CA2549951A1 - Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii - Google Patents
Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii Download PDFInfo
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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Abstract
An improvement has been provided in the preparation of docetaxel. This improvement process involves the conversion of 9-dihydro-13-acetylbaccatinIII to docetaxel by the step of removing the docetoxyl protective side chain from 7-O-triethylsilyl-9,10--diketodocetaxel.
Description
. =
SEMI-SYNTHETIC ROUTE FOR'I'HE P'RE?AItATIOPI OF PACI.iTAREI~CMT'AXEL
AND l0-DEACETYLBACCATIhT III FROM 9-DISYDRO-13-ACETYL.BACCATIN III
BACKGROUND OF IZMENTION
FIELD OF THE INVENTION
[00011 The present invention relates to a semi-synthetic process for the preparation docetaxel, an anticancer drug and 10-deacetylbacxatin III, a useful precursor for making paclitaxel, the most polwlar anticancer drug, and other taxane compounds.
More partiicularly, this invention relates to a semi-syntlsctic route to synthesim docetaxel and l0-deacetylbaccatin III from 9-dihydru-13-acetylbaacatin III, a taxane compound which is isolated from Taxus Canadensis, a evergt+een bush found in Eastern Canada and Northeasbern United States.
PRIOR ART
SEMI-SYNTHETIC ROUTE FOR'I'HE P'RE?AItATIOPI OF PACI.iTAREI~CMT'AXEL
AND l0-DEACETYLBACCATIhT III FROM 9-DISYDRO-13-ACETYL.BACCATIN III
BACKGROUND OF IZMENTION
FIELD OF THE INVENTION
[00011 The present invention relates to a semi-synthetic process for the preparation docetaxel, an anticancer drug and 10-deacetylbacxatin III, a useful precursor for making paclitaxel, the most polwlar anticancer drug, and other taxane compounds.
More partiicularly, this invention relates to a semi-syntlsctic route to synthesim docetaxel and l0-deacetylbaccatin III from 9-dihydru-13-acetylbaacatin III, a taxane compound which is isolated from Taxus Canadensis, a evergt+een bush found in Eastern Canada and Northeasbern United States.
PRIOR ART
[0002] Taxanes are substances occurring naturally in yew trees such as Taxus canadensis, which is common in Eastern Canada and the United States. One of the chemicals extracted from the needles of Taxus canadensis is 9-dihydro-13-acetylbaccatin III, which is used to produce, inter alia,l0-deacetylbaccatin II[, which is a useful intermediate for the preparation of paclitaxel and analogues tlereof.
[0003] The uucane family of terpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents. Many taxane derivatives, including paclitaxel, docetaxel, taxoultine canadensol are highly cytotoxic and possess strcmg in vivo activities in a niunber of leukemic and other tnmor systems. Paclitaxel, and a number of its derivatives, have been shown to be effective against advanced breast and ovarian cancers in clinical trials. hey have also exhibited promising activity against a number of other tumor types in preliminary investigations. Paclitaxel has recently been approved in the U.S. and Canada for the treatment of ovarian cancers.
[0004] The only available natural source of paclitaxel to date are several species of a slow growing yew (genus Taxus), wherein paclitaxel is found in very low concentratons (less than 400 parts per million) in the bark of these trees.
Thus, paclitaxel . =
can be isolated from the bark of the pacific yew tree (Taxus brevifolia) and ground hemlock (Taacv.t Canadensis), but the yield is very low (0.01 /.-0 .02'/s), and the isolation and purification process is too coinplicate. Furthermore the extraction is ditTicult, and the poccss is eapensive. Since removal of the bark destroys the trees and endangers the species, isolation of taxanes from the stems and needles of various Taxus species was believed to offer hope that the supply of taxanes, in pacticular paclitaxel, would become more abundant. This led to the switching from paclitaxel derived from natural to the production of semi-synthetic, starting from 10-deacetylbaccatin III, which was isolated from the needles of English yew (Tazus baccata).
Thus, paclitaxel . =
can be isolated from the bark of the pacific yew tree (Taxus brevifolia) and ground hemlock (Taacv.t Canadensis), but the yield is very low (0.01 /.-0 .02'/s), and the isolation and purification process is too coinplicate. Furthermore the extraction is ditTicult, and the poccss is eapensive. Since removal of the bark destroys the trees and endangers the species, isolation of taxanes from the stems and needles of various Taxus species was believed to offer hope that the supply of taxanes, in pacticular paclitaxel, would become more abundant. This led to the switching from paclitaxel derived from natural to the production of semi-synthetic, starting from 10-deacetylbaccatin III, which was isolated from the needles of English yew (Tazus baccata).
[0005] Due to the structural complexity of peclitaxel, and docetaxel, partial syathesis is a far more viable approach to providing adequate supplies of paclitaxel and docetaxel. Docetaxel was originally invented by Aventis, It went to the market in 1995 and it is a fast growing anticancer drug. This drug is semi-synthetic product, also starting from 10-deacetylbacatin M. So far the commercial supply of docetaxel comes substantiatly completely from 10-deacetylbacxatin III. To date, however, the supply of 10-deacetylbaccatin III is limited due to the limited biomass resource and low isol.ation yield (ranging from 50-165 mg per ldlogcam of needles of Taxus baccata [0006] Various processes of converting 9-dihydro-13,acetylbaccatin III into 10-deacetylbaccatin III have been proposed. However, it has been found that such processes result in poor yields of final product. Thus, a need still e)ists for an efficient method for converting 9-dihydro-13 acetylbaccatin III to 10-deacetylbaccatin DI (DAB
III).
III).
[0007] The pmaration of paclitaxel derivatives, some of which have been reported to demonstrate enhanced chemotherapeutic activity, ultimately depends upon the supply of the parent compound, namely, baccatin III. The struottue of baccatin III has the basic diterpenoid struchue of paclitaxel without the side chain at the C-13 position.
