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CAS NO.33069-62-4
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| Product Name: | Paclitaxel |
| Synonyms: | N-BENZYL-BETA-PHENYLISOSERINE ESTER;PACLITAXEL, TAXUS BREVIFOLIA;PACLITAXEL, TAXUS SPECIES;PACLITAXOL;PACLITAXEL;TAXOL(TM);taxol a;TAXOL EQUIVALENT |
| CAS: | 33069-62-4 |
| MF: | C47H51NO14 |
| MW: | 853.91 |
| EINECS: | 205-285-7 |
| Product Categories: | Active Pharmaceutical Ingredients;Pharmaceutical material and intermeidates;Antineoplastics;Antineoplastic;APIs;Antitumors for Research and Experimental Use;Biochemistry;Natural Plant Extract;Intermediates & Fine Chemicals;Pharmaceuticals;Natural Anti-cancer Medical Materials and It's Derivatives;Antitumour;Signalling;Aromatics;Chiral Reagents;Heterocycles;Plant extract;API;Plant extracts;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;CLOBEX;Isolabel;antibiotic;Anti-cancer&immunity;Inhibitors |
| Mol File: | 33069-62-4.mol |
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| Paclitaxel Chemical Properties |
| mp | 213 °C (dec.)(lit.) |
| refractive index | -49 ° (C=1, MeOH) |
| storage temp. | 2-8°C |
| solubility | methanol: 50 mg/mL, clear, colorless |
| form | powder |
| color | white |
| Merck | 6982 |
| Stability: | Stable. Incompatible with strong oxidizing agents. Combustible. |
| CAS DataBase Reference | 33069-62-4(CAS DataBase Reference) |
| EPA Substance Registry System | Benzenepropanoic acid, .beta.-(benzoylamino)-.alpha.- hydroxy-, (2aR,4S,4aS,6R,9S,11S,12S, 12aR,12bS)-6,12b-bis(acetyloxy)- 12-(benzoyloxy)-2a,3,4,4a, 5,6,9,10,11,12,12a,12b-dodecahydro- 4,11-dihydroxy-4a,8,13,13- tetramethyl-5-oxo-7,11-methano- 1H-cyclodeca[3,4]benz[1,2- b]oxet-9-yl ester, (.alpha.R,.beta.S)-(33069-62-4) |
| Safety Information |
| Hazard Codes | Xn |
| Risk Statements | 37/38-41-42/43-62-68-40-48-20/21/22-68/20/21/22 |
| Safety Statements | 22-26-36/37/39-45 |
| RIDADR | 1544 |
| WGK Germany | 3 |
| RTECS | DA8340700 |
| F | 10-21 |
| HazardClass | 6.1(b) |
| PackingGroup | III |
| Hazardous Substances Data | 33069-62-4(Hazardous Substances Data) |
| MSDS Information |
| Provider | Language |
|---|---|
| 7,11-Methano-5H-cyclodeca[3,4]benz[1,2-b]oxete benzenepropanoic acid deriv. | English |
| SigmaAldrich | English |
| ACROS | English |
| Paclitaxel Usage And Synthesis |
| Outline | Paclitaxel is a monomer diterpenoid compound extracted from bark of the natural plant, taxus. It is a kind of complex secondary metabolites and is currently known as the only kind drug that can promote microtubule polymerization and stabilize polymerized microtubules. Isotopic tracing has showed that paclitaxel only binds to polymerized microtubules without reacting with the non-polymerized tubulin dimer. Cells will accumulate large amount of microtubules inside cells after exposure to paclitaxel with the accumulation of these microtubules being able to interfere with various kinds of cellular functions, in particular, being able to stop cell division in the mitosis phase, blocking the normal cell division. ThroughⅡ-Ⅲ clinical study, paclitaxel is mainly applied to the treatment of ovarian and breast cancer and also has certain efficacy in the treatment of lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma and brain tumors. |
| Indications | It has good efficacy in the treatment of ovarian cancer and refractory ovarian cancer already being resistant to existing platinum and breast cancer. It also has good prospect on the treatment of prostate cancer, head and neck cancer, esophageal cancer, germ cell tumors, endometrial carcinoma, lymphoma, bladder cancer, upper gastrointestinal cancer, small cell and non-small cell lung cancer. |
| Small history |
In 1963, American chemist MC Wani and Monre E. Wall had isolated for the first time of the paclitaxel crude extract from the bark and wood of the pacific yew growing in the western forest of United States. During the screening experiments of taxus, Wani and Wall have discovered that crude extracts of paclitaxel are of great activity to the in vitro culture of mouse tumor cells and began to separate this active ingredient. Owing to the very low levels of the active ingredient in the plant, it was not until 1971 that they, through the cooperation with Professor Andre T. McPhail in Duke University, used x-ray analysis and successfully determined the chemical structure of the active ingredient - a kind of tetracylicditerpene and named it as paclitaxel (Paclitaxel). In 1971, it had been found of paclitaxel in taxus and found a unique anticancer mechanism. In 1992 the US government assigned the patent to Bristol-Myers Squibb and the paclitaxel emerged. In 1994, Paclitaxel ranks first in the global sales of