CA2479828A1 - Intermediates and methods useful in the semisynthesis of paclitaxel and analogs - Google Patents

Abstract

The semisynthesis of paclitaxel and its analogs uses new intermediates which are derivatives of 10-deacetyl-baccatin III, the invention also provides methods of preparing these derivatives. These novel derivatives have alkyl carbonate or alkyl carbonyl substituents in the 7 position.

Description

WO 99!26939 PCT/IB98/01912 INTERMEDIATES AND METHODS USEFUL IN THE
SEMISYNTHESIS OF PACLITAXEL AND ANALOGS
TECHNICAL FIELD
The present invention relates to semisynthesis of paclitaxel and its analogs using new intermediates which are derivatives of 10-deacetyl-baccatine Ill, as well as to a method for preparing these derivatives. These novel derivatives have carbonate substituents in the 7 position, such as t-butoxy-carbonate.
BACKGROUND ART
Paciitaxel, a well known potent antitumor compound having a broad spectrum of antitumor activities, has the following structure of formula (I):
/O Q OH
~O

~NH O
/ \ 3~~ \',. 13 ~~ ' 1 2 ~~,,_2//. ~\O HO p o" ~ o Commercial pharmaceutical products containing this compound are available, e.g., for treating ovarian and breast cancer in women. For these reasons, greater and greater supplies of this compound are required each year.
Paclitaxel and baccatine III are extracted with difficulty and in general in low yields from the trunk barks of different Taxus species. Thus, alternative sources of this compound are necessary.

,._ Several synthetic methods have been reported both in scientific and patent literature, U.S, patent RE-34,277 (a reissue of U.S. patent 4,924,Oi 1) discloses the semisynthesis at paclitaxel using a 1 O-deacetyl-baccatine 111 derivative which is protected in the 7 position with a tri-alkyl-silyl group which is specifically shown as a tri-ethyl-siiyl ("TES") group and which is also protected in the 10 position with an acetyl group. This baccatine 111 derivative is allowed to react with a 12R,35)-N-benzoyl-2-0-(1-ethoxyethyl)-3-phenyl-isoserine compound before removal of the protecting groups to obtain the paclitaxel.
In PCT application WO-93l0fi094, paclitaxe) was prepared By reacting a side c3~ain precursor of a p-lactam compound with 7-0-TES-baccatine lil derivative to provide a 7-TES-baccatln !ll reaction product. After a mild acidic post-reaction t.~eatment, paclitaxei was obtained.
an U.S. patent 5,476,954, the synthesis of paclitaxel was conducted starting from a protzcted 10-deacetyl-baccatine Ili derivative that contained a 2,2,2-tri-chloroethoxy-carbonyl ("TROC") protective group in both the 7 and 10 positions of the derivative.

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EP 0 617 034 discloses a process to form 2-debenzoyl-2-acy! taxol*
derivatives. In the disclosed process, C-13-substituted, 2-benzoyt taxol analogues in which the C-7 and C-10 hydroxyl groups are protected with various protecting groups inctudlng 'i3QC, are selectively deprotected and re-acylated at the C-Z
position to form the 2-debenzoyf-2-acyl analogues.
W0 94/07879 discloses a method for preparing taxane der(vatives by esterification of a protected baccatine I1! or 10-deacetyfbaccatine I1l using an oxazolid(ne acid. The baccatine starting materials are preferably protected at the C7-position with a trichloroethyl carbonyl or a trichloropropyl carbonyl radical.
EP 0735 036 discloses a method for the preparation of taxanes using substituted oxaxolidines. In the discloser3 procedure, C-'i 3-substituted taxanes are prepared by reacting the oxazoi(dines with a taxane moiety which is protected using various protecting groups. Tha C-7 hydroxyl group of the taxane moiety is preferably protected with trialkyfsilyi.
It is well known that the key step in the semisynthesis of pac(itaxel is to selectively protect the 7 position with a leaving group that can be easily removed.
This is because the hydroxy group in that position of tha taxane structure is much more reactive than those in position i 0 or 13, and the paclitaxel product to be synthesized needs to have a hydroxy group in that position. Until now, however, the most useful protecting group was considered to be TES. The derivatization yield of 10-deacety!-baccatine I11 with TES is typically about 85 % ~nrhen 20 moles of the reagent are used. The acetyiation step, using 5 equivalents of acptylchloride, provides about 85°Jo of 7-TES-baccatine I11. as per the teachings of PCT application W0-93!06094 and its U.S. equavalent documents such as U.S.
Qatent 5,574,15fi.
* Trade-mark ,. ~~ ~.~~~r~~a : ~ r _ ._ _.._. _ ___ - . . .._ _. __~ 02479828 2004-09-29 ~-~~ -~~~ _._ _ ..__ ..
_3_ In view of tfie importance of paclitaxel, however, new and improved methods for its production are desirable, The present invention provides such improved syntheses of paclitaxel and its analogs primarily using new derivatives of 1O-deacetyl-baccetin Ill as intermediates.
SUMMARY OF THE INVENTION
The present invention relates to an intermediate for use in the semlsynthesis f of paCiitaxel, comprising a compound of formula (II):
Rt0 Q
p-A
Oi>» ~~~rl,f ~l~ O 00 --. ' Ao~
wherein:
A is CH3 ---COCCH~