[00081 Since baccatin III is an important staring material in paclitaxel semi-synthesis, the significance of baccatin III will likely increases as more clinical studies are performed using paclitaxel. One such reason is that it appears that water-soluble paclitaxel-like compounds with slightly modified C-13 side chains may be more desirable as cancer chemotherapeutYc agents than the naturally-occurring, less water soluble . =
paclitaxel. This increases the urgent need for the peoductioa of bacartin M as a starting material to synthesize both paclitaxel and second or third generation p clitaxel-hke compounds. There is, therefore, a need for an improved method of isolating and/or syathesizing Baccatin IIL
[0009] In fact, most of the research to date regarding the semi-synthesis of pacGtaxel has involved 10-deacetylbaccatin III. The conversion of 10-deacetylbaccatin III
into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-10 position, attachment of a C-13 beta-amicb ester side chain at the C-13 position through esterification of the C-13 alcohol with the.beta.-lactam moiety, and deprotecting C-7. Since the supply of 10-deacetylbaccatin IlI is limited, other sources should be pursued [00010] The following is a non-exhaustive list of patents which are believed to be relevant to the pmesent invention.
[00011] Canadian Patent Application No. 2,188,190, published Apr. 18,1998, in the name of Zamir et al, descnbed a senii-synthetic process to convert a rnKdually-occuring taxane into a suitable starting material for the synthesis of such taxane derivatives as paclitaxel, cephelomanine and other taxenes which are structurally-related to baccatn III.
[00012] US Patent No 6,878,834, patented Apr 12, 2005 by R.H. Holton et al, related to the prepatation of a derivative, or analog of, baccatin IIi or 10-desacatyl baccatin having a C-9 substituent other that a keto substituent of a taxol. a keto in which the C-9 keto substituant of a toxo analalog, baccatinIII or 10-a taxol analog, of 10-desbaccatine bacatin III was selectively reduced to the corresponding hydroxyl group.
[000131 US Patent No. 6,812,356, patented Nov 2, 2004, by Findly, provided a process for the use of 9-hdroxyl3 9-baccatin III for the production of C-13 acyloxy sidechain-bearing taxanes ,e.g., paclitaxol and analogs thereof . It related particularly to novel processes of coupling the oxazolines to form the taxanes.
[00014] US Patent No. 6,734,304, patented Aug 31, 2004, by Bristol-Myers (.._ Squibb Company provided novel oxazolidines,, which found ut0ity as internnediates in the preparation of C-13-acyloxy side chain-bearing toxanes, e.g., paclitaxol and analogs thereof. It related more specifically, to procedures for coupling the oxazolidines to form the taxanes.
[00015] US Patent 6,710,191, patented Mar 23, 2004 by R.A. Holton et al, provided a process for the preparation of a derivative or analog of baccatin III, or 10-desacetyl baccatin III , having a C9 substituent other than a keto, in which the C9 keto substituent of taxol, a taxol analog, baccatin III, or 10-desacetyl baccatin III was selectively reduced to the correspondi.ng hydroxyl group.
[00016] US Patent No. 6,593,482 patented Jul 15, 2003 by H. Bouchard et al, provided a procedure for preparing methylthiomethyl taxoids from baccatin III
and beta lactam. [00017] US Patent No. 6,576,777, patented Jun 10 2003 by L. Zamir et al, provided a semi-synthetic process to convert a naturally-occuring taxane into a suitable statting compound for the synthesis of paclitaxol and related compounds. It specifically related to a process for the conversion of 9-dihydroxy-13-acetyl baccatin III
into a 7-protected baccatin III., which can be used for the synthesis of taxol derivatives, e.g., paclitaxol, docataxel cephalomannine and other taxanes which were stractncally related to baccatin III..
[00018] US Patent No. 6 495,701, patented Dec 17, 2002-by R.A. Holton et al, provided a process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III having a C9 substituent other than keto in which the C9 keto, in which the C9 keto substituent of taxol, a taxol analog baccatinIII or 10-dasacetyl baccatin III was selectively reduced to the corresponding hydroxyl group.
[00019] Other patents which provided processes for the preparation of novel taxoids included U.S. Patent No. 6,384,071 patented May 7, 2002 by Aventis Pharma S.A., US Patent No. 6,331, 635 patented Dec 18 2001, by Aventis Pharma S.A.
and US
Patent No. 6, 232,477 patented May 15, 2001 by Aventis Pharma S.A.
[00020] US Patent No. 6,222,053, patented Apr 24, 2001, by Institut National de la Research Scientific, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting material for the synthesis of paclitaxel and related compounds. Specifically, it related to a process for the conversion of 9-dihydro-13-acetylbaccatin III into a 7-protected baccatin III which can then be used as staRing material for the synthesis of such taxane derivatives as paclitaxel, docetaxel, cephalomawine and other taxanes Mrctarally related to baccatin III.
[00021] US Patent No 6,197,981, patented Mar 6, 2001, by J. Liu, provided a process for preparing taxol, baccatin III and 1 Q-deacetylbaccatin III by oxidation of 9-dihydroxy-13-wetylbaccatin.
[00022] US Patent No. 6, 175,023, patented Jan 16, 2001 by J. Liu, provided for the semisynthesis of 9-dihydrotaxanes using 9-dihydroxy-13-acetylbaccatinIII
as the initial compound [00023] US Patent No 6,066,747, patented May 23 2000 by RH.Holton et al, provided a process for the preparation of taxol, baccatin III and 10-desacetylbaccatinIII
derivatives or other taxanes having new C9 functional groups.
[00024] US Patent No. 5,763,477, pat,ented Jun 9 1998 by Dr Reddy's Resesarch Foundation provided a process for the preparation of taxane derivatives from 14-beta hydroxy-l0-deacetlybaccatin.
[00025] US Patent No. 5,616,740, patented Apr 1, 1997 by Abbott Laboratories, US Patent No 5,594,157, patented Jan 14, 1997 by Abbott Laboratories and US
Patent No. 5,530,020 patented Jun 25, 1996 by Abbott Laboratories each provided deoxygenated taxol compounds which were prepared from a natural product which was isolated from taxus canadansis, as well as analogs of taxol which were prepared therefrom.