world anti-cancer drugs. In 2000, the Paclitaxel sales had reached ten billion (after that, due to the supply limit of raw materials, the sales amount got no further rise). In 2002, the central government had forbidden the cutting of wild yew and had encouraged artificial cultivation. In 2004, the patent of Bristol-Myers Squibb has expired. More and more global pharmaceutical companies have been involved in Paclitaxel production. In 2004, Huayuan started to conduct the taxus project and build direct paclitaxel-specific extraction factory with the aims of becoming the largest yew base in China and Asia. In 2005, the Central government again issued a document for the national census of yew resources to encourage planting. In 2005, this project received investment from individual investors. The above information is edited by the chemicalbook of Dai Xiongfeng. |
| High efficient method for separation and purification of paclitaxel | It includes a, extraction: take yew as a raw material to obtain the extract containing paclitaxel; B, remove the gum: remove the gum impurities in the extract; C, separation and purification. Wherein: Paclitaxel production process is as follows: pulverize the bark of yew (the thinner the better), 85% to 95% alcohol ( what’s the ratio between material over liquid) heat reflux at 35-55 ℃ for extraction for three times (how long does it take each time ), 50-70 ℃ vacuum evaporated to heat measurement with the proportion of 1.1 ~ 1.2g / ml; extract with chloroform and the extract was concentrated into paste-like to obtain the chloroform paste with paclitaxel content being 1%. Add chloroform to the chloroform paste containing 1% paclitaxel to dissolve it completely. Add silicone gel the stir uniformly, dry, sieve and pack into a chromatography column; apply chloroform - methanol gradient elution, TLC detection, segmentation, mergence and concentration to give semi-finished product containing 5 to 8% Paclitaxel. Add acetone to the semi-finished content containing 5 to 8% Paclitaxel to dissolve completely; Add silicone gel the stir uniformly, dry, sieve and pack into a chromatography column; apply chloroform - methanol gradient elution, TLC detection, segmentation, mergence and concentration to give semi-finished product containing 20 to 25% Paclitaxel. Use acetone - petroleum ether system for crystallization of 3 to 4 times, apply filtration, 50 ℃ vacuum drying under reduced pressure to give semi-finished product with Paclitaxel content being 75 to 80%. apply 16Mpa pressure chromatography, TLC detection, segmentation, mergence and concentration; the target segment concentrates are subject to acetone - petroleum ether crystallization, filtration, drying to obtain finished product with paclitaxel content ≥99.5%; gum removal process: apply high-pressure silica column chromatography to remove gum while separating the taxane compound to three parts including paclitaxel, cephalomannine, 7-epi Paclitaxel. |
| Docetaxel | Docetaxel is a kind of highly strong bone marrow activity inhibitor drug extracted from yew trees. During the treatment, the patients should be subject to monitoring of blood cell and platelet counts. The mechanism of action for the drug is similar to paclitaxel, namely inhibiting the depolymerization of microtubules and inhibiting cell division. Through intravenous infusion of this drug for administration, it can be used for the treatment of advanced or metastatic breast cancer as well as non-small cell lung cancer. |
| International market analysis |
So far, there are only two kinds of paclitaxel API in the international market with one derived from a variety of yew bark; the other being derived from the “10-baccatin” extracted from ornamental yew branches in Europe and further semi-synthesis, namely docetaxel with its structure being highly similar as natural extracts paclitaxel. These two kinds of APIs are both best-selling drug products on the international pharmaceutical market and are in long-term short supply, according to the estimate, the sales ratio of drug paclitaxel and docetaxel API is about 10: 1. In the United States, the paclitaxel injection (trade name: Paclitaxel) is mainly subject to exclusive manufacturing by Bristol-Myers Squibb. There is now about two to three pharmaceutical companies which produce paclitaxel bulk drugs and formulations. But the market is mostly subject to monopoly by Bristol-Myers Squibb while total sales of the paclitaxel formulation in other few companies only can account for only a small fraction of that in Bristol-Myers Squibb. The docetaxel bulk drugs and formulations are mainly from the co-production of France Poulenc Company and several companies in the United Kingdom and Italy