WO2011134067A1

WO2011134067A1 - Novel amino acid molecule and uses thereof

Info

Publication number: WO2011134067A1
Application number: PCT/CA2011/000492
Authority: WO
Inventors: Jian Liu
Original assignee: 6570763 Canada Inc.
Priority date: 2010-04-29
Filing date: 2011-04-27
Publication date: 2011-11-03

Abstract

There is provided novel amino acid molecules and processes for their preparation. There is also provided novel amino acid molecules and their use in processes for preparing the compounds that are useful for the synthesis of paclitaxel, and docetaxel, the anticancer drug.

Description

Title: Novel amino acid molecule and uses thereof

BACKGROUND

(a) Field

[0001] The subject matter disclosed generally relates to novel amino acid molecules and processes for their preparation. More particularly, the subject matter generally relates to novel amino acid molecules and their use in processes for preparing the compounds that are useful for the synthesis of paclitaxel, and docetaxel, the anticancer drug.

(b) Related Prior Art

[0002] Taxanes are substances occurring naturally in yew trees such as Taxus brevifolia, Taxus baccata and Taxus canadensis, which is common in Eastern Canada and Northeast United States. One of the chemicals extracted from the needles of Taxus Canadensis is 9-dihydro-13- acetylbaccatin III, which is used to produce 10-deacetylbaccatin III, a useful intermediate for the preparation of paclitaxel, docetaxel and their analogues thereof.

[0003] The taxane family of diterpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents. Many taxane derivatives, including paclitaxel, docetaxel, taxol C and cephalomannine 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. They have also exhibited promising activity against a number of other tumor types in preliminary investigations. Paclitaxel, docetaxel have recently been approved in the U.S. and Canada for the treatment of ovarian and breast cancers.

[0004] The only available natural source of paclitaxel to date are several species of a slow growing yew trees (genus Taxus), wherein paclitaxel is found in very low concentrations (less than 400 parts per million) in the bark or needles of these trees. Thus, paclitaxel can be isolated from the bark of the pacific yew tree {Taxus brevifolia) and ground hemlock {Taxus 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 of paclitaxel derived from natural to the production of semisynthetic, 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 first commercialized 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] 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 β-amido ester side chain at the C-13 position through esterification of the C-13 alcohol with the side chain moiety, and deprotecting C-7. Since the supply of 10-deacetylbaccatin III is limited, other sources should be pursued.

[0007] Canadian Patent Application No. 2,188,190, published on Apr. 18, 1998, in the name of Zamir et al, described a semi-synthetic process to convert a naturally occurring taxane, 9-dihydro-13-acetylbaccatin III, into a suitable starting material for the synthesis of such taxane derivatives as paclitaxel, cephelomanine and other taxanes, which are structurally related to baccatin III.

[0008] U.S. Pat. No. 6,812,356, issued on Nov. 2, 2004, in the name of Findly, provided a process for the use of 9-dihydro-13-acetyl baccatin III for the production of 10-deacetylbaccatin III.

[0009] U.S. Pat. No. 6,784,304, issued on Aug. 31 , 2004, in the name of Bristol-Myers Squibb Company provided novel oxazolidines, which found utility as intermediates in the preparation of C-13 side chain-bearing taxanes, e.g., paclitaxel and analogs thereof. It related more specifically, to procedures for coupling the oxazolidines to form the taxanes.

[0010] U.S. Pat. No. 6,576,777, issued on Jun. 10, 2003 in the name of L. Zamir et al, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting compound for the synthesis of paclitaxel and related compounds. It specifically relates to a process for the conversion of 9-dihydro-13-acetylbaccatin III into a 7-protected baccatin III, which can be used for the synthesis of taxol derivatives, e.g., paclitaxel, docataxel, cephalomannine and other taxanes, which were structurally related to baccatin III.

[0011] U.S. Pat. No. 6,197,981 , issued on Mar. 6, 2001 , in the name of J. Liu, provided a process for preparing taxol, baccatin III and 10- deacetylbaccatin III by oxidation of 9-dihydro-13-acetylbaccatin.

[0012] U.S. Pat. No. 6,175,023, issued on Jan. 16, 2001 in the name of J. Liu, provided for the semi-synthesis of 9-di hydro taxanes using 9-dihydro- 13-acetylbaccatinlll as the initial compound.