[00026] US Patent No. 5,440,056, patented Aug 8, 1995 by Abbott Laboratories, provided deoxygenated taxol products prepared from a natural product which is isolated from taxus canadansis.
[00027] U.S.Patent No. 5,352,806 patented Oct 4,1994 by Abbott Laboratories provided 9-dihydro-l3-acetyl a natutal product which is derived from taxm canadansis.
[00028] U.S. Pat. US Patent No. 4,924,011, re-issued as U.S. Patent No. 34,277 by Denis et al provided the first sucoessfal semi-synthesis of paclitaxel using the starting material 10-deacetylbaccatin III which can be extracted in relatively high yield from the needles of specific species.
[00029] The invention in its general form will first be described, and then its implementation in terms of specific embodiments will be detailed with reference to the drawings following hereafter. These embodiments are intended to demonstrate the principle of the invention, and the manner of its implementation. the invention in its broadest sense and more specific forms will then be fiuther described, and defined, in each of the individual claims which conclude this Specification SiTNIIMIARY OF THE IIWENTION
[00030] It is therefore desirable to provide a process for the semi-synthesis of docataxel.
[000311 It is also desirable to provide a semi-synthesis of 10-deacetylbaccatin III .
It is also desirable provide a semi-synthetic process for the preparation of docatexel and I0-deacetylbaccatin III from 9-dihydrxy-l3-acetylbaccatin III .
[00032] There is also a need for an improved proces of isolating and/or synthesizing Baccatin III.
[00033] A need still exists for an efficient process for converting 9-dihydro-acetylbaccatin III to 10-deacetylbaccatin III (DAB III).
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f07 STATEMENTS OF INYENTION
[00034J A first broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro- l3-acetylbaccatin IIl to docetaxel, the improvement comprising the final step of removing the docetoxyl protective side chain ~ from 7-O-triethylsilyl 9,10-diketodocetaxel.
[00035] A second broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acetylbaccatin III to docetaxei, the improvement comprising the two steps of firstly, reacting a beta-lactam protected docetaxel side chain precursor with 7- 7-O-triethylsilyl-9,10-diketobaccatin III, thereby to produce 7-O-triethy6ilyl-9,10-diketodocetaxel containing a beta-Iactam protected docetaxel side chain, and the second or final step of removing the beta lactam protected side chain from 7-O-triethylsilyl-9,10-diketodocetaxel.
[00036] A third broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acehylbaccatin III to docetaxel, the improvement comprising the sequential steps of converting 7-0-triethylsilyl-l0-deacetylbaccatin II to 10-deacetylbaccatin III, converting said 10-deacetylbaccatin III to 7-O-trisilyl-9,10-diketobaccatin IIl, reacting said 7-0-trisilyl-9,10-diketobaccatin III, with a beta-lactam docetaxel protective side chain precursor to produce 7-0-triethylsilyl-9,10-diketobaccatin III, and the final step of removing the beta lactam docetoxyl protective side chain from 7-0-triethylsilyl-9,10-diketodocetaxel, [00037] A fourth broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acetylbaccatinlII to docetaxel the improvement of which comprises the sequential steps of effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro-13-acetylbaccatin III while substantially-simultaneously converting the 10-acetyl group to a 10-hyroxy group, thereby to produce 7-O-triethylsilyl-l0-deacetyl-9-dihydro-13-acetylbaccatin III; converting the 13-acetyl group on 7-0-triethylsilyl-l0-deacetyl-9-dihydro-13-acetylbaccatin III to a 13-hydroxy group, thereby to produce 7-0-triethylsilyl-9,10-diketo-ljobaccatin III; C7 7 reducing the 9-ketogroup on 7-0-triethylsilyi-9,10-diketo- 13-hydroxy-acetylbaccatin III, thereby to produce 7-0-triethylsilyl-l0-deacetylbaccatin IIl; reducing the 9-10-dihydrxy groups from 7-0-triethylsilyl-l0-deacetyl-9,10-dihydroxy-l3-acetylbaccatin III, thereby to produce 7-0-triethylsilyl-9,10-diketo-baccatin III; effecting a triethylsilylation reaction on the 9-hyroxy group of 9-dihydro- 13-acetylbaccatin III , thereby to produce 7,9-0- di(-g triethylsilyl} 10-deacetyl-9-ketobaccatin III ; reacting 7,9-0- di(-triethylsilyl)- 10-~ deacetyl9-ketobsccatin 191 with a protected beta-lactam ddocatexl side chain precursor thereby to produce 7-O-triethylsily19,10-ddcetodocetaxel;and removing the beta-lactam docatexl side chain precursor, thereby to produce docetaxel.
2. OTHER FEATURES OF THE INVENTION
[00038] By one feature of the above aspects of the present invention, the deprotection step is carried out using lithium aluminum hydride.
[00039] The foregoing summarizes the principal features of the invention and some of its optional aspects. The invention may be further understood by the description of the preferred embodiments which now follow.
DESCRIPTION OF PREFERRED EMBODIIVIENTS
[00040] The following are non-limiting examples of the process of aspects of the present invention.