with Planck having the maximal yield. Paclitaxel is always the first-choice anticancer drugs in hospitals around the world. In the past few years, the cancer incidence around the world has nearly doubled compared to that at 10 years ago with lung, breast and ovarian cancer and other malignancies also showing high-incidence trend. These cancer patients are the major users of paclitaxel. From the overall perspective, before the emergence of a new plant anticancer drug being able to take its place, the sales of paclitaxel will only rise rather than fall. According to the latest number released by the World Health Organization, the United States has become the country of the world's first national high incidence of cancer with the annual newly cancer cases increasing by 1.4 million, accounting for 14% of the cases of cancer patients worldwide in that year. The United States has remained the largest consumer of paclitaxel. With the increasing of US cancer incidence, the toxal is used as the major anti-advanced malignancy drug. It is believed that its sales will continue to maintain a rapid upward trend. The United States and other developed countries, during the process of 10 years of clinical use, have already summarized a set of optimal compatibility program for paclitaxel and other anti-cancer drugs. Paclitaxel has become the “backbone” for the related health sector and therefore, the demand for paclitaxel drug will still in the potential of keeping rise. |
| Domestic situation |
At three to four years ago, Jiangsu Hongdou Group has invested tens of millions in eastern China to build the largest yew fast-growing forest base with the total area being ??7400 acres. Now, the cultivated yew seedlings have already occupied large areas and have obtained the high praise from the relevant United Nations and national leaders of forestry sectors. It is also predicted that the Hongdou Group expect to start production and injection drug of Paclitaxel with the designed production amount being 6 million paclitaxel injection, the project has passed the inspection by the national drug bureau and the provincial Food and Drug Administration. In addition, Yunnan and Guizhou Provinces in Northeast China Forest and some mountainous areas are developing yew forest cultivation techniques and it is expected that, in the next three to five years, these areas expect to form a new yew forest, so as to provide new sources for valuable domestic paclitaxel API. There have been also some Taxus cultivation bases under construction in Hunan, Hubei and other provinces in Southern Mountain area as one of the measures to help local farmers become rich. According to this trend, in the next few years, the annual output of paclitaxel API is expected to exceed more than 100 kg mark, thus becoming the largest producer of the world's major bulk drugs and formulations of paclitaxel. |
| Precaution for the use of injections |
1. Hematological toxicity: The major factor for limiting the increase of the dose. Generally, at WBC less than 1500 / mm3, it should be combined with adjuvant application of G-CSF. At platelets less than 30,000 / mm3, it should be subject to transfusion of blood components. 2. Allergies: In addition to pre-treatment, in case of only mild symptoms such as facial flushing, skin reactions, slightly faster heart rate and slightly lower blood pressure, there is no need for withdrawal and instead we can just slow down the drip rate. However, upon severe reactions such as low blood pressure, angioedema, dyspnea, body hives, the drug should be discontinued and subject to appropriate treatment. Patients with severe allergies should not be applied again of paclitaxel treatment. 3. Nervous System: The most common adverse reaction is numbed fingers and toes. About 4% of the patients, in particular upon high dosage, may exhibit obvious sensory and motor deficits and reduced tendon reflexes. There have been isolated reports of grand mal seizures occur during infusion. 4. Cardiovascular: tachycardia and hypotension are relatively common and generally do not need treatment. In the first hour of infusion, it should be closely monitored. Later there is no need for monitoring once per hour unless in cases of patients with serious conduction blockage. 5. Joints and muscles: about half of the patients will fee joint and muscle pain at 2 to 3 days after drug treatment and are associated with the dose. This usually can recover within a few days. Patients subject to administration of G-CSF will have more severe muscle pain. 6. Hepatobiliary system: Since most paclitaxel is excreted from the bile, patients with hepatobiliary disease should be carefully monitored. In thousands of cases, there are about 8% cases in which the patients had elevated bilirubin, 23% cases of patients got elevated alkaline phosphatase while 18% had elevated aspartate aminotransferase. But there is no information showing that paclitaxel can cause severe liver impairment. 7. Other: gastrointestinal reactions, although uncommon but are generally not heavy with a few cases in which patients may have diarrhea and mucositis. Mild hair loss is also common. |