R, is a hydroxy-protecting group or a hydrogen atom; and R~ is a hydroxy-protecting group selected from the group Consisting of C,,~
carboxylic acid acyl groups (such as acetyll, trialkylsiiyl groups. wherein , each alkyl group contains 1-3 carbon atoms, and the group A as defined above; or a hydrogen atom, Examples of hydroxy-protecting groups include C,.4 carboxylic acid acyl groups, for example acetyl, trialkylsilyl groups wherein each alkyl group contains 1 to 3 carbon atoms and the group A defined above, e.g. a t-butoxycarbonyl group of formula CHs It Preferably, therefore R, is a C,.~ carboxylic acid acyl group, for example acetyl, a trialkylsilyl group wherein each alkyl group contains 1 to 3 carbon atoms or the group A defined above, e.g. a t-butoxycarbonyl group RZ may be any of these groups, but because the 13-hydroxy group is less reactive, protection is not essential, so R2 can conveniently be hydrogen.
During the semisynthesis of paclitaxel, an N-benzoyl (2R, 3S)-3-phenyiisoserine group is introduced at the 13-position of an appropriately protected derivative of baccatine 111. The resulting protected derivatives of paclitaxel have the general formula (lla) RIO

O-A
""
/ (Ila) HO
C6HsC0(~' Ac0 O
wherein A is _ __...._ C- 0- C CH3 R, is a hydroxy-protecting group or a hydrogen atom; and ~.. ,~,i~.t_., n, ni,_~c,ynWV ,..c,- :lg-.1-, V _.~ _. ~,~2479828 2004-09-29 gg0 0001-! ._.. ~~:~ 89_23994.465:x/ 8 a:::; v~ . _ ~ _ Rz, is a (2R,3S)-3-phenylisoserine derivative having the structure:

GO~-CsHs where R~ is a hydroxy-protecting group, such as A tas defined above), a methoxy methyl, 1-ethoxyethyl, benZyloxymethyl, ~-triaikylsilyiethoxy)methyi where each alkyl group contains 1 to 3 carbon atoms, tetrahydropyranyl or 2,2,2-trichloroethoxycarbonyi group; or a hydrogen atom.
The invention further relates to a process for producing paclitaxel by the steps of formi.-~g the intermediate compound of formula (!fa) and removing the A
and R3 groups xo form paclitaxel.
For the preparation of compounds of formula fl and f la where R, is acetyl the process of the invention preferably comprises forming the intermediate compound il by reactir7g 10-deacetylbaccatine III with a reagent capable of introducing a t-butoxycarbonyl group, for example t-butoxy-pyrocarbonate to obtain 7-t-butoxycarbonyl-10-deacetyl baccatine III. The thus obtained 7-t-butoxycarbonyl-10-deacetyl baccatine Ill may then be acetyiated to obtain 7-t-butoxycarbonyl-baccatine III.
10-Deacetylbaccatine fit is highly irtsoiuble in most common solvents and accordingly the choice of solvent is important in order to ensure that the reaction in which the t-butoxycarbonyl group is introduced proceeds at an acceptable rate and in high yields. Thus, for example, 10-deacetyl is highly insoluble in methylene dichloride. If methylene dichloride is used as a solvent for the reaction of deacetyibaccatire with t-butoxypyrocarbonate (see, e.g. Example 1 below7, the WO 99/26939 PCTlIB98l01912 reaction proceeds at a reasonably fast rate on a small scale, but when operated on a large scale, the reaction can be unacceptably slow.
On the other hand, if a polar aprotic nitrogen-containing solvent such as pyridine is used for carrying out the reaction (see Example 8 below) the reaction proceeds more rapidly, but the yield can be lower as a result of formation of 7,10-di(t-butoxycarbonyl) baccatin as a by-product.
Although there may be a minor penalty in terms of lower yield, the use of pyridine as a solvent has advantages on the industrial scale in view of the higher rate of the reaction. Also it is possible to carry out the next step in the process, i.e. the introduction of an acetyl group in the 10-position, without separating or purifying the desired 7-t-butoxycarbonyl 10-deacetylbaccatin. I.e. the reaction in which the t-butoxycarbonyl group is introduced and the acetylation reaction can be carried out in one pot.
Further, if the starting material is in the amorphous (anhydrous) form the reaction proceeds more rapidly than if the starting material is in the form of the crystalline hernihydrate.
The hydroxy group in position 13 of the 7-t-butoxy- carbonyl baccatine III
may then be converted to a (2R,3S)-3-phenylisoserine group having the structure O R3.
C6H~CONH
CO-CsHs wherein R3 is hydrogen by reaching the 7-t-butoxy-carbonyl-baccatine Ill with an oxazolidine derivative of formula (tll):

vvi':rrh nmmvm~:v ~.m_ :=-f--.'=- ~_.~ __~ X2479828 2004-09-29 ~~() IJUUl~_._ _+~~ 89-?39~J49~E;5:~1 S

,N d Rs-C
O Rfl R7 wherein R4 is an aryl group or a straight or branched chain alkyl or aikenyi group having 1-5 carbon atoms; and R6 is R,, or a t-butoxy group, and each Qf R6 and R~
is a halogenated methyE group. Advantageously, an excess of the 7-t-butoxy-carbonyl-baccatine Ill compound is used relative to the oxazolid.ine derivative.
The oxaTOiidine derivatives of formula (Ills N O
R~-C~

Rs Rr ~rvhere R4, R$, R6 and R~ are as defined above from a further aspect of the present invention. Preferably, R4 is phenyl, R~ is phenyl or a t-butaxy group, and each of Rs and R, is a CICH2-, 6rCHi or FCC- group.
The oxazolidine derivatives of Formula Ill may be prepared by reacting a compound of >=~ormula IV with a ketone of formula RpR~ CO (V) R4 OORg tlvy NH ~H
R CO
In formula IV and V R4, R3, Rg and R1 are as defined above, anc~ Re is a residue of an alcohol Ige OH in whit Re is, e.g, a C,_,~ alkyl group, e.g, methyl.

_g_ The present invention provides novel methods for the semisynthesis of paclitaxei of the general formula (I) given above through the use of the new intermediates of formulae (ll) and (Ila). These new intermediates are versatile intermediates which also can be used for the semisynthesis of docetaxel and other analogs of paclitaxel. The process for their preparation is also described.
It has been found, surprisingly, that protecting the hydroxy group at position 7 of 10-deacetylbaccatine III or similar taxane derivatives with the same basic structure, with certain carbonate compounds provides enhancements in the preparation of paclitaxel from such derivatives.
A preferred protective group is t-butoxy-pyrocarbonate (BOC):

This protective group can be substituted in position 7 and, if desired, as well as in position 10. .
As position 10 is not as reactive as position 7, a number of other protective groups can be used in position 10. in particular, the group -OR, can be used, where R, is a hydroxy-protecting group or a hydrogen atom. Any of a wide variety of hydroxy-protecting groups can be used, including the carbonate groups described above for A, the G, groups of the compounds of formula 1l1 of U.S.
Patents 5,578,739 or 5,621,121, the R2 groups of the compounds of formula III