EXAMPLE 1: PREPARATION OF 7-TES-10-DEACETYL-9-DIHYDRO-13-ACETYLBACCATIN III C 5-, glna w r, a-Q-~ CO-94 p c~ u~ ~~ uti ~.1 [00041] To 10 ml of acetonitrile, 102 mg of 9-dihydro-13-acetylbaccatin III
and 173 mg of n tetrabutylammonium iodide were added, the mixture was stined for 5 minutes until 9-dihydro-l3-acetylbaccatin III was completely dissolved. The mixture was kept in -10 C, then chlorotriethylsilane was added dropwise. The mixture was stirred for another 5-10 minutes at -10 C before 26 mg of sodium methoxide was poured into the round bottom flask. This mixture was kept stirred for another one hour at the same temperature then the temperature was raised to 0 C, and maintained at 0 C for about 1 hour. Then the temperature was raised to room temperature the mixture was kept stirred for 2 more hours. The reaction was quenched by dilution with brine, and extracted with ethyl acetate for three times. The organic phase was combined and evaporated to dryness in vacuum. The residue was purified by preparative TLC to yield 7-0-triethylsilyl-l0-deacetyl-9-dihydro-13-acetylbaccatin III as a white solid (85 mg, 85%). ('Ap ujx GLa.J
cmii ,44 EXA1bIlPLE 2: PREPARATION OF 7-TES-9,10-DIKETO-13-ACETYLBACCATIIN
]I[ (b) [00042] T o 5m1 of a c e t n n i t r i l and acqtonemixture~(3~ 1), 73 mg of -STFS-9,10-cem diketo- 13-acetYlbaccatin IIIvasadded 4methylmorpholine-N-oxide (NMdf~ a round bottom flask, and the mixture was dissolved in 3 ml dichloromethane. 4 A
molecular sieve was added to the mixture which stiffed for 5 minutes. 5 mg of tetra-n-propylammonium perruthenate (TPAP) was added, and the mixture was stirred for about 6 hours at room temperature, following which the temperature was raised to 40 C. The mixture was maintained at that temperature overnight until the reaction was completed.
Once the reaction was completed, the rnixture was poured into a short silica gel column.
The column was eluted with 50 ml of dichloromethane (CH2C12) to give a CH2C12 fraction which was concentrated to dryness. The residue was purified by preparative TLC
to yield 60 mg white solid which identified as 7-TES-9,10-diketo-13-acetylbaccatin III
QA ~tn~. P~. 2- 04) Crir~vj2ewr,~( Co EXAMPLE 3: PREPARATION OF 10-DEACETYLBACCATIN III ~? ~ =
[00043] Step A: To a solution of 95% of ethanol, 45 mg of the compound &,~,~
added and stirred until the solid was completely dissolved, and then hydrazine monohydrate (0.6m1) and 10 mg of LiAlH4 was added, then the solution was stirred for 8 hours at room temperature, after that the reaction was quenched by brine and extracted with dichloromethane and organic phase was collected and concentrated to dryness in vacuum. The residue was purified through silica gel column. Product 7-TES-10-deacetylbaccatin III was obtained as slightly yellow crystals.
17- a4wn-, A--. IG'.is. 2 a4. C;,V~ $ .
[00044] Step B: 7-TES-10-deacetylbacca.tin III was dissolved in a mixture of acetonitrile and acetone (3:1), the solution then was stirred at room temperature for a few minutes before 5 ml of sodium hypochioride was added dropwise. The mixture was reacted at room temperature for 2 hours and then quenched with brine and extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness and the residue was re-crystallized from acetonitrile to yield 10-deacetylbaccatin III as a white powdert .44ouM u,d,_ ?1 EXAMPLE 4: PREPARATION OF 7-TES-9,10-DIIKETODOCETAXEL C 1 Z
[00045] Step A: To a solution of 95% ethanol, 40 mg of compound 6 was added and stined for a few minutes until the solid was dissolved, then lml of hydrazine monohydrate was added The mixture was stimed at room temperature for 2 hours, then diluted with ethyl acetate (50 mt) and poured into saturated NH{Cl solution (40m1). The organic layer was separated and concentiated. The residue was purified by precipitation using TLC to 14e 30,õ,~~õ7-TES-9,10-diketobaccatin III C &~pw4 7 FG~, [00046] Step B: 35 mg of 7-TES-9,10-diketobaccatin III was placed in a 25 ml round bottom flask, and 3 mole equivalents of protected &lactam docetaxel side chain precursor were dissolved in 20 ml of tetrahydrofuran (TI-1F) at -45 C, then 6 mole equivalents of LiHMDS was added slowly. The mixture was stined at -45 C for 30minutes then warmed to room temperature. The reaction progress was detec.~ted by TLC
until completion. Once completed, the mixture was diluted with dichloromethane (50 ml) and poured into saturated N114C1 solution (40m1). The organic layer was separated and concentrated. The residue was purified by ptecipitation using TLC to yield 7-TES-9,10-diketodocetaxel ? 444wv~
EXA.MPLE 5: PREPARATION OF DOCETAXEL
[00047] Step A: 7-TES-9,10-diketodocetaxel was dissolved in tetrahydrofuran (THF), and then LiAlH4 was added, the mixture was stirred at -15 C for about I hour or until the reaction was completed The reaction was quenched with 50 ml of ethyl acetate and saturated NH4C1 mixture (3:1). The organic layer was separated and concentrated to dtyness, the residue was took to next step without purification C4et (p~ 13 vr, ~.G~= ~~
[00048] Step B: The residue was redissolved in THF, and sodium hypochloride (NaOCI) was added dropwise. The mixture was stimod for 2hours at room temperature then work-up as above. The residue was purified through flash column chromatography.
Docetaxel was obtained as white needles( QQ~ y~W~aw ~.~, F,L9 . Y I
i~
CONCLUSION
[00049] The foregoing has constitlrted a description of specific embodiments showing how the invention may be applied and put into use. these embodiments are only exemplary. The invention in its broadest form, and more specific aspects is further descnbed and defined in the claims which follow.
[00050] These claims, and the language used therein are to be understood in terms of the variants of the invention which have been described They are not to be restricted to such variants, but are to be read as covering the fiill scope of the invention as is implicit within the invention and the disclosure that has been provided herein.
[00081 Since baccatin III is an important staring material in paclitaxel semi-synthesis, the significance of baccatin III will likely increases as more clinical studies are performed using paclitaxel. One such reason is that it appears that water-soluble paclitaxel-like compounds with slightly modified C-13 side chains may be more desirable as cancer chemotherapeutYc agents than the naturally-occurring, less water soluble . =
paclitaxel. This increases the urgent need for the peoductioa of bacartin M as a starting material to synthesize both paclitaxel and second or third generation p clitaxel-hke compounds. There is, therefore, a need for an improved method of isolating and/or syathesizing Baccatin IIL
[0009] In fact, most of the research to date regarding the semi-synthesis of pacGtaxel has involved 10-deacetylbaccatin III. The conversion of 10-deacetylbaccatin III
into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-10 position, attachment of a C-13 beta-amicb ester side chain at the C-13 position through esterification of the C-13 alcohol with the.beta.-lactam moiety, and deprotecting C-7. Since the supply of 10-deacetylbaccatin IlI is limited, other sources should be pursued [00010] The following is a non-exhaustive list of patents which are believed to be relevant to the pmesent invention.