[0013] U.S. Pat. No. 4,924,01 1 , re-issued as U.S. Pat. No. 34,277 in the name of Denis et al provided the first successful semi-synthesis of paclitaxel using the starting material 10-deacetylbaccatin III which can be extracted in relatively high yield from the needles of Taxus baccata species. [0014] It would be highly desirable to be provided with a novel semisynthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and other useful taxane precursor compounds for making them.

SUMMARY

[0015] In a first embodiment there is disclosed an acid of the formula (VI):

(VI)

wherein

R₂ may be tert-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₄ may be OR5 or ;

R₅ is a C-1-C6 alkyl linear or branched, C1-C20 acyl group, d- C20 halogenated acyl group, C3-Ci2cycloalkyl, C1-C12 heterocyclyl, C₂- C20 alkenyl, C2-C20 alkynyl, C6-C12 aryl, C6-C20 aralkyl, C C₂o alkyloxy C6-C2oalkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH,— COOR₆ in which R₆ may be a Ci-C₆ alkyl, C1-C-12 alkyl linear or branched, C₆-Ci₂ aryl, C2-C20 alkenyl, C1-C20 alkoxy, C C₂o alkyl, C₂-C₂₀alkynyl, C₆-C₂₀ aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, C1-C20 aminoalkyl, C₆-Ci₂ aminoaryl, C1-C12 aminoheteroaryl, C1-C20 hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C₁-C₁₂ hydroxyheteroaryl, C₁-C₁₂ heterocyclyl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

[0016] The acid may be in the form of a salt, ester, anhydride, mixed anhydride, or halide.

[0017] In a second embodiment, there is disclosed a process for preparing a compound of formula (VI):

(VI)

said process comprising reacting a compound of formula (VII):

(VII)

with a compound of formula (VIII):

(VIII)

wherein R₂ may be ferf-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R5 may be a Ci-C₆ alkyl linear or branched, C1-C20 acyl group, C

C₂₀ halogenated acyl group, C₃-Ci2cycloalkyl, C1-C12 heterocyclyl, C₂-

C₂o alkenyl, C₂-C₂₀ alkynyl, C6-C12 aryl, C₆-C₂o aralkyl, C1-C20 alkyloxy

C₆-C₂oalkylaryl, C1-C1₂ heteroaryl, C2-C20 alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH,— COOR₆ in which R₆ may be a C₁-C6 alkyl, C₁-C₁₂ alkyl linear or branched, C6-Ci₂ aryl, C₂- C₂o alkenyl, C C₂o alkoxy, C1-C₂₀ alkyl, C2-C2oalkynyl, C6-C₂0 aralkyl, C₆-Ci₂ aryl, C₃-Ce cycloalkyl, C1-C20 aminoalkyl, C6-C12 aminoaryl, C1-C12 aminoheteroaryl, C₁-C₂₀ hydroxyalkyl, C6-Ci₂ hydroxyaryl, C Ci₂ hydroxyheteroaryl, C1-C12 heterocyclyl, Ci-d₂ heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl.

[0018] The R₂ may be tert-butoxycarbonyl (t-BOC).

[0019] The R₃ may be OCH₃.

[0020] The R₄ may be OCH₃.

[0021] In a third embodiment there is disclosed a process for preparing a compound of formula (VI):

(VI)

said process comprising reacting (2S,3R)-A/-Boc-3-phenylisoserine methyl

in anhydrous toluene under nitrogen, with 4-Methoxy benzaldehyde:

and 4-dimethylaminopyridine (DMAP).

[0022] In a fifth embodiment there is disclosed a compound of formula (II), (III), or (IV):

wherein

Ri may be a suitable protecting group for a hydroxyl group;

R₂ may be terf-butoxycarbonyl (ί-BOC) or benzoyl (Bz);

R5 may be a C1-C6 alkyl linear or branched, C1-C20 acyl group, Ci- C20 halogenated acyl group, C3-Ci₂cycloalkyl, C1-C12 heterocyclyl, C2- C₂o alkenyl, C2-C2₀ alkynyl, C6-C12 aryl, C6-C20 aralkyl, C-1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COORe in which R₆ may be a Ci-C₆ alkyl, C1-C12 alkyl linear or branched, C₆-C₁₂ aryl, C₂-C₂o alkenyl, Ci-C₂₀ alkoxy, Ci-C₂₀ alkyl, C₂- C₂oalkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, C1-C2₀ aminoalkyl, C6-C12 aminoaryl, C1-C12 aminoheteroaryl, C1-C20 hydroxyalkyl, C6-C12 hydroxyaryl, C1-C12 hydroxyheteroaryl, C Ci₂ heterocyclyl, C Ci₂ heteroaryl, C2-C20 alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

[0023] The suitable protecting group for a hydroxyl group may be chosen from C1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, Ci-C₂₅ esters, Ci-C₂₅ carbonates, and C1-C25 sulfonates.

