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WO2005037840A1 - Methode pour inverser le groupe hydroxyle c2' d'esters de taxane - Google Patents

Methode pour inverser le groupe hydroxyle c2' d'esters de taxane Download PDF

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Publication number
WO2005037840A1
WO2005037840A1 PCT/US2004/033858 US2004033858W WO2005037840A1 WO 2005037840 A1 WO2005037840 A1 WO 2005037840A1 US 2004033858 W US2004033858 W US 2004033858W WO 2005037840 A1 WO2005037840 A1 WO 2005037840A1
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Prior art keywords
taxane
group
paclitaxel
olefinic
oxazole
Prior art date
Application number
PCT/US2004/033858
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English (en)
Inventor
James D. Mcchesney
Madhavi C. Chander
John T. Henri
James V. Ferrara
Herbert R. Brinkman
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Mayne Pharma (Usa), Inc.
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Publication of WO2005037840A1 publication Critical patent/WO2005037840A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention generally relates to the production of taxanes, such as paclitaxel, docetaxel and analogs and derivatives thereof.
  • the invention concerns the synthesis of taxanes from coupled ester byproducts produced during the esterification of a protected baccatin III backbone and an isoserine acid.
  • the present invention especially concerns the inversion of the C2' hydroxyl group of 2'epi coupled ester taxane compounds.
  • BACKGROUND OF THE INVENTION Various taxane compounds are known to exhibit anti-tumor activity. As a result of this activity, taxanes such as paclitaxel and docetaxel, as well as their analogs and derivatives, have received increasing attention in the scientific and medical community.
  • paclitaxel is currently regarded as one of the best anticancer agents due to its demonstration of anti-tumor activity.
  • Paclitaxel binds to a site on cell microtubules, disrupting the cell cycle and causing the cell to die. As such, paclitaxel impairs the proliferation of tumor cells.
  • the success of paclitaxel is largely due to its ability to work in combination with other anticancer therapeutic agents.
  • the U.S. Food and Drug Administration has approved the use of paclitaxel for chemotherapeutic treatment of several different varieties of tumors, including the treatment of breast and ovarian cancers, lung cancers, and AIDS- related cancers.
  • Paclitaxel is one of the largest selling cytotoxic agents in the world.
  • Taxanes In 1999, the global sales of paclitaxel from all manufacturers constituted 22% of all major cytotoxic compounds used in cancer chemotherapy. Docetaxel has also been found to exhibit anti-tumor activity, and additional taxanes and their derivatives may show promising activity as well. Accordingly, organic chemists are spending substantial time and resources in attempting to devise cost effective and efficient methods of synthesizing paclitaxel, docetaxel and other taxane compounds.
  • One approach to the partial synthesis of such taxanes generally involves the esterification of an appropriate isoserine acid or derivative thereof with baccatin III or a closely related diterpenoid substance.
  • U.S. Patent Nos. 5,675,025; 5,688,977; 5,750,737; 5,770,745; 5,939,566; 5,948,919; 6,072,060; and 6,448,417 disclose several methods for synthesizing taxanes through such esterifications, which explore a number of variations in starting materials, protecting groups, acylations and chemosynthetic steps.
  • Yields of 2'-epi paclitaxel may be approximately 12-20% of the total yield of the paclitaxel provided by the method described in that patent.
  • other corresponding 2' epi coupled ester byproducts may be formed during the esterification step of other known processes for the partial synthesis of taxanes, such as those described in the patents listed above.
  • the formation of these byproducts therefore, can substantially reduce the yield of the desired final taxane product formed by such processes. Accordingly, it is desirable to provide a process that allows for the utilization of these 2'epi coupled ester byproducts.
  • a process that inverts the C2' hydroxyl group of 2'epi coupled ester byproducts into the corresponding desired taxane products, or other useful intermediates thereby improve the overall yield of important anti-cancer agents such as paclitaxel and docetaxel. .
  • the present invention is directed to such a process.
  • a method is provided for inverting the 2'-hydroxy position of a 2'-hydroxy taxane that includes at the 3'-N position a group containing an aromatic functionality, such as a benzoyl group or a carbobenzyloxy (CBZ) group.