[00011] Canadian Patent Application No. 2,188,190, published Apr. 18,1998, in the name of Zamir et al, descnbed a senii-synthetic process to convert a rnKdually-occuring taxane into a suitable starting material for the synthesis of such taxane derivatives as paclitaxel, cephelomanine and other taxenes which are structurally-related to baccatn III.
[00012] US Patent No 6,878,834, patented Apr 12, 2005 by R.H. Holton et al, related to the prepatation of a derivative, or analog of, baccatin IIi or 10-desacatyl baccatin having a C-9 substituent other that a keto substituent of a taxol. a keto in which the C-9 keto substituant of a toxo analalog, baccatinIII or 10-a taxol analog, of 10-desbaccatine bacatin III was selectively reduced to the corresponding hydroxyl group.
[000131 US Patent No. 6,812,356, patented Nov 2, 2004, by Findly, provided a process for the use of 9-hdroxyl3 9-baccatin III for the production of C-13 acyloxy sidechain-bearing taxanes ,e.g., paclitaxol and analogs thereof . It related particularly to novel processes of coupling the oxazolines to form the taxanes.
[00014] US Patent No. 6,734,304, patented Aug 31, 2004, by Bristol-Myers (.._ Squibb Company provided novel oxazolidines,, which found ut0ity as internnediates in the preparation of C-13-acyloxy side chain-bearing toxanes, e.g., paclitaxol and analogs thereof. It related more specifically, to procedures for coupling the oxazolidines to form the taxanes.
[00015] US Patent 6,710,191, patented Mar 23, 2004 by R.A. Holton et al, provided a process for the preparation of a derivative or analog of baccatin III, or 10-desacetyl baccatin III , having a C9 substituent other than a keto, in which the C9 keto substituent of taxol, a taxol analog, baccatin III, or 10-desacetyl baccatin III was selectively reduced to the correspondi.ng hydroxyl group.
[00016] US Patent No. 6,593,482 patented Jul 15, 2003 by H. Bouchard et al, provided a procedure for preparing methylthiomethyl taxoids from baccatin III
and beta lactam. [00017] US Patent No. 6,576,777, patented Jun 10 2003 by L. Zamir et al, provided a semi-synthetic process to convert a naturally-occuring taxane into a suitable statting compound for the synthesis of paclitaxol and related compounds. It specifically related to a process for the conversion of 9-dihydroxy-13-acetyl baccatin III
into a 7-protected baccatin III., which can be used for the synthesis of taxol derivatives, e.g., paclitaxol, docataxel cephalomannine and other taxanes which were stractncally related to baccatin III..
[00018] US Patent No. 6 495,701, patented Dec 17, 2002-by R.A. Holton et al, provided a process for the preparation of a derivative or analog of baccatin III or 10-desacetyl baccatin III having a C9 substituent other than keto in which the C9 keto, in which the C9 keto substituent of taxol, a taxol analog baccatinIII or 10-dasacetyl baccatin III was selectively reduced to the corresponding hydroxyl group.
[00019] Other patents which provided processes for the preparation of novel taxoids included U.S. Patent No. 6,384,071 patented May 7, 2002 by Aventis Pharma S.A., US Patent No. 6,331, 635 patented Dec 18 2001, by Aventis Pharma S.A.
and US
Patent No. 6, 232,477 patented May 15, 2001 by Aventis Pharma S.A.
[00020] US Patent No. 6,222,053, patented Apr 24, 2001, by Institut National de la Research Scientific, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting material for the synthesis of paclitaxel and related compounds. Specifically, it related to a process for the conversion of 9-dihydro-13-acetylbaccatin III into a 7-protected baccatin III which can then be used as staRing material for the synthesis of such taxane derivatives as paclitaxel, docetaxel, cephalomawine and other taxanes Mrctarally related to baccatin III.
[00021] US Patent No 6,197,981, patented Mar 6, 2001, by J. Liu, provided a process for preparing taxol, baccatin III and 1 Q-deacetylbaccatin III by oxidation of 9-dihydroxy-13-wetylbaccatin.
[00022] US Patent No. 6, 175,023, patented Jan 16, 2001 by J. Liu, provided for the semisynthesis of 9-dihydrotaxanes using 9-dihydroxy-13-acetylbaccatinIII
as the initial compound [00023] US Patent No 6,066,747, patented May 23 2000 by RH.Holton et al, provided a process for the preparation of taxol, baccatin III and 10-desacetylbaccatinIII
derivatives or other taxanes having new C9 functional groups.
[00024] US Patent No. 5,763,477, pat,ented Jun 9 1998 by Dr Reddy's Resesarch Foundation provided a process for the preparation of taxane derivatives from 14-beta hydroxy-l0-deacetlybaccatin.
[00025] US Patent No. 5,616,740, patented Apr 1, 1997 by Abbott Laboratories, US Patent No 5,594,157, patented Jan 14, 1997 by Abbott Laboratories and US
Patent No. 5,530,020 patented Jun 25, 1996 by Abbott Laboratories each provided deoxygenated taxol compounds which were prepared from a natural product which was isolated from taxus canadansis, as well as analogs of taxol which were prepared therefrom.
[00026] US Patent No. 5,440,056, patented Aug 8, 1995 by Abbott Laboratories, provided deoxygenated taxol products prepared from a natural product which is isolated from taxus canadansis.
[00027] U.S.Patent No. 5,352,806 patented Oct 4,1994 by Abbott Laboratories provided 9-dihydro-l3-acetyl a natutal product which is derived from taxm canadansis.
