CA2533414A1 - Semi-synthetic route for the preparation of paclitaxel ocetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii - Google Patents

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 THE PREPARATION OF PACLITAXEL OCETAXEL

BACKGROUND OF INVENTION

FIELD OF THE INVENTION

[00011 The present invention relates to a semi-synthetic process for the preparation docetaxel, an anticancer drug and 10-deacetylbaccatin III, a useful precursor for making paclitaxel, the most popular anticancer drug, and other taxane compounds.
More particularly, this invention relates to a semi-synthetic route to synthesize docetaxel and 10-deacetylbaccatin III from 9-dihydro-l3-acetylbaccatin III, a taxane compound which is isolated from Mxus Canadensis, a evergreen bush found in Eastern Canada and Northeastern 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-l3-acetylbaccatin III, which is used to produce, inter alia, 10-deacetylbaccatin III, which is a useful intermediate for the preparation of paclitaxel and analogues thereof.

[0003] The taxane family of terpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents. Many taxane derivatives, including paclitaxel, docetaxel, taxcultine canadensol are highly cytotoxic and possess strong in vivo activities in a number of leukemic and other tumor 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 concentrations (less than 400 parts per million) in the bark of these trees.
Thus, paclitaxel l can be isolated from the bark of the pacific yew tree (Taxus brevifi~lia) and ground hemlock (7'axus Canadensis), but the yield is very low (0.01%-0.02%), and the isolation and purification process is too complicate. Furthermore the extraction is difficult, and the process is expensive. 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 particular 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 (Taxus baccata).

[0005] Due to the structural complexity of paclitaxel, and docetaxel, partial synthesis 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 III. So far the commercial supply of docetaxel comes substantially completely from 10-deacetylbaccatin III. To date, however, the supply of 10-deacetylbaccatin III is limited due to the limited biomass resource and low isolation yield (ranging from 50-165 mg per kilogram of needles of Taxus baccata.

[0006] Various processes of converting 9-dihydro-l3-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 exists for an efficient method for converting 9-dihydro- 13 acetylbaccatin III to l0-deacetylbaccatin III (DAB
III).

[0007] The preparation 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 structure of baccatin III has the basic diterpenoid structure of paclitaxel without the side chain at the C-13 position.

[0008] 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 chemotherapeutic agents than the naturally-occurring, less water soluble paclitaxel. This increases the urgent need for the production of baccatin III
as a starting material to synthesize both paclitaxel and second or third generation paclitaxel-like compounds. There is, therefore, a need for an improved method of isolating and/or synthesizing Baccatin III.

[0009] In fact, most of the research to date regarding the semi-synthesis of paclitaxel 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.-amido 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 III 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 present invention.

[00011] Canadian Patent Application No. 2,188,190, published Apr. 18, 1998, in the name of Zamir et al, described a semi-synthetic process to convert a naturally-occunng 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 111.

[00012] US Patent No 6,878,834, patented Apr 12, 2005 by R.H. Holton et al, related to the preparation 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, baccatinlll or 10-a taxol analog, of 10-desbaccatine bacatin III was selectively reduced to the conesponding hydroxyl group.

[00013] 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 utility as intermediates 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 IlI, or 10-desacetyl baccatin III was selectively reduced to the corresponding hydroxyl group.

[00016] US Patent No. 6,593,482 patented Jul 15, 2003 by H. Bouchard et al, provided a procedure for preparing methylthiomethyi 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 starting 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 structurally 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 Ill having a C9 substituent other than keto in which the C9 keto, in which the C9 keto substituent of taxol, a taxoi analog baccatinlII or 10-dasacetyl baccatin Ill 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 starting material for the synthesis of such taxane derivatives as paclitaxel, docetaxel, cephalomannine and other taxanes structurally 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 10-deacetylbaccatin III by oxidation of 9-dihydroxy-13-acetylbaccatin.

[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-acetylbaccatinlIl as the initial compound.

[00023] US Patent No 6,066,747, patented May 23 2000 by R.H.Holton et al, provided a process for the preparation of taxol, baccatin III and 10-desacetylbaccatinlll derivatives or other taxanes having new C9 functional groups.

[00024] US Patent No. 5,763,477, patented 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-13-acetyl a natural product which is derived from taxus 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 successful semi-synthesis of paclitaxel using the starting materi al l0-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 further described, and defined, in each of the individual claims which conclude this Specification SUMMARY OF THE INVENTION

[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 10-deacetylbaccatin III from 9-dihydrxy-13-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).

