CN100420681C - Production of polyenoic taxad alcohol trihydrate - Google Patents
Production of polyenoic taxad alcohol trihydrate Download PDFInfo
- Publication number
- CN100420681C CN100420681C CNB2005100255800A CN200510025580A CN100420681C CN 100420681 C CN100420681 C CN 100420681C CN B2005100255800 A CNB2005100255800 A CN B2005100255800A CN 200510025580 A CN200510025580 A CN 200510025580A CN 100420681 C CN100420681 C CN 100420681C
- Authority
- CN
- China
- Prior art keywords
- trihydrate
- polyenoic
- thf
- under
- tetrahydrofuran
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The present invention relates to a preparation method of polyenoic taxad alcohol trihydrate, which adopts tetrahydrofuran and water mixtures to refine polyenoic taxad alcohol trihydrate. The present invention has advantages of high yield, favorable stabillity of products and easy operation, and is suitable for scale production of the polyenoic taxad alcohol trihydrate.
Description
Technical field:
The present invention relates to technical field of medicine synthesis, be specifically related to the preparation method of polyenoic taxad alcohol trihydrate.
Background technology:
Docetaxel is first semisynthetic Japanese yew class medicine, goes on the market the America and Europe.
Docetaxel all has antitumour activity to kinds of tumor cells, comprising mammary cancer, and nonsmall-cell lung cancer and other malignant tumour such as prostate cancer, esophagus cancer and head malignant tumour etc.It is one of the most effective single medicine of treatment metastatic breast cancer.
Docetaxel can promote tubulin to be assembled into microtubule and suppress its depolymerization also have bioavailability preferably, the retention time in the higher IC, longer cell.
The Docetaxel chemical name: 5 β, the 20-epoxy-[1 β, 2 α, 4 α, 7 β, 10 β, 13 α-hexahydroxy--Japanese yew-11 alkene-9-ketone-4 acetate fat-2-benzoate-13-[(2 ' R, 3 ' S)-N-tertbutyloxycarbonyl-3 '-the different silk of phenyl amino acid fat] trihydrate.
Docetaxel is a s-generation taxanes cancer therapy drug, and its cytosis mechanism is identical with taxol, but Docetaxel (Docetaxel) is subjected to people's attention day by day with the water-soluble and excellent anticancer broad spectrum of its increase.The mechanism of action of polyenoic taxad alcohol trihydrate is to strengthen the tubulin polymerization effect and suppress the microtubule depolymerization effect, causes forming stable non-functional microtubule fasolculus, thereby tumoricidal mitotic division.It is higher 3 times than taxol at IC, and in cell the residence time long, thereby the anti-tumor activity than taxol is big in vitro tests.In vivo in the test, effectively to the colorectal carcinoma of mouse, mammary cancer, lung cancer, ovarian tumor graft etc.To the cell strain of cis-platinum, etoposide, 5Fu or taxol resistance, and have the advantages that not produce crossing drug resistant.
According to Chinese patent 95193984.x, polyenoic taxad alcohol trihydrate is more stable than its anhydride, so increase by a step crystallization reaction when the raw materials for production medicine, reaction solvent selects to have the alcohol and water of 1-3 carbon atom.
But the inventor finds in experimentation, when using alcoholic solvent to carry out crystallization, when being dissolved, anhydride needs to heat up, and polyenoid stable bad in alcoholic solvent, for example under the condition about 40 ℃, placed about 5 hours, and produced 1.47% impure point, influenced stability.
Summary of the invention:
Technical problem to be solved by this invention is to overcome the weak point of aforesaid method, designs a kind of improved preparation method.