[0024] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropy Isilyl , dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

[0025] The R_n may be diphenylmethylchlorosilane (DPMS).

[0026] The R₂ may be tert-butoxycarbonyl (t-BOC).

[0027] The R₃ may be OCH₃.

[0028] In a sixth embodiment there is disclosed a process for preparing a compound of formula (II):

said process comprising reacting 4-dimethylaminopyridine (DMAP) and Ν,Ν'- dicyclohexylcarbodiimide (DCC) with a compound of formula (I):

(I)

and a compound of formula (VI):

(VI)

wherein

i may be a suitable protecting group for a hydroxyl group;

R₂ may be iert-butoxycarbonyl (ί-BOC) or benzoyl (Bz);

R₃ may be OR5 or N0₂;

R₅ may be a CrC₆ alkyl linear or branched, C1-C20 acyl group, d-

C₂o halogenated acyl group, C₃-C₁₂cycloalkyl, C1-C12 heterocyclyl, C₂- C₂o alkenyl, C2-C20 alkynyl, C₆-Ci2 aryl, C6-C20 aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyi, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, H₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR₆ in which R₆ may be a C C₆ alkyl, C1-C12 alkyl linear or branched, C6-C12 aryl, C2-C20 alkenyl, C1-C20 alkoxy, C1-C20 alkyl, C₂- C₂oalkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyi, Ci-C₂₀ aminoalkyl, C₆-Ci₂ aminoaryl, C1-C-12 aminoheteroaryl, C C₂o hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C1-C12 hydroxyheteroaryl, C1-C12 heterocyclyl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl.

[0029] The suitable protecting group for a hydroxyl group may be chosen from C1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, C1-C25 carbonates, and C1-C25 sulfonates.

[0030] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl. [0031] The Ri may be diphenylmethylchlorosilane (DPMS).

[0032] The R2 may be ferf-butoxycarbonyl (f-BOC).

[0033] The R₃ may be OCH₃.

[0034] In a seventh embodiment there is disclosed a process for preparing a compound of formula (III):

(III)

said process comprising reacting an oxidizing agent with a compound of formula (II):

wherein

Ri may be a suitable protecting group for a hydroxyl group;

R₂ may be ferf-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₃ may be OR₅ or N0₂;

R₅ may be a C1-C6 alkyl linear or branched, C1-C20 acyl group, Ci- C₂o halogenated acyl group, C₃-Ci₂cycloalkyl, Ci-Ci₂ heterocyclyl, C₂- C₂o alkenyl, C2-C20 alkynyl, C₆-C₁₂ aryl, C₆-C₂₀ aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl, said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COO 6 in which R₆ may be a CrC₆ alkyl, d-d₂ alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂₀ alkenyl, CrC₂₀ alkoxy, Ci-C₂₀ alkyl, C₂- C₂₀alkynyl, C₆-C₂₀ aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, CrC₂₀ aminoalkyl, C₆-Ci₂ aminoaryl, C Ci₂ aminoheteroaryl, CrC₂₀ hydroxyalkyl, C6-Ci₂ hydroxyaryl, Ci-Ci₂ hydroxyheteroaryl, C1-C12 heterocyclyl, Ci-Ci₂ heteroaryl, C^C^ alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

[0035] The oxidizing agent may be chosen from N-methylmorpholine N- oxide (NMO) Tetrapropylammonium perruthenate (TPAP) and Dess-Martin periodinane.

[0036] The suitable protecting group for a hydroxyl group may be chosen from Ci-C₂₅ ethers, C C₂₅ substituted methyl ethers, Ci-C₂₅ substituted ethyl ethers, Ci-C₂5 acyl groups, Ci-C₂5 halogenated acyl groups, Ci-C₂5 substituted benzyl ethers, Ci-C₂5 silyl ethers, Ci-C₂s esters, C C₂5 carbonates, and Ci-C₂5 sulfonates.

[0037] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl. [0038] The Ri may be diphenylmethylchlorosilane (DPMS).