[00028] U.S. Pat. US Patent No. 4,924,011, re-issued as U.S. Patent No. 34,277 by Denis et al provided the first sucoessfal semi-synthesis of paclitaxel using the starting material 10-deacetylbaccatin III which can be extracted in relatively high yield from the needles of specific species.
[00029] The invention in its general form will first be described, and then its implementation in terms of specific embodiments will be detailed with reference to the drawings following hereafter. These embodiments are intended to demonstrate the principle of the invention, and the manner of its implementation. the invention in its broadest sense and more specific forms will then be fiuther described, and defined, in each of the individual claims which conclude this Specification SiTNIIMIARY OF THE IIWENTION
[00030] It is therefore desirable to provide a process for the semi-synthesis of docataxel.
[000311 It is also desirable to provide a semi-synthesis of 10-deacetylbaccatin III .
It is also desirable provide a semi-synthetic process for the preparation of docatexel and I0-deacetylbaccatin III from 9-dihydrxy-l3-acetylbaccatin III .
[00032] There is also a need for an improved proces of isolating and/or synthesizing Baccatin III.
[00033] A need still exists for an efficient process for converting 9-dihydro-acetylbaccatin III to 10-deacetylbaccatin III (DAB III).
~
C"
v ( =
s dupa ~ ~
f07 STATEMENTS OF INYENTION
[00034J A first broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro- l3-acetylbaccatin IIl to docetaxel, the improvement comprising the final step of removing the docetoxyl protective side chain ~ from 7-O-triethylsilyl 9,10-diketodocetaxel.
[00035] A second broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acetylbaccatin III to docetaxei, the improvement comprising the two steps of firstly, reacting a beta-lactam protected docetaxel side chain precursor with 7- 7-O-triethylsilyl-9,10-diketobaccatin III, thereby to produce 7-O-triethy6ilyl-9,10-diketodocetaxel containing a beta-Iactam protected docetaxel side chain, and the second or final step of removing the beta lactam protected side chain from 7-O-triethylsilyl-9,10-diketodocetaxel.
[00036] A third broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acehylbaccatin III to docetaxel, the improvement comprising the sequential steps of converting 7-0-triethylsilyl-l0-deacetylbaccatin II to 10-deacetylbaccatin III, converting said 10-deacetylbaccatin III to 7-O-trisilyl-9,10-diketobaccatin IIl, reacting said 7-0-trisilyl-9,10-diketobaccatin III, with a beta-lactam docetaxel protective side chain precursor to produce 7-0-triethylsilyl-9,10-diketobaccatin III, and the final step of removing the beta lactam docetoxyl protective side chain from 7-0-triethylsilyl-9,10-diketodocetaxel, [00037] A fourth broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acetylbaccatinlII to docetaxel the improvement of which comprises the sequential steps of effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro-13-acetylbaccatin III while substantially-simultaneously converting the 10-acetyl group to a 10-hyroxy group, thereby to produce 7-O-triethylsilyl-l0-deacetyl-9-dihydro-13-acetylbaccatin III; converting the 13-acetyl group on 7-0-triethylsilyl-l0-deacetyl-9-dihydro-13-acetylbaccatin III to a 13-hydroxy group, thereby to produce 7-0-triethylsilyl-9,10-diketo-ljobaccatin III; C7 7 reducing the 9-ketogroup on 7-0-triethylsilyi-9,10-diketo- 13-hydroxy-acetylbaccatin III, thereby to produce 7-0-triethylsilyl-l0-deacetylbaccatin IIl; reducing the 9-10-dihydrxy groups from 7-0-triethylsilyl-l0-deacetyl-9,10-dihydroxy-l3-acetylbaccatin III, thereby to produce 7-0-triethylsilyl-9,10-diketo-baccatin III; effecting a triethylsilylation reaction on the 9-hyroxy group of 9-dihydro- 13-acetylbaccatin III , thereby to produce 7,9-0- di(-g triethylsilyl} 10-deacetyl-9-ketobaccatin III ; reacting 7,9-0- di(-triethylsilyl)- 10-~ deacetyl9-ketobsccatin 191 with a protected beta-lactam ddocatexl side chain precursor thereby to produce 7-O-triethylsily19,10-ddcetodocetaxel;and removing the beta-lactam docatexl side chain precursor, thereby to produce docetaxel.
2. OTHER FEATURES OF THE INVENTION
[00038] By one feature of the above aspects of the present invention, the deprotection step is carried out using lithium aluminum hydride.
[00039] The foregoing summarizes the principal features of the invention and some of its optional aspects. The invention may be further understood by the description of the preferred embodiments which now follow.
DESCRIPTION OF PREFERRED EMBODIIVIENTS
[00040] The following are non-limiting examples of the process of aspects of the present invention.
EXAMPLE 1: PREPARATION OF 7-TES-10-DEACETYL-9-DIHYDRO-13-ACETYLBACCATIN III C 5-, glna w r, a-Q-~ CO-94 p c~ u~ ~~ uti ~.1 [00041] To 10 ml of acetonitrile, 102 mg of 9-dihydro-13-acetylbaccatin III
and 173 mg of n tetrabutylammonium iodide were added, the mixture was stined for 5 minutes until 9-dihydro-l3-acetylbaccatin III was completely dissolved. The mixture was kept in -10 C, then chlorotriethylsilane was added dropwise. The mixture was stirred for another 5-10 minutes at -10 C before 26 mg of sodium methoxide was poured into the round bottom flask. This mixture was kept stirred for another one hour at the same temperature then the temperature was raised to 0 C, and maintained at 0 C for about 1 hour. Then the temperature was raised to room temperature the mixture was kept stirred for 2 more hours. The reaction was quenched by dilution with brine, and extracted with ethyl acetate for three times. The organic phase was combined and evaporated to dryness in vacuum. The residue was purified by preparative TLC to yield 7-0-triethylsilyl-l0-deacetyl-9-dihydro-13-acetylbaccatin III as a white solid (85 mg, 85%). ('Ap ujx GLa.J
cmii ,44 EXA1bIlPLE 2: PREPARATION OF 7-TES-9,10-DIKETO-13-ACETYLBACCATIIN
]I[ (b) [00042] T o 5m1 of a c e t n n i t r i l and acqtonemixture~(3~ 1), 73 mg of -STFS-9,10-cem diketo- 13-acetYlbaccatin IIIvasadded 4methylmorpholine-N-oxide (NMdf~ a round bottom flask, and the mixture was dissolved in 3 ml dichloromethane. 4 A
molecular sieve was added to the mixture which stiffed for 5 minutes. 5 mg of tetra-n-propylammonium perruthenate (TPAP) was added, and the mixture was stirred for about 6 hours at room temperature, following which the temperature was raised to 40 C. The mixture was maintained at that temperature overnight until the reaction was completed.