The invention provides a kind of preparation method of polyenoic taxad alcohol trihydrate, method of the present invention has adopted tetrahydrofuran (THF) and the refining polyenoic taxad alcohol trihydrate of water mixture, this method is: with HPLC purity greater than the methylene dichloride dissolving of 99% polyenoid anhydride with 18-22 times of volume, the tetrahydrofuran (THF) that adds double distilled about 18-22 times of volume again, under 25-35 ℃ of 0.08MPa vacuum degree condition, concentrate then and remove methylene dichloride, be warmed up to 40-50 ℃, under stirring condition, drip the purified water of 0.7-0.9 times of volume of tetrahydrofuran (THF) fast, place 2-8 ℃ refrigerator and cooled to hide placement 2-3 hour reaction flask after adding, continue system is placed-20 ℃ refrigerator and cooled to freeze preservation 3-4 hour again, vacuum concentration is removed tetrahydrofuran (THF) under the condition of 35-45 ℃ of 0.09MPa vacuum tightness then, suction filtration, filter cake is placed under the 0.095MPa vacuum degree condition, and 35-45 ℃, relative humidity is 60-75%, constant temperature and humidity drying, dry 12-24 hour, obtain polyenoic taxad alcohol trihydrate, yield is 104.2%.It is 6.46% that moisture detects through Ka Erfeixiu reagent, the coincidence detection requirement.
What adopt that thermogravimetric analysis and differential thermal analysis confirm to obtain by this method is polyenoic taxad alcohol trihydrate.Mass loss between 65-130 ℃ is 6.67%, and this contains three crystal water with reactant is consistent, and the dissolvent residual of product meets the ICH regulation simultaneously.
Method of the present invention has following advantage:
1, simple to operate, because polyenoic taxad alcohol trihydrate is to adopt slow crystallization method, therefore the crystal grain that forms is bigger, and the suction filtration ratio is easier to, and the planar water on surface is less, has therefore shortened time of drying, thereby has reduced the destruction of heat to the polyenoid product.
2, because tetrahydrofuran (THF) is smaller to the solubleness of polyenoid product, be the choice solvent that the polyenoid series products is cultivated monocrystalline, the purified yield reaches about 104% than higher, and the yield of other method is 80%-90%.
3, the product stability that obtains of the inventive method is good, and at 40 ℃, relative humidity is that this polyenoic taxad alcohol trihydrate is placed 30 days product purities without any variation, good stability simultaneously without any change under 75%, 18 month situation under 60 ℃ of conditions.
Embodiment:
Example 1
HPLC purity is used the methylene dichloride dissolving of 1720ml greater than 99% Docetaxel anhydride 86 grams, then at the tetrahydrofuran (THF) that adds the 1720ml volume that heavily steamed, under 30 ℃ of 0.08MPa vacuum degree condition, methylene dichloride is concentrated then, be warmed up to 45 ℃ then, be added dropwise to the purified water of 1376ml volume under the stirring condition fast, then system is placed 2-8 ℃ refrigerator and cooled to hide placement 2 hours, continue system is placed the refrigerator and cooled about-20 ℃ to freeze preservation 3 hours then, vacuum concentration falls tetrahydrofuran (THF) under the condition of 40 ℃ of 0.09MPa vacuum tightnesss then, suction filtration, filter cake is placed under the 0.095MPa vacuum degree condition, 40 ℃, constant temperature and humidity drying, relative humidity is 60-75%, dry 18 hours, obtain polyenoic taxad alcohol trihydrate 89.35 grams, yield is 103.9%.It is 6.52% that moisture detects through Ka Erfeixiu reagent.
Example 2
With HPLC purity greater than 99% Docetaxel anhydride, 59 grams, methylene dichloride dissolving with the 1180ml volume, then at the tetrahydrofuran (THF) that adds the 1180ml volume that heavily steamed, under 30 ℃ of 0.08MPa vacuum degree condition, methylene dichloride is concentrated then, be warmed up to 45 ℃ then, be added dropwise to the purified water of 0.5 times of volume of tetrahydrofuran (THF) under the stirring condition fast, adding a small amount of polyenoid three water thing crystal seeds then arrives till the little muddiness of system, placing 2-8 ℃ refrigerator and cooled to hide system placed 2 hours, continue system is placed the refrigerator and cooled about-20 ℃ to freeze preservation 3 hours then, vacuum concentration falls tetrahydrofuran (THF) under the condition of 40 ℃ of 0.09MPa vacuum tightnesss then, suction filtration, filter cake is placed under the 0.095MPa vacuum degree condition, 40 ℃, constant temperature and humidity drying, relative humidity is 60-75%, dry 16 hours, obtain polyenoic taxad alcohol trihydrate 61.66 grams, yield is 104.5%.It is 6.52% that moisture detects through Ka Erfeixiu reagent.