  • the method comprises converting the 2'-hydroxy taxane to an oxazole intermediate, hydrolyzing the oxazole intermediate to an amine salt intermediate, and treating the amine salt intermediate with a base thereby to form an inverted 2'-hydroxy taxane.
  • the 2'-hydroxy taxane may specifically be 2'- epi-paclitaxel, paclitaxel, a 3'-N-protected taxane such as 3'-N-CBZ-protected 2'-epi paclitaxel or 3'-N-CBZ-protected paclitaxel, or analogs or derivatives thereof.
  • the oxazole intermediate may be formed by protecting the 2'-hydroxyl of the 2'-hydroxy taxane with a protecting group that is a good leaving group, such as various sulfonyl groups including tosyl, mesyl or nosyl groups, to form a protected intermediate that then undergoes cyclization to the oxazole intermediate.
  • a protecting group that is a good leaving group such as various sulfonyl groups including tosyl, mesyl or nosyl groups
  • conversion of the 2'-hydroxy taxane to the oxazole intermediate may be accomplished by addition of an agent such as tosyl chloride, mesyl chloride or nosyl chloride in the presence of a base such as pyridine, triethylamine, dimethyla inopyridine, or 1 ,4- diazabicyclo[2.2.2]octane (DabcoTM).
  • the step of hydrolyzing the oxazole intermediate to the amine salt intermediate may be accomplished by adding an acid, such as an organic acid or inorganic acid, including hydrochloric acid.
  • the amine salt intermediate may be treated with a base such as triethylamine or pyridine to form the inverted 2'-hydroxy taxane. More specifically, the present invention provides a method for converting a first taxane of formula:
  • Ri may be an aromatic group such as Ph or PhCH 2 or an O-aromatic group such as PhCH 2 O-;
  • R 2 may be H, an alkyl group, an olefinic group, or an aromatic group such as Ph; and
  • R 3 may be a taxane backbone.
  • R 3 may be baccatin III, 10-deacetyl baccatin III taxane backbone or analogs or derivatives thereof, as well as C-7 and/or C-10 protected taxane backbones, and analogs or derivatives thereof.
  • the method comprises converting the first taxane to an oxazole intermediate of formula: then hydrolyzing the oxazole intermediate to an amine salt intermediate of formula:
  • a " is an anion of an acid, and then converting the amine salt intermediate to the second taxane.
  • the step of converting the first taxane to the oxazole intermediate may be accomplished by providing a 2' protecting group that is a good leaving group, such as a tosyl, mesyl or nosyl group, for example, and cyclization by elimination of the 2'-protected hydroxy to form the oxazole intermediate.
  • the step of hydrolyzing the oxazole intermediate to the amine salt intermediate may be accomplished by addition of an organic acid or inorganic acid, such as hydrochloric acid (whereby A " in the above formula would be the chloride anion).
  • the step of converting the amine salt intermediate to the second taxane may be accomplished by treating the amine salt intermediate with a base, such as triethylamine or pyridine.
  • the method may include the further step of converting the second taxane to a third taxane of formula:
  • R may be an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO-, an O-olefinic group, or an O-aromatic group such as PhCH 2 O-.
  • the first taxane may specifically be 2'-epi paclitaxel or 3'-N-CBZ- protected 2'-epi paclitaxel or an analog or derivative thereof.
  • the third taxane may specifically be paclitaxel, docetaxel or an analog or derivative thereof. Additionally, the present invention provides a method for converting a first taxane of formula:
  • the method comprises converting the first taxane to an oxazole intermediate of formula:
  • a " is an anion of an acid, and then converting the amine salt intermediate to the second taxane.
  • the step of converting the first taxane to the oxazole intermediate may be accomplished by providing a 2' protecting group that is a good leaving group, such as a tosyl, mesyl or nosyl group, for example, and cyclization by elimination of the 2'-protected hydroxy to form the oxazole intermediate.
  • the step of hydrolyzing the oxazole intermediate to the amine salt intermediate may be accomplished by addition of an organic acid or inorganic acid, such as hydrochloric acid (whereby A " in the above formula would be the chloride anion).