[0039] The R₂ may be fert-butoxycarbonyl (i-BOC).

[0040] The R₃ may be OCH₃.

[0041] In an eighth embodiment there is disclosed a process of preparing a compound of formula (IV):

(IV)

said process comprising reacting p-toluenesulfonic acid (pTsOH) with a compound of formula (III):

(III)

wherein

Ri may be a suitable protecting group for a hydroxyl group;

R2 may be terf-butoxycarbonyl (i-BOC);

R₃ may be OR₅ or N0₂;

R5 may be a C1-C6 alkyl linear or branched, C1-C20 acyl group, C C20 halogenated acyl group, C3-Ci2cycloalkyl, C1-C12 heterocyclyl, C₂- C20 alkenyl, C2-C₂o alkynyl, C6-C12 aryl, C6-C20 aralkyl, C1-C20 alkyloxy C6-C2oalkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR6 in which R₆ may be a C-i-C₆ alkyl, C1-C12 alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂₀ alkenyl, Ci-C₂₀ alkoxy, C C₂o alkyl, C₂- C₂oalkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, Ci-C₂₀ aminoalkyl, C6-Ci₂ aminoaryl, C Ci₂ aminoheteroaryl, Ci-C₂o hydroxyalkyl, C₆-Ci₂ hydroxyaryl, Ci-Ci₂ hydroxyheteroaryl, C1-C12 heterocyclyl, C d₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

[0042] The suitable protecting group for a hydroxyl group may be chosen from Ci-C₂5 ethers, Ci-C₂5 substituted methyl ethers, Ci-C₂5 substituted ethyl ethers, C1-C25 acyl groups, C C₂5 halogenated acyl groups, Ci-C₂₅ substituted benzyl ethers, C1-C25 silyl ethers, C C₂5 esters, C C₂5 carbonates, and C1-C25 sulfonates.

[0043] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

[0044] The Ri may be diphenylmethylchlorosilane (DPMS). [0045] The R₂ may be tert-butoxycarbonyl (t-BOC).

[0046] The R₃ may be OCH₃.

[0047] In a ninth embodiment there is disclosed a process of preparing a compound of formula (V)

(V)

said process comprising reacting an oxidizing agent with a compound of formula (IV):

(IV)

wherein

R₂ may be tert-butoxycarbonyl (f-BOC).

[0048] The oxidizing agent may be hydrogen peroxide (H₂0₂) and sodium bicarbonate (NaHCOa).

[0049] In a tenth embodiment there is disclose a process of preparing a compound of formula (V):

(V)

said process comprising reacting p-toluenesulfonic acid (pTsOH) with a compound of formula (III), followed by oxidation with hydrogen peroxide (H2O2) and sodium bicarbonate (NaHCCb):

(III)

wherein

Ri may be a suitable protecting group for a hydroxyl group;

R2 may be terf-butoxycarbonyl (f-BOC);

R₃ may be OR₅ or N0₂;

R5 may be a C C6 alkyl linear or branched, C1-C20 acyl group, d- C20 halogenated acyl group, C3-Ci₂cycloalkyl, C1-C12 heterocyclyl, C₂- C₂o alkenyl, C2-C20 alkynyl, C6-C 2 aryl, C6-C20 aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COORe in which R₆ may be a Ci-C₆ alkyl, C1-C12 alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂o alkenyl, C1-C20 alkoxy, C C₂o alkyl, C₂- C₂oalkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, C1-C20 aminoalkyl, C6-Ci₂ aminoaryl, Ci-Ci₂ aminoheteroaryl, C1-C20 hydroxyalkyl, C₆-Ci₂ hydroxyaryl, d-Ci₂ hydroxyheteroaryl, C1-C12 heterocyclyl, C Ci₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C₂-C₂o alkylheteroaryl.

[0050] The suitable protecting group for a hydroxyl group may be chosen from d-C₂₅ ethers, C_rC₂5 substituted methyl ethers, C1-C25 substituted ethyl ethers, Ci-C₂₅ acyl groups, Ci-C₂₅ halogenated acyl groups, Ci-C₂5 substituted benzyl ethers, Ci-C₂₅ silyl ethers, C1-C25 esters, C1-C25 carbonates, and C C₂5 sulfonates.

[0051] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesuifonyl, and p-toluenesulfonyl.

[0052] The R-i may be diphenylmethylchlorosilane (DPMS).

[0053] The R₃ may be OCH₃.