Claims (1)
1. the preparation method of a polyenoic taxad alcohol trihydrate, it is characterized in that this method for HPLC purity greater than the methylene dichloride dissolving of 99% Docetaxel anhydride with 18-22 times of volume, the tetrahydrofuran (THF) that adds the 18-22 times of volume that heavily steamed again, then at 25-35 ℃, 0.08MPa concentrate under the vacuum degree condition and remove methylene dichloride, be warmed up to 40-50 ℃, under stirring condition, be added dropwise to the purified water of tetrahydrofuran (THF) 0.7-0.9 times volume fast, place 2-8 ℃ refrigerator and cooled to hide placement 2-3 hour reaction flask after adding, continue system is placed-20 ℃ refrigerator and cooled to freeze preservation 3-4 hour again, then at 35-45 ℃, 0.09MPa vacuum concentration is removed tetrahydrofuran (THF) under the condition of vacuum tightness, suction filtration, filter cake is placed under the 0.095MPa vacuum degree condition, 35-45 ℃, relative humidity is 60-75%, constant temperature and humidity drying dry 12-24 hour, obtains polyenoic taxad alcohol trihydrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100255800A CN100420681C (en) | 2005-04-29 | 2005-04-29 | Production of polyenoic taxad alcohol trihydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100255800A CN100420681C (en) | 2005-04-29 | 2005-04-29 | Production of polyenoic taxad alcohol trihydrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1854132A CN1854132A (en) | 2006-11-01 |
| CN100420681C true CN100420681C (en) | 2008-09-24 |
Family
ID=37194624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100255800A Expired - Fee Related CN100420681C (en) | 2005-04-29 | 2005-04-29 | Production of polyenoic taxad alcohol trihydrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100420681C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100995390B1 (en) * | 2006-01-02 | 2010-11-19 | 주식회사 삼양제넥스 | Method for preparation of amorphous anhydrous crystalline or hydrated crystalline docetaxel |
| KR100878455B1 (en) | 2007-04-10 | 2009-01-13 | 한미약품 주식회사 | Stable anhydrous crystalline docetaxel and method for the preparation therof |
| WO2012160568A1 (en) * | 2011-05-23 | 2012-11-29 | Shilpa Medicare Limited | Process for preparing docetaxel trihydrate polymorph |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1075722A (en) * | 1991-12-20 | 1993-09-01 | 鲁索-艾克勒夫公司 | New steroide and method for making thereof, intermediate and application |
| US6002022A (en) * | 1995-01-25 | 1999-12-14 | Rhone-Poulenc Rorer S.A. | Method for preparing 4, 10-diacetoxy-2α-benzoyloxy-5β, 20-Epoxy-1, 7β-dihydroxy-9-oxo-tax-11-en-13α-yl(2R,3S)-3-benzoylamino-2-h ydroxy-3-phenylpropionate trihydrate |
| US6022985A (en) * | 1994-07-08 | 2000-02-08 | Rhone-Poulenc Rorer S.A. | Process for the preparation of 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1, 7β-10β-trihydroxy-9-oxo-tax-11-en-13α-yl(2R,3S)-3-tert-b utoxy-carbonYlamino-2-hydroxy-3-phenylpropionate trihydrate |
| US6150541A (en) * | 1995-12-14 | 2000-11-21 | Aventis Pharma S.A. | 4,10-β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]t ax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and its process of preparation |
-
2005
- 2005-04-29 CN CNB2005100255800A patent/CN100420681C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1075722A (en) * | 1991-12-20 | 1993-09-01 | 鲁索-艾克勒夫公司 | New steroide and method for making thereof, intermediate and application |
| US6022985A (en) * | 1994-07-08 | 2000-02-08 | Rhone-Poulenc Rorer S.A. | Process for the preparation of 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1, 7β-10β-trihydroxy-9-oxo-tax-11-en-13α-yl(2R,3S)-3-tert-b utoxy-carbonYlamino-2-hydroxy-3-phenylpropionate trihydrate |