of U.S. patent 6,476,954, or the R~ substituents of the compounds of formula lV
of U.S. patent Re. 34,277.
It is possible to obtain almost quantitative yields of the 7-BOC-10-deacetylbaccatine III derivative from 10-deacetylbaccatine III. The BOC
protecting group is easily and selectively removed in very mild acidic conditions using a catalytic amount of mineral or organic acids, preferably formic or F3C-COOH.
The synthesis of 7-BOC-10-deacety(bac~atine I11 or its analog rrtay be performed in chlorinated solvents, preferably in methylene chloride using dimethylformamide as a co-sclvent. 1 Mole of 10-deacetyl-baccatine III or the chosen taxane analog rnay be reacted with 1.2 to 2.5 equivalents t-terbutoxy-pyrocarbonate in the presence of 1.2 equivalents of ethyldiisopropylamine and a catalytic amount or 4-dimethylaminopyridine. Under these conditions, it is possible to obtain in almost quantitative yields the 7-BQC-derivativa. This compound can be converted into 7-BOC-10-acetyl derivative using a;,etyl chloride, bromide or diketene as shown in the examples.
These derivatives can then be converted to biologically active compounds by esterifying the hydr oxy group at the 13 position with an oxazolidine derivative of formula tall:
Rø GOZH
N O
R~.,C
Q. Rs R7 wherein R~ is an aryl group or a straight or branched chain alkyl or alkenyl group having 1-5 carbon atoms; and R5 is R4 or a t-butoxy group, and each of R6 and R~
is a halogenated methyl group.

WO 99/26939 PC'T/1B98/01912 The reaction is generally performed in aprotic solvents, preferably benzene, toluene, xyfene, chlorobenzene or ethylbenzene, preferably in the presence ~of a condensing agent such as dicyclohexylcarbodiimmide (DCC) and a catalytic amount of a base such as dialkylamino pyridine, preferably 4-dimethylaminopyridine at temperatures ranging from about 50°C to 100°C, and preferably 70°C.
Preferably, to obtain the desired compounds, 4 Moles of condensing agent and 1.5 Mole of the oxazolidine derivative are used for 1 Mole of protected taxane.
After elimination of the reaction byproducts and the solvent, the 13-ester may be isolated in crude form. This compound may then be treated in methanol with a catalytic amount of anhydrous HCI at room temperature or at temperatures ranging from about 5°C to 10°C, and preferably at 0°C, with concentrated formic acid (98%) until complete deprotection of the BOC group at the 7 position and of the protective group R3 of the side chain at position 13 is achieved. After treatment of the reaction mixture with brine, the taxane derivative may be extracted with a solvent that is non-miscible with water, and preferably with ethylacetate, After distillation of the extraction solvent, the taxane derivatives may directly be crystallized with suitable solvents or subjected to chromatographic process using silica-gel and as eluting solvents, a mixture preferably constituted by hexane/ethylacetate in a suitable ratio.
Alternatively, paclitaxel and its analogs can be prepared by esterifying the protected baccatine with a phenylisoserine chain esterified at 2 position with BOC.
The reaction conditions described above for the reaction using a oxazolidine derivative may be used.
The hydroxy group at position 13 can be esterified in a number of other ways as disclosed, e.g., in U.S. patents 5,578,739, 5,574,156, 5,621,121, 5,476,954, 5,470,866, 4,857,653, 4,814,470, and Re. 34,277, and in European Patent Application 0,525,589-A1.

WO 99!26939 PCT/IB98/01912 EXAMPLES
The examples below are reported, without implied limitation, to show how the invention can be put in practice.
Example 1: Synthesis of 7-BOC-10-deacetylbaccatine III.
A 500 mg sample of 10-deacetylbaccatine III (0.92 mMol) was suspended in CHZC12 (5 mL) and ethyldiisopropylammine (1.10 mMol, 1.2 Equiv.), t-butoxypyrocarbonate (240 mg, 1.10 mMol, 1.2 Equiv.) and DMAP
(4-dimethytaminopyridine, 20 mg) were added.
The reaction was stirred 48 h at room temperature and then additioned with the same quantity of reagents and allowed to stay under stirring per other 48 h.
The reaction was worked up by dilution with CH2C12 washing with HCI and brine.
After drying, 580 mg of 7-Boc- 10-deacetylbaccatine 111 were obtained having the following characteristics: mp 148°C and 162°C; 1 H-NMR 200 Mhz, CDC13, TMS
as internal standard; Bz 8.10, br d, J 8; Bz 7.70, br t J 8; Bz 7.55, br t J
8;
H2, 5.64 d J 7; H10, 5.54, s; H7, 5.36, dd, J 1 1.0, 8.0; H5, 4.95, d J 8;
H13, 4.91, br t, J7.5; H20a, 4.32 d, J 8.0; H20b 4.26, d, J 8.0; H3, 4.09 d, J 8.8;
Ac. 2.29 s; H 18 2.09 s; H 19 1.83 s; Boc 1.46 s; H 16 1.34 s; H 17 1.20 s; IR
(KBr) 3480 (OH), 1740 (br, C = O), 1603, 1371, 1275, 1259, i 158, 1092, 712.
Example 2: Synthesis of 7-BOC-10-deacetylbaccatine ll!
A 500 mg sample of 10-deacetylbaccatine III (0.92 mMol) was solubilized in 1 ml of dimethylformamide and diluted with 4 ml of CHZC12. The reagents and the reaction conditions are the same of Example 1.