[0054] In an eleventh embodiment there is disclosed a process of preparing paclitaxel, docetaxel and derivatives thereof comprising the steps of:

(a) attaching a compound of formula (VI):

(VI)

to the C-15 hydroxyl position of the compound of formula (I):

to obtain a compound of formula (II):

(HI):

(e) reacting the compound of formula (III) with p-toluenesulfonic acid (pTsOH), to obtain a compound of formula (IV):

(IV),

and

(f) when R₂ is ferf-butoxycarbonyl (f-BOC), oxidizing the compound of formula (IV) with an oxidizing agent to obtain a compound of formula (V):

wherein

Ri may be a suitable protecting group for a hydroxyl group;

R₂ may be terf-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₃ may be OR₅ or N0₂;

Rs may be a C1-C6 alkyl linear or branched, C1-C2₀ acyl group, C C20 halogenated acyl group, C₃-Ci₂cycloalkyl, C1-C12 heterocyclyl, C₂- C₂o alkenyl, C₂-C₂₀ alkynyl, C6-C12 aryl, C₆-C₂₀ aralkyl, CrC₂₀ alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COO ₆ in which R₆ may be a C C6 alkyl, Ci-Ci₂ alkyl linear or branched, C₆-Ci₂ aryl, C₂-C2o alkenyl, Ci-C₂₀ alkoxy, CrC₂₀ alkyl, C₂- C₂₀alkynyl, C₆-C₂₀ aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, C C₂₀ aminoalkyl, C6-Ci₂ aminoaryl, C C₁₂ aminoheteroaryl, CrC₂₀ hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C Ci₂ hydroxy heteroaryl, Ci-Ci₂ heterocyclyl, C Ci₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

[0055] The suitable protecting group for a hydroxyl group may be chosen from Ci-C₂5 ethers, Ci-C₂₅ substituted methyl ethers, Ci-C₂₅ substituted ethyl ethers, Ci-C₂₅ acyl groups, C C₂₅ halogenated acyl groups, C1-C25 substituted benzyl ethers, Ci-C₂s silyl ethers, Ci-C₂₅ esters, C C₂₅ carbonates, and Ci-C₂5 sulfonates.

[0056] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

[0057] The Ri may be diphenylmethylchlorosilane (DPMS).

[0058] The R₂ may be terf-butoxycarbonyl (f-BOC).

[0059] The R₃ may be OCH₃.

[0060] The taxane derivative may be paclitaxel or docetaxel. [0061] In a twelfth embodiment there is disclosed a process preparing docetaxel and derivatives thereof comprising the steps of:

(a) attaching a compound of formula VI):

(VI)

to the C-15 hydroxyl position of the compound of formula (I):

(I)

to obtain a compound of formula (II):

(ii);

(d) oxidizing the compound of formula (II) with an oxidizing agent to obtain a compound of formula (III):

(HI):

and,

(e) reacting the compound of formula (III) with p-toluenesulfonic acid (pTsOH), followed by oxidation with an oxidizing agent to obtain a compound of formula (V):

(V),

wherein

Ri may be a suitable protecting group for a hydroxyl group;

R₂ may be ferf-butoxycarbonyl (f-BOC);

R5 may be a C1-C6 alkyl linear or branched, C1-C20 acyl group, Ci- C₂o halogenated acyl group, C₃-Ci₂cycloalkyl, d-Ci₂ heterocyclyl, C₂- C₂o alkenyl, C₂-C₂₀ alkynyl, C₆-Ci₂ aryl, C₆-C₂₀ aralkyl, C C₂o alkyloxy C6-C₂oalkylaryl, Ci-Ci₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl may be unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR₆ in which R₆ may be a C -C₆ alkyl, C1-C12 alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂₀ alkenyl, Ci-C₂₀ alkoxy, Ci-C₂₀ alkyl, C₂- C₂₀alkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, CrC₂₀ aminoalkyl, C₆-Ci₂ aminoaryl, Crd₂ aminoheteroaryl, C1-C20 hydroxyalkyl, C₆-C₁₂ hydroxyaryl, C Ci₂ hydroxyheteroaryl, C Ci₂ heterocyclyl, C Ci₂ heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

[0062] The suitable protecting group for a hydroxyl group may be chosen from Ci-C₂5 ethers, Ci-C₂₅ substituted methyl ethers, CrC₂₅ substituted ethyl ethers, CrC₂₅ acyl groups, C1-C25 halogenated acyl groups, C C₂5 substituted benzyl ethers, C-i-C₂5 silyl ethers, Ci-C₂5 esters, Ci-C₂₅ carbonates, and Ci-C₂5 sulfonates.

