基本的な属性 MSDS 用途と合成の方法 サプライヤー

パクリタキセル

基本的な属性 MSDS 用途と合成の方法 サプライヤー
パクリタキセル
  • 化学名:パクリタキセル
  • 英語化学名:Paclitaxel
  • CAS番号:33069-62-4
  • 分子式:C47H51NO14
  • 分子量:853.92
  • EINECS:608-826-9
  • Mol File:33069-62-4.mol
  • パクリタキセル
パクリタキセル 性質
  • 融点 213 °C (dec.)(lit.)
  • 比旋光度 D20 -49° (methanol)
  • 沸点 774.66°C (rough estimate)
  • 比重(密度) 0.200
  • 屈折率 -49 ° (C=1, MeOH)
  • 闪点 9℃
  • 貯蔵温度 2-8°C
  • 溶解性methanol: 50 mg/mL, clear, colorless
  • 外見 powder
  • 酸解離定数(Pka)11.90±0.20(Predicted)
  • white
  • 水溶解度 0.3mg/L(37 ºC)
  • 極大吸収波長 (λmax)227nm(MeOH)(lit.)
  • Merck 14,6982
  • BRN 1420457
  • 安定性:Stable. Incompatible with strong oxidizing agents. Combustible.
  • InChIKeyRCINICONZNJXQF-MZXODVADSA-N
  • CAS データベース33069-62-4(CAS DataBase Reference)
  • EPAの化学物質情報Paclitaxel (33069-62-4)
セキュリティ情報
MSDS Information
パクリタキセル 用途と合成の方法
  • 外観白色~ごくうすい褐色、結晶~粉末
  • 溶解性メタノール溶状:試験適合アセトニトリル及びメタノールにやや溶けやすく、エタノール(99.5)に溶けにくく、水にほとんど溶けない。
  • 用途パクリタキセルは肺がん、卵巣がん、乳がん、頭頸部がん、進行性カポジ肉腫患者の治療に用いられている。また再狭窄の予防にも用いられている。 パクリタキセルは微小管を安定化させることで微小管のダイナミクスを抑制し、その結果正常な細胞分裂の進行を妨げる。ドセタキセルと共に医薬品分類のタキサン類を構成する。フロリダ州立大学のロバート?ホルトンによって初めて全合成された。
  • 用途タキソイド系化合物です。β - チューブリンへ結合して微小管を安定化さ せ、微小管ダイナミクスを抑制することによ り有糸分裂阻害作用を示します。
  • 効能抗悪性腫瘍薬, 微小管脱重合阻害薬
  • 商品名アブラキサン (大鵬薬品工業); タキソール (ブリストル・マイヤーズスクイブ)
  • 説明Paclitaxel, a natural product isolated from the bark of the Pacific yew, is effective in treating refractory metastatic ovarian cancer. Unlike any other antineoplastic agents, paclitaxel appears to have several possible mechanisms of action, including an antimicrotubule action through the promotion of tubulin polymerization and stabilization of microtubules, thereby, halting mitosis and promoting cell death. The supply of paclitaxel is limited by its low natural abundance and currently it is being manufactured by a semi-synthetic route from deacetylbaccatin Ⅲ that is isolated from the needles of the yew tree. Recent completion of two total syntheses of taxol conquered the structural complexity of the title compound and may be useful in obtaining certain closely related analogs, some of which have been found to have antitumor activity. Paclitaxel has potential uses in the treatment of metastatic breast cancer, lung cancer, head and neck cancer, and malignant melanoma.
  • 化学的特性White Powder
  • OriginatorNIH (U.S.A.)
  • 使用glucocorticoid, antiinflammatory
  • 使用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.
  • 使用Tool in study of structure and function of microtubules.
  • 適応症Paclitaxel (Taxol) is a highly complex, organic compound isolated from the bark of the Pacific yew tree. It binds to tubulin dimers and microtubulin filaments, promoting the assembly of filaments and preventing their depolymerization. This increase in the stability of microfilaments results in disruption of mitosis and cytotoxicity and disrupts other normal microtubular functions, such as axonal transport in nerve fibers. The major mechanism of resistance that has been identified for paclitaxel is transport out of tumor cells, which leads to decreased intracellular drug accumulation. This form of resistance is mediated by the multidrug transporter P-glycoprotein.