Example 3: Synthesis of 7-BOC-baccatine III.
644 mg (1 mMol) of 7-Boc-10-deacetylbaccatine II( prepared according to example 1 or 2 were dissolved in 5 mL of pyridine and at 0°C under stirring 1.2 g of acetylchloride were added (15 mMol) in 15 h. When the reaction is finished the solution is diluted with CH2CI2 under stirring and washed with 60 mL of H20.
The organic phase is washed several times with HZO and diluted HCI until the elimination of pyridine. The solvent dried on Na2S04 is evaporated under vacuum and the residue crystallized from hexanelacetone. 660 mg of 7-Boc-baccatine III
were obtained having the following characteristics: mp 190-97°C. 1 H-Mhz, CDC13, TMS as internal standard; Bz 8.10 br d, J 8; Bz 7.70 br t, J 8; Bz 7.55, br t J 8; H2, 5.64 d, J 7; H10, 5.52 s; H7, 5.44 dd, J 10.3, 7.0; H5, 4.98, d, J 7.9; H 13, 4.50 br t; H20a, 4.32 d, J 8.0; H20b 4.22 d, J 8.0; H3, 4.02 d, J
6.7; Ac. 2.30 s; H 18 2. 7 9 s; Ac. 2.16 s; H 19 1.80 s; Boc 1.48 s; H 16 1.17 s;
H17 1.07 s.
Example 4: Synthesis of paclitaxel.
1.65 gr of (4S,5R)-2,2 -di(chloromethyl)-4-phenyl-N-benzoyl-5-oxazolidine acid were allowed to react in toluene with 0.69 gr o~t 7-Boc-baccatine III in the presence of 1.1 Equival. of DCC and 60 mg of 4-dimethylaminopyridine. The reaction mixture was maintained at 60°C for 12h under stirring in Argon atmosphere.
At the end of the reaction (TLC) the reaction mixture was filtered form insoluble byproducts and the solvent washed with H20 and distilled under vacuum.
The residue is solubilized in 10 mL of conc. formic acid at 0°C and kept in this condition for 2h. The reaction mixture was diluted with 100 mL of H20 and cloudy solution extracted three times with 50 mL CH2C12. The organic phase was washed with a solution of NaHC03 and then with H20. The organic phase after drying on NaZS04 is concentrated under vacuum. The residue was crystallized from ethanoilwater and 0.81 gr of paclitaxei having the welt known characteristics which have been reported in the literature was obtained.
Example 5: Reaction of 10-deacetylbaccatin III with Boc-pyrocarbonate A 500 mg sample of 10-deacetylbaccatin 111 (0.92 mMol) was suspended in CHZCIz (5 mL) and ethyldiisopropyiamine (190 ~L, 1.10 mMol, 1.2 mot. Equiv.), BOC-pyrocarbonate (240 mg, 1.10 mMol, 1.2 mol. Equiv) and DMAP (4-dimethylaminopyridine, 20 mg) were added. The reaction was stirred 48 h at room temp, and then further BOC-pyrocarbonate (240 mg, 1.10 mMol, overall 2.4 mot equiv.) and ethyidiisopropylamine (190,uL, 1.10 mMoi, overall 2.4 mol , equiv.) were added. After stirring for an additional 120 hours, the reaction was worked up by dilution with CHZCl2, washing with HCl and brine. After drying the residue was purified by column chromatography (ca. 5 g silica gel). Elution with hexane-EtOAc 6:4 gave 327 mg BOC DAB (yield: 55% conversion: 92%) Elution with ETOAc gave 195 mg recovered DAB.
Example 6 - Reaction of 10-deacetylbaccatin lII With BOC-ON
To a solution of 10-deacetylbaccatin ill (400 mg, 0.73 mmol) in pyridine (3 mL), BOC-ON ( = 2-(tert-butoxycarbonyloxiymino)2-phenylacetonitrile] - (543 mg, 2.19 rnmol, 3 mol. equiv.) and 4-dimethylaminopyridine (90 mg, 0.73 mmol, 1 mof.equiv) were added.
The reaction was followed by TLC (hexane-EtOAc 4:6, Rf starting material:
0.1; Rf 7-BOC derivative 0.50; Rf 7,10-diBOC derivative: 0.56). After stirring at roam temp, for 10 days, the reaction was worked up by dilution with water and extraction with chloroform. After washing with sat. citric acid, sat. NaHC03 and brine, the solution was dried (MgS04) and evaporated, to afford a semi-solid residue (1.07 g). The latter, when analyzed by'H NMR spectroscopy (200 MHz), turned out to contain the 7-BOC and the 7,10-diBOC derivatives in a 85:15 ratio.