[0063] The suitable protecting group for a hydroxyl group may be chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2- (trimethylsilyl)ethoxymethyl, dioxanyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, thbenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

[0064] The Ri may be diphenylmethylchlorosilane (DPMS).

[0065] The oxidation may be with hydrogen peroxide (H₂0₂) and sodium bicarbonate (NaHC0₃).

[0066] The R₃ may be OCH₃. [0067] The taxane derivative may be docetaxel.

[0068] Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and the description are to be regarded as illustrative in nature, and not as restrictive and the full scope of the subject matter is set forth in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Fig. 1 illustrates taxanes derivatives.

[0070] Fig. 2 illustrates a reaction for the preparation of the novel amino acid molecule according to the present invention.

[0071] Fig. 3 illustrates a reaction for the preparation of docetaxel according to the present invention.

[0072] Fig. 4 illustrates a reaction scheme for the preparation of paclitaxel or docetaxel according to the present invention.

[0073] Fig. 5 illustrates a reaction for the preparation of docetaxel according to the present invention.

[0074] Fig. 6 illustrates a reaction scheme for the preparation of paclitaxel or docetaxel according to the present invention.

[0075] Fig. 7 is an NMR spectra of Docetaxel obtained according to a process of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] In embodiments, there is disclosed a compound of the general formula (VI):

[0078] in which R₂, 3 and R₄ are defined herein above. The compound of formula (VI) may be useful in the synthesis of chemical compounds, and more particularly in the synthesis of taxane derivatives.

[0079] In embodiments there are disclosed taxanes derivatives that are formed in chemical conversion processes from 9-dihydro-13-acetylbaccatin III for the efficient production of paclitaxel and docetaxel analogs and their intermediates. Such conversion processes may include deacetylation of the C-10 position, protection of the C-7 hydroxyl, and attachment of the acid compound of formula (VI), to the C-13 hydroxyl to yield the compound of formula (II). These processes may also include the oxidation of the C-9 hydroxyl group to yield useful intermediate taxane compounds.

[0080] Now referring to Figs. 1 and 2 concurrently. A first broad aspect of the present invention provides a compound of formula (VI) as well as the synthetic processes to prepare the compound of formula (VI). The process comprises reacting a compound of formula (VII) with a compound of formula (VIII) to yield a compound of formula (VI).

[0081] Now referring to Figs. 3 and 4 concurrently. A second broad aspect of the present invention provides a novel synthetic route in a process for the preparation of paclitaxel and docetaxel. The process comprises reacting a C-7 protected compound of formula (I) with an acid of formula (VI) to yield a compound of formula (II). The compound of formula (II) is then oxidized at the C-9 hydroxyl to yield a compound of formula (III). The opening of the side chain ring as well as deprotection of the C-7 hydroxyl group of formula (III) is then effected, to yield compound of formula (IV). The compound of formula (IV) is next oxidized to be converted to paclitaxel or docetaxel.

[0082] A third broad aspect of the present invention provides a process for the preparation of docetaxel and paclitaxel which comprises the sequential steps of: attaching a compound of formula (VI) to the compound C-15 hydroxyl position of the compound of formula (I) to obtain a compound of formula (II), oxidizing the compound of formula (II) with an oxidizing agent to obtain a compound of formula (III), opening of the side chain ring as well as deprotecting the C-7 hydroxyl group of formula (III) to obtain a compound of formula (IV), and oxidizing the compound of formula (IV) with an oxidizing agent to obtain docetaxel.

[0083] A fourth broad aspect of the present invention is that the compounds and process of the present invention provide for improved yield over other known processes. For example, yield is improved over a process which uses an oxazolidine docetaxel side chain precursor: (4S,5R)-N-Boc- 2,2-dimethyl-4-phenyl-5-oxazolidine carboxylic acid methyl ester which the N, and O were cyclised with 2-methoxypropene. The new side chain precursor of the present invention requires less steps to be performed and provides higher yields, therefore makes better economic sense.

[0084] The suitable protecting groups for hydroxyl groups can be any protecting group that would be used by a person skilled in the art. Such protecting groups can be those described in Theodora W. Greene et al., Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, Inc., 1999, pp. 17-21.