  • the step of converting the amine salt intermediate to the second taxane may be accomplished by treating the amine salt intermediate with a base, such as triethylamine or pyridine.
  • the method may include a further step of converting the second taxane to a third taxane of formula:
  • the first taxane may specifically be paclitaxel or 3'-N-CBZ- protected paclitaxel or an analog or derivative thereof.
  • the third taxane may specifically be 2'-epi paclitaxel, 2'-epi docetaxel or an analog or derivative thereof.
  • the present invention additionally provides a method for forming an oxazole intermediate compound for use in the production of taxanes.
  • the oxazole intermediate may be formed by protecting the 2'-hydroxyl of a 2'-hydroxy taxane with a protecting group that is a good leaving group, such as various sulfonyl groups including tosyl, mesyl or nosyl groups, to form a protected intermediate that then undergoes cyclization to the oxazole intermediate.
  • a protecting group that is a good leaving group such as various sulfonyl groups including tosyl, mesyl or nosyl groups
  • conversion of the 2'-hydroxy taxane to the oxazole intermediate may be accomplished by addition of an agent such as tosyl chloride, mesyl chloride or nosyl chloride in the presence of a base such as pyridine, triethylamine or acetonitrile.
  • the present invention also relates to novel compounds and intermediates formed by the processes of the present invention.
  • the present invention provides an oxazole compound having a formula selected from:
  • Ri is alkyl, olefinic, aromatic, O-alkyl, O-olefinic, or O-aromatic;
  • R 2 is H, alkyl, olefinic, aromatic,
  • R 3 is a taxane backbone, and
  • a " is the anion of an acid.
  • Ri is preferably aromatic such as Ph or O-aromatic such as PhCH 2 0-,
  • R 2 is preferably Ph, and
  • R 3 is preferably a baccatin III or 10-deacetyl baccatin III taxane backbone or a C-7 and/or C-10 protected analog or derivative thereof.
  • FIG. 1 (a) illustrates the inversion of 2'-epi paclitaxel to paclitaxel and back according to the method of the present invention
  • FIG. 1(b) illustrates the inversion of the 2' stereocenter of 3'-N-CBZ protected paclitaxel and the inversion of the 2' stereocenter of 3'-N-CBZ protected docetaxel according to the method of the present invention
  • FIG. 1 (b) illustrates the inversion of the 2' stereocenter of 3'-N-CBZ protected paclitaxel and the inversion of the 2' stereocenter of 3'-N-CBZ protected docetaxel according to the method of the present invention
  • FIG. 1 (c) illustrates the inversion of the 2' stereocenter of (2S,3S) taxanes and (2R,3S) taxanes according to the method of the present invention
  • FIG. 2(a) shows an exemplary process for converting 2'-epi paclitaxel to paclitaxel according to the present invention
  • FIG. 2(b) shows an exemplary process for converting paclitaxel to 2'-epi paclitaxel according to the present invention
  • Fig. 3 shows a generalized process according to the present invention
  • FIG. 4 shows a generalized process for forming oxazole intermediate compounds from either (2S,3S) taxanes or (2R,3S) taxanes.
  • the present invention concerns a chemical process for the efficient production of taxanes such as paclitaxel, docetaxel and their intermediates.
  • the present invention provides a process for improving the overall yield of desired taxanes produced through reactions involving the esterification of an isoserine side chain with a baccatin III backbone.
  • the present disclosure is directed to a process that converts 2'-epimer byproducts of taxane semi-synthesis to more useful anti-cancer treating agents.
  • the chemical process described herein especially relates to the conversion of 2'epi paclitaxel into paclitaxel.
  • Figures 1(a) through 1(c) show exemplary conversions of various taxane compounds that are possible utilizing the process of the present invention, although it should be appreciated that numerous other taxane compounds may be inverted at the 2' position according to the teachings of the present invention.
  • Figure 1 (a) illustrates the conversion of 2' epi paclitaxel to paclitaxel. It should be appreciated that the process of the present invention may be reversed, as shown by the double arrows, such that paclitaxel may also be inverted to its 2'-epimer following the same steps of the present invention.