Once the reaction was completed, the rnixture was poured into a short silica gel column.
The column was eluted with 50 ml of dichloromethane (CH2C12) to give a CH2C12 fraction which was concentrated to dryness. The residue was purified by preparative TLC
to yield 60 mg white solid which identified as 7-TES-9,10-diketo-13-acetylbaccatin III
QA ~tn~. P~. 2- 04) Crir~vj2ewr,~( Co EXAMPLE 3: PREPARATION OF 10-DEACETYLBACCATIN III ~? ~ =
[00043] Step A: To a solution of 95% of ethanol, 45 mg of the compound &,~,~
added and stirred until the solid was completely dissolved, and then hydrazine monohydrate (0.6m1) and 10 mg of LiAlH4 was added, then the solution was stirred for 8 hours at room temperature, after that the reaction was quenched by brine and extracted with dichloromethane and organic phase was collected and concentrated to dryness in vacuum. The residue was purified through silica gel column. Product 7-TES-10-deacetylbaccatin III was obtained as slightly yellow crystals.
17- a4wn-, A--. IG'.is. 2 a4. C;,V~ $ .
[00044] Step B: 7-TES-10-deacetylbacca.tin III was dissolved in a mixture of acetonitrile and acetone (3:1), the solution then was stirred at room temperature for a few minutes before 5 ml of sodium hypochioride was added dropwise. The mixture was reacted at room temperature for 2 hours and then quenched with brine and extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness and the residue was re-crystallized from acetonitrile to yield 10-deacetylbaccatin III as a white powdert .44ouM u,d,_ ?1 EXAMPLE 4: PREPARATION OF 7-TES-9,10-DIIKETODOCETAXEL C 1 Z
[00045] Step A: To a solution of 95% ethanol, 40 mg of compound 6 was added and stined for a few minutes until the solid was dissolved, then lml of hydrazine monohydrate was added The mixture was stimed at room temperature for 2 hours, then diluted with ethyl acetate (50 mt) and poured into saturated NH{Cl solution (40m1). The organic layer was separated and concentiated. The residue was purified by precipitation using TLC to 14e 30,õ,~~õ7-TES-9,10-diketobaccatin III C &~pw4 7 FG~, [00046] Step B: 35 mg of 7-TES-9,10-diketobaccatin III was placed in a 25 ml round bottom flask, and 3 mole equivalents of protected &lactam docetaxel side chain precursor were dissolved in 20 ml of tetrahydrofuran (TI-1F) at -45 C, then 6 mole equivalents of LiHMDS was added slowly. The mixture was stined at -45 C for 30minutes then warmed to room temperature. The reaction progress was detec.~ted by TLC
until completion. Once completed, the mixture was diluted with dichloromethane (50 ml) and poured into saturated N114C1 solution (40m1). The organic layer was separated and concentrated. The residue was purified by ptecipitation using TLC to yield 7-TES-9,10-diketodocetaxel ? 444wv~
EXA.MPLE 5: PREPARATION OF DOCETAXEL
[00047] Step A: 7-TES-9,10-diketodocetaxel was dissolved in tetrahydrofuran (THF), and then LiAlH4 was added, the mixture was stirred at -15 C for about I hour or until the reaction was completed The reaction was quenched with 50 ml of ethyl acetate and saturated NH4C1 mixture (3:1). The organic layer was separated and concentrated to dtyness, the residue was took to next step without purification C4et (p~ 13 vr, ~.G~= ~~
[00048] Step B: The residue was redissolved in THF, and sodium hypochloride (NaOCI) was added dropwise. The mixture was stimod for 2hours at room temperature then work-up as above. The residue was purified through flash column chromatography.
Docetaxel was obtained as white needles( QQ~ y~W~aw ~.~, F,L9 . Y I
i~
CONCLUSION
[00049] The foregoing has constitlrted a description of specific embodiments showing how the invention may be applied and put into use. these embodiments are only exemplary. The invention in its broadest form, and more specific aspects is further descnbed and defined in the claims which follow.
[00050] These claims, and the language used therein are to be understood in terms of the variants of the invention which have been described They are not to be restricted to such variants, but are to be read as covering the fiill scope of the invention as is implicit within the invention and the disclosure that has been provided herein.
Claims (4)
1. In a process for the conversion of 9-dihydro-13-acetylbaccatinIII to docetaxel, the final step of removing the docetoxyl protective side chain from 7-O-triethylsilyl-9,10-diketodocetaxel.
2. The process as claimed in claim 1, wherein said deprotection step is carried out using lithium aluminum hydride.
3. In a process for the conversion of 9-dihydro- 13-acetylbaccatin III to docetaxel, the step of reacting beta lactam protected docetaxel side chain precursor with triethylsilyl-9,10-diketobaccatin III, thereby to produce 7-O-triethylsilyl-9,10-diketodocetaxel a beta-lactam protected docetaxel side chain , and the final step of removing the docetoxyl protective side chain from 7-O-triethylsilyl-9,10-diketodocetaxel.