[0085] The protecting group for hydroxyl groups can be for example protecting groups for hydroxyl groups can be, for example, ethers (such as methyl), or substituted methyl ethers (such as methoxy methyl; methylthiomethyl; (phenyldimethylsilyl)methoxymethyl; benzyloxymethyl; p- methoxybenzyloxymethyl; p-nitrobenzyloxymethyl; o-nitrobenzyloxy methyl; (4- methoxyphenoxy)methyl; guaiacolmethyl; t-butoxymethyl; 4- pentenyloxymethyl; siloxymethyl; 2-methoxyethoxymethyl; 2,2,2- trichloroethoxymethyl; bis(2-chloroethoxy)methyl; 2-

(trimethylsilyl)ethoxymethyl; menthoxymethyl; tetrahydropyranyl; 3- bromotetrahydropyranyl; tetrahydrothiopyranyl; 1-methoxycyclohexyl; 4- methoxytetrahydropyranyl; 4-methoxytetrahydrothiopyranyl; 4- methoxytetrahydrothiopyranyl s,s-dioxide; 1 -[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl; 1 -(2-fluorophenyl)-4-methoxypiperidin-4-yl; 1 ,4-dioxan- 2-yl; tetrahydrofuranyl; tetrahydrothiofuranyl; 2,3,3a,4,5,6,7,7a-octahydro- 7,8,8-trimethyl-4,7-methanobenzofuran-2-yl), diphenylmethylchlorosilane (DPMS), and Tosyl.

[0086] The protecting groups for hydroxyl groups can be, for example, substituted ethyl ethers (such as 1 -ethoxyethyl; 1 -(2-chloroethoxy)ethyl; 1-[2- (trimethylsilyl)ethoxy]ethyl; 1-methyl-1-methoxyethyl; 1 -methyl-1 - benzyloxyethyl; 1 -methyl-1 -benzyloxy-2-fluoroethyl; 1 -methyl-1 -phenoxyethyl; 2,2,2-trichloroethyl; 1 ,1-dianisyl-2,2,2-trichloroethyl; 1 ,1 ,1 ,3,3,3-hexafluoro-2- phenylisopropyl; 2-trimethylsilylethyl; 2-(benzylthio)ethyl; 2- (phenylselenyl)ethyl; t-butyl; allyl; propargy; p-chlorophenyl; p-methoxyphenyl; p-nitrophenyl; 2,4-dinitrophenyl; 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl; benzyl), substituted benzyl ethers (such as p-methoxybenzyl; 3,4- dimethoxybenzyl; o-nitrobenzyl; p-nitrobenzyl; p-halobenzyl; 2,6- dichlorobenzyl; p-cyanobenzyl; p-phenylbenzyl; 2,6-difluorobenzyl; p- acylaminobenzyl; p-azidobenzyl; 4-azido-3-chlorobenzyl; 2- trifluoromethylbenzyl; p-(methylsulfinyl)benzyl; 2- and 4-picolyl; 3-methyl-2- picolyl n-oxido; 2-quinolinylmethyl; 1 -pyrenylmethyl; diphenylmethyl; ρ,ρ'- dinitrobenzhydryl; 5-dibenzosuberyl; triphenylmethyl; a- naphthyldiphenylmethyl; p-methoxyphenyldiphenylmethyl; di(p- methoxyphenyl)phenylmethyl; tri(p-methoxyphenyl)methyl; 4-(4'- bromophenacyloxy)phenyldiphenylmethyl; 4_i4'_!4"-tris(4,5- dichlorophthalimidophenyl)methyl; 4,4',4"-tris(levulinoyloxyphenyl)methyl; 4,4',4"-tris(benzoyloxyphenyl)methyl; 4,4'-dimethoxy-3"-[n- (imidazolylmethyl)]trityl; 4,4'-dimethoxy-3"-[n-(imidazolylethyl)carbamoyl]trityl; 1 ,1-bis(4-methoxyphenyl)-1 '-pyrenylmethyl; 4-(17- tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4"-dimethoxytrityl; 9-anthryl; 9-(9- phenyl)xanthenyl; 9-(9-phenyl-10-oxo)anthryl; 1 ,3-benzodithiolan-2-yl; benzisothiazolyl s,s-dioxido) silyl ethers (such as trim ethyl si lyl; triethylsilyi; triisopropylsilyl; dimethylisopropylsilyl; diethylisopropylsilyl; dimethylthexylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; tri-p-xylylsilyl; triphenylsilyl; diphenylmethylsilyl; di-t-butylmethylsilyl; tris(trimethylsilyl)silyl: sisyl; (2-hydroxystyryl)dimethylsilyl; (2-hydroxystyryl)diisopropylsilyl; t- butylmethoxyphenylsilyl; t-butoxydiphenylsilyl), esters (such as formate; benzoylformate; acetate; chloroacetate; dichloroacetate; trichloroacetate; trifluoroacetate; methoxyacetate; triphenylmethoxyacetate; phenoxyacetate; p-chlorophenoxyacetate; phenylacetate; p-p-phenylacetate; diphenylacetate; nicotinate; 3-phenylpropionate; 4-pentenoate; 4-oxopentanoate (levulinate); 4,4-(ethylenedithio)pentanoate; 5, -[3-bis(4- methoxyphenyl)hydroxymethylphenoxy]levulinate; pivaloate; 1 -adamantoate; crotonate; 4-methoxycrotonate; benzoate; β-phenylbenzoate; 2,4,6- trimethylbenzoate (mesitoate), carbonates (such as methylcarbonyl; methoxymethylcarbonyl; 9-fluorenylmethylcarbonyl; ethylcarbonyl; 2,2,2- trichloroethylcarbonyl; 1 ,1-dimethyl-2,2,2-trichloroethylcarbonyl; 2- (trimethylsilyl)ethylcarbonyl; 2-(phenylsulfonyl)ethylcarbonyl; 2-

