 ℃, pulping for 2 hours, then cooling to 0-20 ℃, continuing to crystallize for 2 hours, filtering to obtain a 7- (2,2, 2-trichloroethyloxycarbonyl) taxol wet product, and drying the 7- (2,2, 2-trichloroethyloxycarbonyl) taxol wet product at 50 ℃ to obtain 40.4g of white crystalline solid, wherein the yield is 91.5%, the purity is 99.2%, and the content of single impurities is less than 0.1%.
Example 2
Taking 50g of taxol intermediate crude product, adding into 1000ml of ethanol, heating to 30-60 ℃, and stirring until the dissolution is finished. Preserving heat, dripping 1000ml of water, stirring for 2 hours after dripping is finished, then cooling to 0-20 ℃, continuously crystallizing for 2 hours, and filtering to obtain wet crystals.
Adding the wet crystals into 500ml of ethanol, heating to 30-60 ℃, pulping for 2 hours, then cooling to 0-20 ℃, continuing to crystallize for 2 hours, filtering to obtain a 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel wet product, and drying the 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel wet product at 50 ℃ to obtain a white crystalline solid, wherein the yield of 40.8g of the white crystalline solid is 92.4%, the purity of the white crystalline solid is 99.1%, and the content of single impurities is less than 0.1%.
Example 3
Taking 50g of taxol intermediate crude product, adding into 1000ml of isopropanol, heating to 30-60 ℃, stirring until the dissolution is finished, preserving heat, dropwise adding 1000ml of water, stirring for 2 hours after the dropwise adding is finished, cooling to 0-20 ℃, continuously crystallizing for 2 hours, and filtering to obtain wet crystals.
Adding the wet crystals into 500ml of isopropanol, heating to 30-60 ℃, pulping for 2 hours, then cooling to 0-20 ℃, continuing to crystallize for 2 hours, filtering to obtain a 7- (2,2, 2-trichloroethyloxycarbonyl) taxol wet product, and drying the 7- (2,2, 2-trichloroethyloxycarbonyl) taxol wet product at 50 ℃ to obtain 40.1g of white crystalline solid, wherein the yield is 90.8%, the purity is 99.3%, and the content of single impurities is less than 0.1%.
Claims (10)
1. A method for purifying 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel, which comprises the following steps:
1) adding the taxol intermediate crude product into an alcohol solvent, and heating to 30-60 ℃ to dissolve;
2) dripping water, stirring, cooling to 0-20 deg.C, and crystallizing to obtain wet crystal;
3) adding wet crystals into an alcohol solvent, heating to 30-60 ℃, and pulping, wherein the mass volume ratio of the wet crystals to the alcohol solvent is 1: 4-10;
4) cooling to 0-20 deg.C, and crystallizing to obtain 7- (2,2, 2-trichloroethyloxycarbonyl) taxol.
2. The purification method as claimed in claim 1, wherein the crude paclitaxel intermediate in step 1) contains p-methoxybenzaldehyde in an amount of 25% -30%.
3. The purification method according to claim 1, wherein the alcoholic solvent in step 1) is any one or more of methanol, ethanol, and isopropanol.
4. The purification method according to claim 1, wherein the mass-to-volume ratio of the crude paclitaxel intermediate product in step 1) to the alcoholic solvent is 1: 10-20.
5. The purification method according to claim 1, wherein the mass-to-volume ratio of the crude paclitaxel intermediate in step 2) to water is 1: 10-20.
6. The purification process according to claim 1, wherein the temperature is maintained at 30-60 ℃ and stirring is carried out for 2h, while adding dropwise water in step 2), and the crystallization time is 2 h.
7. The purification process according to claim 1, wherein the beating of step 3) is carried out for 2 h.
8. Purification process according to claim 1, characterized in that the crystallization time of step 4) is 2 h.
9. The purification method according to claim 1, wherein the alcoholic solvent in step 3) is any one or more of methanol, ethanol and isopropanol.
10. The purification method according to claim 1, wherein the 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel obtained in step 4) is dried at 50 ℃ to obtain the 7- (2,2, 2-trichloroethyloxycarbonyl) paclitaxel product.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5760251A (en) * | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
| CN103130753A (en) * | 2013-03-14 | 2013-06-05 | 上海龙翔生物医药开发有限公司 | Semi-synthesis method of antitumor drug taxol |
| CN109836401A (en) * | 2017-11-28 | 2019-06-04 | 正大天晴药业集团股份有限公司 | A kind of purification process of docetaxel |
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2020
- 2020-12-29 CN CN202011586979.7A patent/CN112661727B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5760251A (en) * | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
| CN103130753A (en) * | 2013-03-14 | 2013-06-05 | 上海龙翔生物医药开发有限公司 | Semi-synthesis method of antitumor drug taxol |
| CN109836401A (en) * | 2017-11-28 | 2019-06-04 | 正大天晴药业集团股份有限公司 | A kind of purification process of docetaxel |
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