4. In a process for the conversion of 9-dihydro-13-acetylbaccatin III to docetaxel, the step converting 7-O-triethylsilyl-l0-deacetylbaccatin II to 10-deacetylbaccatin III, converting said 10-deacetylbaccatin III, to 7-O-trisilyl-9,10-diketobaccatin III, reacting said 7-O-trisilyl-9,10-diketobaccatin III, with a beta-lactam docetaxel side chain precursor to produce 7-O-triethylsilyl-9,10-diketobaccatin III, , and the final step of removing the beta lactam docetoxyl protective side chain from 7-0-triethylsilyl-9,10-diketodocetaxel.
A process for the conversion of 9-dihydro- 13-acetylbaccatinIII to docetaxel which comprises: effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro- 13-acetylbaccatin III while substantially-simultaneously converting the 10-acetyl group to a 10-hyroxy group, thereby to produce 7-O-triethylsilyl-10-deacetyl-9-dihydro-13-acetylbaccatin III; converting the 13-acetyl group on 7-O-triethylsilyl-10-deacetyl-9-dihydro-13-acetylbaccatin III to a 13-hydroxy group, thereby to produce 7-O-triethylsilyl-9,10-diketo-13-hydroxy- acetylbaccatin III; reducing the 9-ketogroup on 7-O-triethylsilyl-9,10-diketo-13-hydroxy-acetylbaccatin III, thereby to produce triethylsilyl-l0-deacetylbaccatin III; reducing the 9-10-dihydrxy groups from triethylsilyl-l0-deacetyl-9,10-dihydroxy-13-acetylbaccatin III, thereby to produce 7-O-triethylsilyl-9,10-diketo-baccatin III; effecting a triethylsilylation reaction on the 9-hyroxy group of 9-dihydro-13-acetylbaccatin III, thereby to produce 7,9-O- di(-triethylsilyl)-10-deacetyl-9-ketobaccatin III ; reacting 7,9-O- di(-triethylsilyl)-10-deacetyl-9-ketobaccatin III with a protected beta-lactam docatexl side chain precursor thereby to produce 7-O-triethylsilyl-9,10-diketodocetaxel;and removing the beta-lactam docatexl side chain precursor, thereby to produce docetaxel.
6.~A compound of formula 5.~
7.~A compound of formula 6.
8.~A compound of formula 7.
9.~A compound of formula 9.
10.~A compound of formula 10.
A process for the conversion of 9-dihydro- 13-acetylbaccatinIII to docetaxel which comprises: effecting a triethylsilylation reaction on the 7-hyroxy group of 9-dihydro- 13-acetylbaccatin III while substantially-simultaneously converting the 10-acetyl group to a 10-hyroxy group, thereby to produce 7-O-triethylsilyl-10-deacetyl-9-dihydro-13-acetylbaccatin III; converting the 13-acetyl group on 7-O-triethylsilyl-10-deacetyl-9-dihydro-13-acetylbaccatin III to a 13-hydroxy group, thereby to produce 7-O-triethylsilyl-9,10-diketo-13-hydroxy- acetylbaccatin III; reducing the 9-ketogroup on 7-O-triethylsilyl-9,10-diketo-13-hydroxy-acetylbaccatin III, thereby to produce triethylsilyl-l0-deacetylbaccatin III; reducing the 9-10-dihydrxy groups from triethylsilyl-l0-deacetyl-9,10-dihydroxy-13-acetylbaccatin III, thereby to produce 7-O-triethylsilyl-9,10-diketo-baccatin III; effecting a triethylsilylation reaction on the 9-hyroxy group of 9-dihydro-13-acetylbaccatin III, thereby to produce 7,9-O- di(-triethylsilyl)-10-deacetyl-9-ketobaccatin III ; reacting 7,9-O- di(-triethylsilyl)-10-deacetyl-9-ketobaccatin III with a protected beta-lactam docatexl side chain precursor thereby to produce 7-O-triethylsilyl-9,10-diketodocetaxel;and removing the beta-lactam docatexl side chain precursor, thereby to produce docetaxel.
6.~A compound of formula 5.~
7.~A compound of formula 6.
8.~A compound of formula 7.
9.~A compound of formula 9.
10.~A compound of formula 10.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002549951A CA2549951A1 (en) | 2006-06-12 | 2006-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
| EP07719967A EP2029563A4 (en) | 2006-06-12 | 2007-06-12 | SEMI-SYNTHETIC PATHWAY FOR THE PREPARATION OF PACLITAXEL, DOCETAXEL AND 10-DEACETYLBACCATINE III FROM 9-DIHYDRO-13-ACETYLBACCATINE III |
| CNA2007800293778A CN101528720A (en) | 2006-06-12 | 2007-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
| PCT/CA2007/001051 WO2007143839A1 (en) | 2006-06-12 | 2007-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002549951A CA2549951A1 (en) | 2006-06-12 | 2006-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
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| Publication Number | Publication Date |
|---|---|
| CA2549951A1 true CA2549951A1 (en) | 2007-12-12 |
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ID=38829282
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|---|---|---|---|
| CA002549951A Abandoned CA2549951A1 (en) | 2006-06-12 | 2006-06-12 | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
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| CA (1) | CA2549951A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009023967A1 (en) * | 2007-08-22 | 2009-02-26 | 6570763 Canada Inc. | Process for converting 9-dihydro-13-acetylbaccatin iii into docetaxel or paclitaxel |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964316A (en) * | 2012-11-14 | 2013-03-13 | 湖北一半天制药有限公司 | Radical protection method for synthesis of docetaxel |
| CN104592173A (en) * | 2014-12-31 | 2015-05-06 | 宁波绿之健药业有限公司 | Preparation method for synthesizing 10-DAB (10-deacetyl baccatin) III from 9-DHB (13-acetyl-9-dihydrobaccatin) III |
| CN114656427A (en) * | 2022-03-31 | 2022-06-24 | 上海健佑生物科技有限公司 | Taxol anticancer drug and synthesis method thereof |
-
2006
- 2006-06-12 CA CA002549951A patent/CA2549951A1/en not_active Abandoned
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009023967A1 (en) * | 2007-08-22 | 2009-02-26 | 6570763 Canada Inc. | Process for converting 9-dihydro-13-acetylbaccatin iii into docetaxel or paclitaxel |
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