  • Manufacturing Process(2R,3S)-β-Phenyl-isoserine methyl ester (4.35 g, 22 mM) is dissolved in dry THF (100 ml) and the flask cooled to 0°C. To the mixture is added t-butyl isocyanate (2.8 ml, 25 mM). TLC after 15 min shows some starting material left so additional isocyanate (0.5 ml) is added. TLC after 1 h shows no starting material so the solvent is concentrated under reduced pressure to give the N(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester.
    Triethylamine (4.8 ml, 34.4 mmol) is added to a stirred solution of methyl (2R,3S)-phenylisoserinate (7.26 g, 31.3 mmol) in methylene chloride (80 ml) at 0°C. To this slurry of is added trimethylsilyl chloride (4.4 ml, 34.7 mmol). Additional methylene chloride (45 ml) is added. The mixture is cooled to 65°C and triethylamine (9.8 ml, 70.3 mmol) is added. p-Nitrophenylsulfonyl chloride (6.93 g, 31.3 mmol) is added. The reaction rate is too slow at -65°C so the temperature is gradually raised to 0°C. Hydrogen fluoride (10% aqueous, 5 equivalents) is added. The aqueous phase is separated from the organic (methylene chloride) phase and methanol is added to the organic phase. The methylene chloride is removed under reduced pressure and the methyl (2R,3S)-3-(4-nitrobenzenesulfonamido)-3-phenyl-2-hydroxypropionate is obtained, melting point 187-189°C.
    Benzaldehyde dimethylacetal (200 μl, 1.33 mmol) and a catalytic amount of p-toluenesulfonic acid (37 mg) are added to methyl (2R,3S)-3-(4nitrobenzenesulfonamido)-3-phenyl-2-hydroxypropionate (315 mg, 0.83 mmol) in toluene 5 ml. The mixture is heated at 100°C under reduced pressure (15 mm mercury) with no condenser. After 1 h the crude reaction mixture is diluted with ethyl acetate and washed with water (2 times). After drying the organic layer over magnesium sulfate the crude material is purified by column chormatography (silica gel; eluting with ethyl acetate/cyclohexane, 35/65) to give the (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5methoxycarbonyl-1,3-oxazolidine, melting point 118°-120°C.
    Water (8 ml), methanol (8 ml) and THF (8 ml) are added to (2S,4S,5R)-2,4diphenyl-3-(4-nitrobenzenesulfonamido)-5-methoxycarbonyl-1,3-oxazolidine (1.50 g, 3.19 mmol). Potassium carbonate (1.018 g, 7.71 mmol) is then added. The resulting mixture is stirred at 20°-25°C until complete by TLC. After 5 h the reaction is complete and the reaction mixture is extracted with basic methylene chloride (2 times). The aqueous phase is then acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is then washed with water, saline and dried over magnesiuim sulfate. Concentration of the organic phase (ethyl acetate) gives the (2S,4S,5R)-2,4diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy-1,3-oxazolidine, melting point 61°-65°C.
    Then the (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy1,3-oxazolidine react with the 7-SDMS Baccatin III, that is 7-(3-methylbut-2yl)dimethylsilyl baccatin III (Baccatin III: 7,11-methano-1H-cyclodeca(3,4) benz(1,2-b)oxet-5-one,6,12b-bis(acetyloxy)-12(benzoyloxy)-1,2a,3,4,4a,6, 9,10,11,12,12a,12b-dodecahydro-4,9,11-trihydroxy-4a,8,13,13-tetramethyl-, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS), isolated from Taxus baccata).