STATEMENTS OF INVENTION

[00034] A first broad aspect of the present invention provides an improvement in a process for the conversion of 9-dihydro-13-acetylbaccatin III 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 docetaxel, 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-triethylsilyl-9,10-diketodocetaxel containing a beta-lactam 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-l3-acetylbaccatin 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 III, reacting said 7-O-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-O-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-acetylbaccatinIIi 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-10-deacetyl-9-dihydro-l3-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-l3-hydroxy-acetylbaccatin III, thereby to produce 7-0-triethylsilyl-l0-deacetylbaccatin III; reducing the 9-1 0-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-l3-acetylbaccatin III , thereby to produce 7,9-0- di(-triethylsilyl)-10-deacetyl-9-ketobaccatin III ; reacting 7,9-0- di(-triethylsilyl)- 10-deacetyl-9-ketobaccatin III with a protected beta-lactam docatexi side chain precursor thereby to produce 7-0-triethylsilyl-9,10-diketodocetaxel;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 EMBODIMENTS

[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

[000411 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 stirred for minutes until 9-dihydro-13-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 I
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-I3-acetylbaccatin III as a white solid (85 mg, 85%).

EXAMPLE 2: PREPARATION OF 7-TES-9,10-DIKETO-13-ACETYLBACCATIN
III

[00042] To 5ml of acetonitrile and acetone mixture (3:1), 73 mg of 7-TES-9,10-diketo-l3-acetylbaccatin III was added. 4-methylmorpholine-N-oxide (NMO) in a round bottom flask, and the mixture was dissolved in 3 ml dichloromethane. 4 A
molecular sieve was added to the mixture which stirred 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 mixture was poured into a short silica gel column.
The column was eluted with 50 ml of dichloromethane (CH2C12) to give a CH2CI2 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-l3-acetylbaccatin III
(yield: ? ).

EXAMPLE 3: PREPARATION OF 10-DEACETYLBACCATIN III

[00043] Step A: To a solution of 95% of ethanol, 45 mg of the compound 2 was added and stirred until the solid was completely dissolved, and then hydrazine monohydrate (0.6m1) and 10 mg of LiAII-I4 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.

[00044] Step B: 7-TES-10-deacetylbaccatin 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 hypochloride 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 powder.

EXAMPLE 4: PREPARATION OF 7-TES-9,10-DIKETODOCETAXEL

[00045] Step A: To a solution of 95% ethanol, 40 mg of compound 2 was added and stirred for a few minutes until the solid was dissolved, then 1 mi of hydrazine monohydrate was added. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (50 ml) and poured into saturated MT,CI solution (40ml). The organic layer was separated and concentrated. The residue was purified by precipitation using TLC to obtaining 7-TES-9,10-diketobaccatin III. Yield, 30 mg (?).

[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 13-lactam docetaxel side chain precursor were dissolved in 20 ml of tetrahydrofuran (THF) at -45 C, then 6 mole equivalents of LiHMDS was added slowly. The mixture was stirred at -45 C for 30minutes then warmed to room temperature. The reaction progress was detected by TLC
until completion. Once completed, the mixture was diluted with dichloromethane (50 ml) and poured into saturated NH4Cl solution (40m1). The organic layer was separated and concentrated. The residue was purified by precipitation using TLC to yield 7-TES-9,10-diketodocetaxel.

EXAMPLE 5: PREPARATION OF DOCETAXEL

[00047] Step A: 7-TES-9,10-diketodocetaxel was dissolved in tetrahydrofuran (THF), and then LiA1I-I4 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 NH4Cl mixture (3:1). The organic layer was separated and concentrated to dryness, the residue was took to next step without purification.

[00048] Step B: The residue was redissolved in THF, and sodium hypochloride (NaOCI) was added dropwise. The mixture was stirred for 2hours at room temperature then work-up as above. The residue was purified through flash column chromatography.
Docetaxel was obtained as white needles.

CONCLUSION

[00049] The foregoing has constituted 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 described 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 full 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-l3-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 claim1, wherein said deprotection step is carried out using lithium aluminum hydride.

3. In a process for the conversion of 9-dihydro-l3-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-l3-acetylbaccatin III to docetaxel, the step converting 7-O-triethylsilyl-10-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-O-triethylsilyl-9,10-diketodocetaxel.

A process for the conversion of 9-dihydro-l3-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-l3-hydroxy-acetylbaccatin III, thereby to produce triethylsilyl-10-deacetylbaccatin III; reducing the 9-10-dihydrxy groups from triethylsilyl-10-deacetyl-9,10-dihydroxy-l3-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.