| Chemical Properties | It is needle-like crystal or amorphous powder precipitated from methanol. Melting point 213 ~ 216 ℃ (decomposition). [α]D20: 49°(methanol). UV absorption maximum (methanol): 227,273nm (ε29800,1700). |
| Production method |
It is natural product isolated and purified from yew bark, woody roots, leaves, twigs and seedlings with the highest content existing in the bark. The scientific name of yew in Chinese botany blog is Taxus. In plant taxonomy, it is classified into Amon gymnosperms, Coniferopsida, Taxales, Taxaceae and Taxus. Taxaceae contains 5 genus, 23 species. China has 4 genera and 12 species and one variety including Taxus wallichinanaZucc, Taxus yunnanensis, Taxus chinensis vat. Mairei and Taxus cuspidata, being respectively distributed in Tibet, Yunnan, Guizhou, Sichuan, Guangxi, Guangdong, Hunan, Hubei, Jiangxi, Fujian, Zhejiang, Anhui, Henan, Shanxi, Shaanxi, Gansu and Jilin mountain areas. It is extracted from the bark or leaves in Taxus plants. Yew bark or leaves were dried, and 95% ethanol extraction after being levigated. The extract was concentrated to dryness and the residue was mixed with water and methylene chloride and stirred. The organic layer was separated after standing with the aqueous layer being extracted several times by methylene chloride. After the merging of extract and the organic layers, they are concentrated to dryness with the residue being dissolved in ethyl acetate - methanol: post (3:1). After the mixing with fresh diatomaceous earth, the solvent was distilled off under reduced pressure. The remaining powder was subjected to flash column chromatography, first washed with hexane, then eluted with dichloromethane with the latter being collected, and the dichloromethane being distilled off under reduced pressure. The residue was dissolved in ethyl acetate and subject to 70 sets (each 3 to 4) of moderate-pressure rapid silica gel column chromatography with the elution of hexane-acetone of different proportions. The product-containing fractions were collected and concentrated. And then the residue is purified with moderate-pressure silica gel chromatography column with elution of methanol - methylene chloride of different proportions. The product-containing fractions were collected, concentrated under reduced pressure to dryness. The residue was then purified by preparative HPLC separation with the resulting product then recrystallized from aqueous methanol twice to obtain pure paclitaxel. Yield: bark: 0.028%, leaves: 0.0088%. Yield: bark: 93.3%, leaves: 88%. Melting point 212 ~ 214 ℃, [α] D20-49 °(1%, chloroform). Chinese yew bark was crushed, dried and soaked with a 1% aqueous solution of citric acid before starting percolation. The percolate was extracted with dichloromethane, the extract was dried, concentrated, and vacuum dried. Use silica gel for two times of column chromatography with the collected effluent containing paclitaxel and cephalomannine. Based on the different side chain structures of them, they are dissolved in carbon tetrachloride for bromination. Only the cephalomannine was brominated, followed by silica gel column chromatography to obtain the effluent only containing Paclitaxel with further treatment giving refined product of Paclitaxel with the content being 99.19%, the yield of 4.5 × 10-5 and the recovery rate of 70% |
| Chemical Properties | White Powder |
| Usage | glucocorticoid, antiinflammatory |
| Usage | An antineoplastic. Used in the study of structure and function of microtubles into tubulin. Paclitaxel is now used to treat patients with lung, ovarian, breast cancer, head and neck cancer, and advanc ed forms of Kaposi's sarcoma. Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. |
| General Description | Needles (from aqueous methanol) or fine white powder. An anti-cancer drug. |
| Air & Water Reactions | May be sensitive to prolonged exposure to moisture. . |
| Health Hazard | TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. |
| Fire Hazard | Flash point data for Paclitaxel are not available. Paclitaxel is probably combustible. |
| Biological Activity | Antitumor agent; promotes and stabilizes tubulin polymerization, causing cell cycle arrest. Induces autocatalytic activation of caspase-10 in CCRF-HSB-2 cells, triggering apoptosis. |