    (2S,4S,5R)-2,4-Diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy-1,3oxazolidine(323 mg, 0.711 mmol) is mixed with toluene (2.5 ml) at 20°-25°C. Dicyclohexylcarbodiimide (160 mg, 0.775 mmol) is then added to the reaction mixture. 7-SDMS Baccatin III (156 mg, 0.218 mmol) is added followed by 4(dimethylamino)pyridine (35 mg, 0.286 mmol) and the reaction mixture is stirred at 20°-25°C until complete (1 h) by TLC. Sodium bicarbonate (50% aqueous, 10 ml) and more toluene (5 ml) is added to the reaction mixture and then stirred at 20°-25°C for 2 h. The reaction mixture is filtered through a medium frit to remove the urea byproduct. After filtering the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with aqueous sodium bicarbonate (50%), water and saline. The organic phases are dried over magnesium sulfate, filtered and then concentrated. The concentrate is purified by column chromatograpy (silica gel; eluting with ethyl acetate/cyclohexane, 20/80) to give the 7-SDMS baccatin III 13-(2R,4S,5R)- and (2S,4S,5R)-2,4-diphenyl-3(4-nitrobenzenesulfonamido)-1,3-oxazolidine-5-carboxylic acid ester.
    THF (13.5 ml) and DMF (1.5 ml) are cooled to -35°C and degased by alternating reduced pressure and nitrogen three times. Thiophenol (0.22 ml, 2.14 mmol) is added followed by potassium butoxide/THF (1.978 M, 0.7 ml, 1.38 mmol). After 5 min, 7-SDMS baccatin III 13-(2R,4S,5R)- and (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-1,3-oxazolidine-5carboxylic acid ester (877 mg, 0.762 mmol) is added. After the solids are added, the reaction mixture is slowly warmed to -10°C. The mixture is stirred at -10°C until the red color fades to yellow. After 3 h the bath is dropped allowing the mixture to warm to 20-25°C. At 20°-25°C the reaction is stirred for 1 h before assaying by TLC and HPLC. Sodium bisulfite (241 mg, 2.31 mmol) is added in water (5 ml). The mixture is stirred at 20°-25°C and after approximately 115 h the reaction is complete (by TLC) giving the free amine 7-SDMS Sodium bicarbonate (485 mg, 5.77 mmol) and water (10 ml) are added to 7SDMS baccatin III 13-(2R,3S)-3-amino-3-phenyl-2-hydroxypropionate. The mixture is cooled to 0°C and then benzoyl chloride (150 ml, 1.3 mmol) is added. After 1 hr the reaction is complete and the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phases are combined and washed with water, saline and dried over magnesium sulfate. Chromatography of the crude product (silica gel column; 20% to 100% ethyl acetate gives the 7-SDMS baccatin III 13-(2R,3S)-3-benzamido-3-phenyl-2hydroxypropionate. 7-SDMS Baccatin III 13-(2R,3S)-3-benzamido-3-phenyl-2-hydroxypropionate (126 mg, 0.128 mmol) is dissolved in acetonitrile (2.5 ml). Triethylamine trihydrofluoride (123 mg, 0.763 mmol) is added under nitrogen and the resulting mixture is stirred at 5°C until complete by HPLC. When complete, the mixture is extracted with methyl t-butylether and washed with sodium bicarbonate solution. The aquesous washes are back extracted and combined with the organic phase. The combined organic phases are washed with water and saline, dried over magnesium sulfate, filtered and concentrated to give the Taxol (Paclitaxel), as needle from methanol with melting point 213-216°C.
    baccatin

    III 13-(2R,3S)-3-amino-3-phenyl-2-hydroxypropionate
  • brand nameAbraxane (Abraxis); Taxol (Bristol-Myers Squibb).
  • Therapeutic FunctionAntineoplastic
  • 一般的な説明Paclitaxel is available in single-dose vials of 30 mg/5 mLand 100 mg/16.7 mL for IV administration in the treatmentof breast, ovarian, NSCLC, and AIDS-related Kaposi sarcoma.Other uses have included treatment of head, neck,esophageal, cervical, prostate, and bladder cancers.
    Paclitaxel is highly plasma protein bound (>90%) anddoes not penetrate the CNS. Metabolism involves CYPmediatedoxidation to give 6 -hydroxypaclitaxel (CYP2C8)and para hydroxylation of the phenyl group attached to the3'-position (CYP3A4). The 6α-hydroxy metabolite normallypredominates, but the para hydroxy metabolite mayoccur to a greater degree in those patients with liver diseaseor when CYP3A4 has been induced. Both metabolites areless active than the parent and do not undergo phase II conjugationreactions. Elimination occurs primarily in the feces,and the elimination half-life is 9 to 50 hours depending onthe infusion period.