  • the method of the present invention inverts the stereochemistry of the 2'-hydroxyl regardless of whether the starting conformation is R or S.
  • the 3'-N position may be protected with a protecting group such as the carbobenzyloxy (CBZ) group, which may be replaced after the 2'- inversion with a desired acyl group R 4 CO-, such as benzoyl for paclitaxel or t- butoxycarbonyl for docetaxel, as known in the art.
  • Figure 1 (c) additionally illustrates the inversion of compounds having protecting groups at the C-7 and/or C-10 position.
  • protecting groups may be removed according to methods known in the art and alternatively substituted with other substituents, such as an acetyl group at the 7-position, either prior to or after the inversion of the 2'-hydroxyl.
  • the R 1 CO- group may be replaced with R 4 CO- after the inversion.
  • the group on the 3'-N position is a group that undergoes O to N aroyl migration, such as the benzoyl group shown at 3'-N in Figure 1 (a) or the CBZ group (PhCH 2 OCO-) shown at 3'-N in Figure 1 (b), although other appropriate groups may be substituted as well.
  • the present invention contemplates numerous further applications of the 2'-inversion process taught herein to compounds and intermediates produced during the semi-synthesis of taxanes.
  • the 2'- inversion process of the present invention may be applied to appropriate compounds formed during the synthetic processes taught in U.S. Patent Nos. 5,675,025; 5,688,977; 5,750,737; 5,770,745; 5,939,566; 5,948,919; 6,072,060; and 6,448,417, for example, and the teachings thereof are incorporated herein by reference.
  • the 2'-epi paclitaxel byproduct may be recovered by HPLC.
  • paclitaxel and 2'epi paclitaxel have the same molecular formula but differ due to the stereochemistry of the C-2' hydroxyl group.
  • the process described herein is directed toward inverting the stereochemistry of that C-2' hydroxyl group to provide paclitaxel from 2'-epi paclitaxel, or to provide 2'-epi paclitaxel from paclitaxel.
  • Figure 2(a) illustrates a generalized reaction scheme for converting 2' epi paclitaxel to paclitaxel according to the method of the present invention.
  • 2'epi paclitaxel is first reacted with a suitable sulfonyl chloride, such as tosyl chloride, mesyl chloride or nosyl chloride in the presence of a base such as pyridine or triethylamine to form an oxazole intermediate.
  • a suitable sulfonyl chloride such as tosyl chloride, mesyl chloride or nosyl chloride
  • a base such as pyridine or triethylamine
  • the oxazole intermediate is formed upon elimination of the 2'-protected hydroxyl as the compound undergoes cyclization to the oxazoie. Accordingly, the 2'-posJtion may alternatively be protected with other protecting groups that are suitable leaving groups, thereby to form the oxazole intermediate.
  • the oxazole intermediate is hydrolyzed by addition of aqueous acid, thereby causing the oxazole ring to open and further causing the desired inversion of the 2' stereocenter, which retains the benzoyl group upon ring opening.
  • a suitable base is added to the hydrolyzed byproduct to neutralize the salt and cause the benzoyl group to undergo O to N aroyl migration back to the 3'-N position to produce paclitaxel.
  • This may be accomplished by changing the pH of the reaction solution to basic conditions.
  • this process may alternatively be performed on paclitaxel to form 2'-epi paclitaxel, such as for use in further experimental procedures, as shown in Figure 2(b).
  • A. Converting 2'epi paclitaxel to an oxazole intermediate As shown in Figure 2(a), the oxazole intermediate is produced by the following reaction oxazole intermediate
  • the oxazole intermediate may be formed by reacting 2'epi paclitaxel with any suitable sulfonyl chloride, including methylsulfonyl chloride (mesyl-chloride) and nitrobenzenesulfonyl chloride (nosyl-chloride) in the presence of a suitable base.
  • any suitable sulfonyl chloride including methylsulfonyl chloride (mesyl-chloride) and nitrobenzenesulfonyl chloride (nosyl-chloride) in the presence of a suitable base.