| US6002022A (en) * | 1995-01-25 | 1999-12-14 | Rhone-Poulenc Rorer S.A. | Method for preparing 4, 10-diacetoxy-2α-benzoyloxy-5β, 20-Epoxy-1, 7β-dihydroxy-9-oxo-tax-11-en-13α-yl(2R,3S)-3-benzoylamino-2-h ydroxy-3-phenylpropionate trihydrate |
| US6150541A (en) * | 1995-12-14 | 2000-11-21 | Aventis Pharma S.A. | 4,10-β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]t ax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and its process of preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1854132A (en) | 2006-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108358973B (en) | Naphthalimide tetravalent platinum compound, preparation method and application thereof in preparation of antitumor drugs | |
| CN105237563A (en) | 2-oxo propionic acid p-hydroxy benzoyl hydrazone bis(2,4-dichlorobenzyl) tin complex and preparation method and application thereof | |
| CN105384770A (en) | 2-oxo-propionic acid salicyloyl hydrazone and di(p-methylbenzyl)tin complex as well as preparation method and application of 2-oxo-propionic acid salicyloyl hydrazone and di(p-methylbenzyl)tin complex | |
| CN108147995A (en) | A kind of low 1,8- Naphthalamide derivatives of toxicity and its synthetic method and application | |
| CN100420681C (en) | Production of polyenoic taxad alcohol trihydrate | |
| CN103044395A (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| CN101511843B (en) | Method for production of hydrochloride 1(10) beta-epoxy-13-dimethylamino-5,7alpha,6,11beta (h)-guaia-3(4)-en-6,12-olide, the lyophilized antitumor preparation 'arglabin' | |
| CN107556361A (en) | Driffractive ring lupinane derivative and its anticancer usage | |
| CN110938032A (en) | Organic selenium compound and use thereof | |
| CN108164463A (en) | A kind of 1,8- Naphthalamide derivatives and its synthetic method and application with non-small cell lung cancer selective inhibitory | |
| CN1268619C (en) | Prepn of polyene taxol trihydrate | |
| CN108101925B (en) | A kind of plectranthin type diterpene split melphalan derivative and its preparation method and application | |
| CN110041342B (en) | Selenium-containing compound and application thereof | |
| CN107043345B (en) | 4-acetylbiphenyl hydrazone-indoline -2,3- diketone Schiff base preparation, structure and purposes | |
| CN105968064B (en) | Two tolyl tetrazine diformamide compounds of one kind and preparation and application | |
| CN110938033A (en) | Selenocyanine compounds and uses thereof | |
| CN113549122B (en) | Glycosylated tetravalent platinum compound targeting GLUTs, synthetic method and application thereof | |
| CN109467560B (en) | Selenocyanine compound and application thereof | |
| CN102731442A (en) | Preparation method and application of water-soluble docetaxel compounds | |
| CN110698383B (en) | Structure, synthesis and application of benzil hydrazone-3-acetyl indole | |
| CN105949139A (en) | Sec-butyl diphenyl tetrazine formamide compound, preparation and application | |
| CN102702140A (en) | Preparation method and application of water-soluble paclitaxel compound | |
| CN102731772A (en) | Camptothecin compound pegylated derivatives | |
| CN106928292B (en) | A kind of nitrate NO donator type scutellarin derivative and its preparation method and application | |
| CN105949140A (en) | Diphenyl tetrazine dicarboamide compound, preparation and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Shanghai Aurisco International Co., Ltd. Assignor: Shanghai Aoruite International Trade Co., Ltd. Contract record no.: 2010330001580 Denomination of invention: Production of polyenoic taxad alcohol trihydrate Granted publication date: 20080924 License type: Exclusive License Open date: 20061101 Record date: 20100804 |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080924 Termination date: 20120429 |