    The major toxicity seen with paclitaxel is a dose-limitingmyelosuppression that normally presents as neutropenia. Thepreviously mentioned hypersensitivity reactions occur but aregreatly reduced by antihistamine pretreatment. Interactionwith the axonal microtubules such as that seen for the vincasalso occurs and leads to numbness and paresthesias (abnormaltouch sensations including burning and prickling). Theagent is also available as an albumin-bound formulation(Abraxane) to eliminate the need for the solubilizing agentsassociated with the hypersensitivity reactions. Other adverseeffects include bradycardia, which may progress to heartblock, alopecia, mucositis, and/or diarrhea. Paclitaxel producesmoderate nausea and vomiting that is short-lived.
  • 一般的な説明Needles (from aqueous methanol) or fine white powder. An anti-cancer drug.
  • 空気と水の反応May be sensitive to prolonged exposure to moisture. .
  • 健康ハザード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.
  • 火災危険Flash point data for Paclitaxel are not available. Paclitaxel is probably combustible.
  • 生物活性Antitumor agent; promotes and stabilizes tubulin polymerization, causing cell cycle arrest. Induces autocatalytic activation of caspase-10 in CCRF-HSB-2 cells, triggering apoptosis.
  • 作用機序Paclitaxel’s large volume of distribution indicates significant tissue binding. The drug is extensively metabolized by the liver, and doses must be reduced in patients with abnormal liver function or with extensive liver metastases.Very little of the drug is excreted in the urine.
  • 臨床応用Paclitaxel is among the most active of all anticancer drugs, with significant efficacy against carcinomas of the breast, ovary, lung, head, and neck. It is combined with cisplatin in the therapy of ovarian and lung carcinomas and with doxorubicin in treating breast cancer.
  • 抗がん研究It is isolated from the bark of Taxus brevifolia generally known as pacific yew. It isprimarily used in ovarian, small, and non-small cell lung cancers and advancedbreast cancer (Shoeb 2006). It binds to tubulin but neither depolymerizes it nor interferes with its assembly (Balunas and Kinghorn 2005). Taxol targets activatorprotein 1 signaling pathways (Singh et al. 2016b).
  • 抗がん研究Paclitaxel (commercial name, Taxol) a complex diterpene alkaloid isnaturally obtained from Taxus species (family Taxaceae). Paclitaxel has been provedas highly effective in the treatment of various types of cancers, since it acts as amicrotubule-stabilizing agent to protect against disassembly. Paclitaxel was developed by the National Cancer Institute, USA, as a drug for cancer therapy andused for the treatment of refractory ovarian cancer, metastatic breast and lung cancer,and Kaposi’s sarcoma (Srivastava et al. 2005). The natural source of paclitaxelis the bark of several Taxus species; however, the cost of extraction is very highsince the concentration of paclitaxel accumulation is very low (0.02% of dry weight)and also entails the destruction of natural resources (Cusido et al. 2014). Eventhough, paclitaxel can be chemically synthesized, but this process is not commerciallyviable. Plant cell cultures have been developed for the production of paclitaxelby Phyton Biotech in 1995, and in 2004 the FDA has approved the use of plantculture supply of paclitaxel/Taxol (Leone and Roberts 2013).
  • 副作用Myelosuppression is the major side effect of paclitaxel. Alopecia is common, as is reversible dose-related peripheral neuropathy. Most patients have mild numbness and tingling of the fingers and toes beginning a few days after treatment. Mild muscle and joint aching also may begin 2 or 3 days after initiation of therapy. Nausea is usually mild or absent. Severe hypersensitivity reactions may occur. Cardiovascular side effects, consisting of mild hypotension and bradycardia, have been noted in up to 25% of patients.
  • 代謝The major use-limiting adverse effect of paclitaxel is dose-dependent myelosuppression, particularly neutropenia, and first doses may need to be decreased in patients with hepatic dysfunction. Subsequent dose reductions, if any, should be tailored to individual response. The drug should not be given to patients who have baseline neutrophil counts below 1,500 cells/mm3. The albumin-bound formulation also is associated with sensory neuropathy.
パクリタキセルサプライヤー
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