  • Alternative bases that may be used with the selected sulfonyl chloride include pyridine, triethylamine (TEA), dimethylaminopyridine (DMAP), 1 ,4- diazabicyclo[2.2.2]octane (DabcoTM), 1 ,2,4-triazole, hexamethylenetetramine (HMTA), 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8-diazabicyclo[5.4.0]undec- 7-ene (DBU).
  • Alternative solvents include THF, IBAc, acetone, DMF, diethoxymethane, toluene, ACN, 1 ,2-DCE and pyridine.
  • the acid hydrolysis of the oxazole intermediate is preferably carried out with aqueous hydrochloric acid.
  • aqueous hydrochloric acid 1.0 g of oxazole product was dissolved in 75 ml of MeOH and 1.32 ml of 1 N HCI was added and the reaction was stirred for 4 hours after dissolution at room temperature (RT).
  • the reaction may be carried out with EtOH/1 N HCI or THF/ 1 N HCI at RT to give the O-benzoyl compound.
  • the amine salt that is the result of the hydrolysis reaction possesses the 2'-O- benzoate, wherein the 2' stereocenter is inverted from the original starting material. It should be appreciated that the use of hydrochloric acid here provided the ammonium chloride salt.
  • the base catalysed transfer was carried out by evaporating the MeOH on the rotavapor and partitioning the residue in 5% NaHCO 3 and EtOAc (100 ml each). The EtOAc was separated and concentrated to 20 ml and 0.5 ml of TEA was added and left to stand overnight. It should be appreciated that the benzoyl group undergoes O to N aroyl migration from the 2'-O position to the 3'-N position when the amine salt is neutralized and paclitaxel is formed.
  • the oxazole intermediate is formed by reacting the paclitaxel with nitrobenzenesulfonyl chloride (nosyl-chloride), for example, in the presence of base according to the following reaction:
  • paclitaxel 10.0 mmol was dissolved in 150 ml of DCM at RT with stirring as 10.0 equivalents each of DABCO and DMAP were added followed by the addition of nosyl-CI under a nitrogen atmosphere. After five hours, the reaction had gone to 50% completion. Two portions of 0.5 g of nosyl-CI were added immediately and after 12hrs the reaction reached completion providing the oxazole intermediate.
  • the DCM was evaporated and 200 ml of EtOAc was added and the solution was washed with 100ml each of 5% NaHC0 3 and 1 N HCI and concentrated on the rotavapor to produce the oxazole intermediate.
  • a compound providing a good leaving group such as tosyl-CI, mesyl- Cl or nosyl-CI and a base such as pyridine or TEA.
  • a compound providing a good leaving group such as tosyl-CI, mesyl- Cl or nosyl-CI
  • a base such as pyridine or TEA.
  • Ri is an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO-, an O-olefinic group, or an O-aromatic group such as PhCH 2 O-;
  • R 2 is H, alkyl, olefinic or aromatic such as Ph;
  • R 3 is a taxane backbone such as a baccatin III or 10-deacetyl baccatin III backbone or analog or derivative thereof.
  • the second taxane may be converted to a third taxane of formula:
  • R 2 and R 3 are as above and R 4 is an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO-, an O-olefinic group, or an O-aromatic group such as PhCH 2 O-.
  • the CBZ group may be removed by hydrogenation, such as in the presence of Pearlman's catalyst, as known in the art.
  • a compound providing a good leaving group such as tosyl-CI, mesyl- Cl or nosyl-CI and a base such as pyridine or TEA.
  • the oxazole intermediate is next hydrolyzed to an amine salt intermediate of formula: by addition of acid, such as hydrochloric acid.
  • the amine salt intermediate is then converted to a second taxane of formula:
  • R-i is an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO-, an O-olefinic group, or an O-aromatic group such as PhCH 2 0-;
  • R 2 is H, alkyl, olefinic or aromatic such as Ph;
  • R 3 is a taxane backbone such as a baccatin III or 10-deacetyl baccatin III backbone or analog or derivative thereof.
  • the second taxane may be converted to a third taxane of formula:
  • R 2 and R 3 are as above and R 4 is an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO-, an O-olefinic group, or an O-aromatic group such as PhCH 2 O-.