WO 99126939 PCT/IB9$/01912 Purification by column chromatography (hexane-EtOAc 6:4) afforded 265 mg of 7-BOC -10-deacetytbaccatin IIt (yield: 56%).
Analysis - 7 BOC-14-deactyibaccatin III
White powder, mp 162 °C;
iR fKBr): 3480, 1740, 1603, 1371, 1275, 1259, 1 158, 1092, 712 CI-MS: 645 (M + H), C34H44012 ~H NMR (200 MHz, CDCt3) : 8.10 (br d, J = 8.0 Hz, Bz); 7.70 (br t, J = 8.0 Hz, BZ) .
7.55 (br t, J = 8.0 Hz, Bz), 5.64 (d, J = 7.0 Hz, H-2), 5.54 (s, H-10), 5.36 (dd, J = 11.0, 8.0 Hz, H-7), 4.95 (d, J = 8.0 Hz, H-5), 4.91 (br t, J = 7.5 Hz, H-13), 4.32 (d, J = 8.0 Hz, H-20a), 4.26 (d, J = 8.0 Hz, H-20b), 4.09 (d, J = 8.0 Hz, H-3), 2.29 (s, OAc?, 2.09 (br s, H-181, 1.83 (s, H-19), 1.46 (s, BOC). 1.34 (s, H-16), 1.20 (s, H-17).
Analysis - 7-BOC-baccatin III
White powder, mp 197 °C;
tR (KBr?: 3580, 3497,1750,1724,1713,1273;1240,1070,980.
M.W.:fi$6, C~gH460r3 tH NMR (200 MHz, CDCI3): 8.10 (br d, J= 8.0 Hz, Bz );7.70 (br t, J = 8.0 Hz, Bz) .
7.55 (br t, J = 8.0 Hz, Bz), fi.52 (s, H-10), 5.64 (d, J = 7.0 Hz, H-2), 5.41 (dd, J =11.0, 8.0 Hz, H-7), 4.98 (d, J = 8.0 Hz, H-5), 4.90 (br t, J = 7.5 Hz, H-2), 4.32 (d, J = 8.0 Hz, H-20a), 4.22 (d, J = 8.0 Hz, H-20b), 4.02 (d,J = 7.0 Hz, H-3), 2.30 (s, OAcI, 2.19 (br s, H-18), 2.16 (s, OAc), 1.80 (s, H-19), 1.48 (s, BOC), 1.17 (s, H-16), 1.07 (s, H-17).

Example 7 - Preparation of Dichiorooxazolidine Derivative llla (Methyl Ester of Compound of Formula 111 with R4 = R~ - phenyl; R6 = R~ = -CHZCI) 500 mg of N-benzoyl-phenyl-isoserine methylester in 30m1 of tetrahydrofuran/benzene 1:1 mixture was allowed to react with 1 g of dichloroacetone arid 50 mg of PTSA (pyridinium p-toluenesulfonate) in the presence of a molecular sieve (3A). The reaction mixture was heated and refluxed for 2 days. At the end of the reaction, the residue was washed with hexane in order to eliminate the excess of dichloroacetone.
The residue in 20m1 of MeOH vvas mixed with 220 mg of KZC03 in 20mi of HZO. After 2 hours, methanol was evaporated under vacuum and the aqueous phase was acidified with a 5% solution of KHS04 and then extracted with ethylacetate.
The obtained acid was used then used directly for the esterification of 7-Boc-acetylbaccatine 111 (see Example 4).
Example 8 - Reaction of 10-Deacetylbaccatin 111 with Boc-Pyrocarbonate BOCZO (800 mg, 37 mMol, 2 mol. equiv.) and DI~tAP (220 mg, 18.5 mMol, 1 rnal. equiv.) were added to a solution of 10-deacetylbaccatin ill (1.0 g, 18.5 mMol) in pyridine ( 15 mL), . The reaction was followed by TLC (hexane-EtOAc f:6, Rf st.m = 0.10; Rf7-boc-derivative 0.50; Rf 7,10-diBOC derivative: 0.56).
After stirring (16 h at room temp.), the reaction mixture was cooled to 0°C, and AcCI (261 NL, 37 mMol, 2 mol. equiv.) was added. The reaction was followed by TLC ( 1,2-dichloroethane-EtOH 96:4 x 4).
After stirring at 0°C for 5 h, two further equivalents of AcCI were added, and stirring is continued at 0° for a further 2 hours. The reaction mixture was then worked up by addition of water (ca 150 mL) to the reaction flask. After min. water was decanted from the reaction flask, and the sticky precipitate on the walls of the was taken up in EtOAc (30 m~.), washed with dil HCI ( 10 mL) and brine (10 mL). After drying (MgSO~) and evaporation of the solvent, 1.18 g of a yellow powder are obtained. When analyzed by NMR, the product was a 82:18 mixture of 7-BOC baccatin III and 7,10-diBOC baccatin II1.

Claims (8)

1. An intermediate for use in the semisynthesis of paclitaxel, comprising a compound of the structure:
wherein:
A is R1 is a hydroxy-protecting group or a hydrogen atom, and R2 is a hydroxy-protecting group selected from the group consisting of C1-4 carboxylic acid aryl groups (such ass acetyl), trialkylsilyl groups, wherein each alkyl group contains 1-3 carbon atoms, end the group A as defined above; or a hydrogen atom.

2. The intermediate of Claim 1 wherein R1 is A, an acetyl group or a trialkylsilyl group wherein each alkyl group contains 1 to 3 carbon atoms.

3. The intermediate of Claim 1 wherein R1 represents H.

4. The intermediate of Claim 1 wherein R1 represents acetyl.

5. A process for producing paclitaxel comprising:
(i) forming an intermediate compound by reacting 10-deacetyl-baccatine III with t-butoxy-pyrocarbonate to obtain 7-t-butoxy-carbonyl-10-deacetyl baccatine III;
(ii) acetylating the 10-position of the 7-t-butoxy-carbonyl-10-deacetyl baccatine III to obtain 7-t-butoxy-carbonyl-baccatine III:
(iii) introducing the group wherein R3 is a hydroxy-protecting group such as tBOC, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, .beta.-trialkylsilylethoxy)-methyl where each alkyl group contains 1 to 3 carbon atoms, tetrahydropyranyl or 2,2,2-trichloroethoxycarbonyl; or a hydrogen atom; in position 13 of 7-t-butoxy-carbonyl baccatine III
by reacting the protected baccatine III with an oxazolidine derivative of formula (III);
wherein R4 is phenyl; and R5 is R4, or a t-butoxy group, and each of R6 and R7 is a halogenated methyl group; and (iv) selectively removing the A and R3 groups in mild acidic conditions using a mineral or organic acid.

6. ~The process of Claim 5 wherein R5 is phenyl or a t-butoxy group, and each of R5 and R7 is a CICH2- of BrCH2- or F3C- group.

7. ~A process according to Claim 5 or Claim 6 wherein an excess of the 7-t-butoxy-carbonyl baccatine III compound is used relative to the oxazolidine derivative.

8. ~The process of Claim 5 wherein the acetylation is carried out using an acetyl halide or diketene compound.