  • the CBZ group may be removed by hydrogenation, such as in the presence of Pearlman's catalyst, as known in the art.
  • the present invention relates to a method for forming an oxazole intermediate compound for use in the production of taxanes, and to oxazole compounds formed thereby.
  • the oxazole intermediate may then be converted to a 2'-O-acyl amine salt of formula:
  • Ri is an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO, an O-olefinic group, or an O-aromatic group such as PhCH 2 0-;
  • R 2 is H, alkyl, olefinic or aromatic such as Ph;
  • R 3 is a taxane backbone such as a baccatin III or 10-deacetyl baccatin III backbone or analog or derivative thereof, and
  • a " is an anion of an acid, such as the chloride anion of hydrochloric acid.
  • oxazole intermediate of formula: is converted to an oxazole intermediate of formula: by protecting the 2'-hydroxy with a protecting group that is a good leaving group, such as by adding various sulfonyl chlorides in the presence of base, as described above.
  • the oxazole intermediate may then be converted to a 2'-O-acyl amine salt of formula:
  • R ⁇ is an alkyl group, an olefinic group, an aromatic group such as Ph, an O-alkyl group such as t-BuO, an O-olefinic group, or an O-aromatic group such as PhCH 2 0-;
  • R 2 is H, alkyl, olefinic or aromatic such as Ph;
  • R 3 is a taxane backbone such as a baccatin III or 10-deacetyl baccatin III backbone or analog or derivative thereof, and
  • a " is an anion of an acid, such as the chloride anion of hydrochloric acid.

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Abstract

L'invention concerne une méthode pour inverser la position 2'-hydroxy de taxanes sélectionnés. Cette méthode consiste à protéger le groupe hydroxyle 2' d'un premier taxane sélectionné, à l'aide d'un groupe de protection hydroxyle, notamment un groupe tosyle, un groupe mésyle ou un groupe nosyle. Le composé de taxane protégé est ensuite converti en un composé oxazole présentant un anneau oxazole. Cet anneau oxazole est ensuite ouvert par un procédé approprié, notamment par hydrolyse du composé oxazole, pour former un composé intermédiaire, qui est ensuite converti en un second taxane. Le composé intermédiaire peut être un sel aminique traité avec une base pour former le second taxane. La méthode de l'invention peut être utilisée pour convertir du paclitaxel 2'epi en paclitaxel. En variante, la méthode peut être utilisée pour convertir du paclitaxel en paclitaxel 2'epi. L'invention concerne encore de nouveaux composés et de nouveaux intermédiaires formés par ce procédé.
PCT/US2004/033858 2003-10-16 2004-10-14 Methode pour inverser le groupe hydroxyle c2' d'esters de taxane WO2005037840A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092306A1 (fr) * 2007-01-26 2008-08-07 Shanghai Parling Pharma-Tech. Co, Ltd. Procédé d'hémisynthèse de taxol et de docétaxel
WO2009023967A1 (fr) * 2007-08-22 2009-02-26 6570763 Canada Inc. Procédé de conversion de la 9-dihydro-13-acétylbaccatine iii en docétaxel ou paclitaxel
KR101787453B1 (ko) 2015-07-28 2017-10-19 주식회사 삼양바이오팜 보관 안정성이 향상된 약학 조성물 및 그의 제조 방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5808102A (en) * 1992-12-23 1998-09-15 Bristol-Myers Squibb Company Phosphorus bearing taxanes intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5808102A (en) * 1992-12-23 1998-09-15 Bristol-Myers Squibb Company Phosphorus bearing taxanes intermediates

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092306A1 (fr) * 2007-01-26 2008-08-07 Shanghai Parling Pharma-Tech. Co, Ltd. Procédé d'hémisynthèse de taxol et de docétaxel
WO2009023967A1 (fr) * 2007-08-22 2009-02-26 6570763 Canada Inc. Procédé de conversion de la 9-dihydro-13-acétylbaccatine iii en docétaxel ou paclitaxel
KR101787453B1 (ko) 2015-07-28 2017-10-19 주식회사 삼양바이오팜 보관 안정성이 향상된 약학 조성물 및 그의 제조 방법

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