(triphenylphosphonio)ethylcarbonyl; isobutylcarbonyl; vinylcarbonyl; allylcarbonyl; p-nitrophenylcarbonyl; benzylcarbonyl; β- methoxybenzylcarbonyl; 3,4-dimethoxybenzylcarbonyl; o-nitrobenzylcarbonyl; β-nitrobenzylcarbonyl), carbonates cleaved by b-elimination (such as 2- dansylethyl; 2-(4-nitrophenyl)ethyl; 2-(2,4-dinitrophenyl)ethyl; 2-cyano-1- phenylethyl; s-benzyl thiocarbonate; 4-ethoxy-1-naphthyl; methyl dithiocarbonate), miscellaneous esters (such as 2,6-dichloro-4- methylphenoxyacetate; 2,6-dichloro-4-(1 ,1 ,3,3- tetramethylbutyl)phenoxyacetate; 2,4-bis(1 ,1-dimethylpropyl)phenoxyacetate; chlorodiphenylacetate; isobutyrate; monosuccinoate; (e)-2-methyl-2- butenoate (tigloate); o-(methoxycarbonyl)benzoate; p-p-benzoate; a- naphthoate; nitrate; alkyl η,η,η',η'-tetramethylphosphorodiamidate; 2- chlorobenzoate; 4-bromobenzoate; 4-nitrobenzoate; 3'5'-dimethoxybenzoin; n-phenylcarbamate; borate; dimethylphosphinothioyl; 2,4- dinitrophenylsulfenate), and sulfonate (such as sulfate; allylsulfonate; methanesulfonate (mesylate); benzylsulfonate; tosylate; 2-[(4- nitrophenyl)ethyl sulfonate).

[0087] The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.

Alternative embodiments

[0088] EXAMPLE 1

[0089] Preparation of Acid of formula (VIII).

Reaction scheme of Example 1

[0090] To a stirred solution of (2S,3f?)-A/-Boc-3-phenylisoserine methyl ester (VII) (46g, 154mmol) in anhydrous toluene (750ml_) under nitrogen, was added 4-Methoxy benzaldehyde (40.8g, 300 mmol) and PTSP (12g, 100 mmol) and the mixture was stirred for 3 hours at room temperature. After TLC showed that the reaction was completed,the reaction mixture was quenched with EtOAc and saturated aqueous sodium bicarbonate, the organic phase was concentrated in vacuum and the residue was purified by column chromatography to give compound (VI) (35g) in 76 % conversion yield. . [0091] EXAMPLE 2

[0092] Preparation of intermediate compound (II):

Reaction scheme of example 2

(VI)

[0093] First to a stirred solution of the acid (VI) (31 g, 0.075mol) in THF (100 ml.) was added LiOH-H₂0 (12.6g, 0.3mol), and this solution was then allowed to react with stirring for 4h. When the TLC showed the disappearance of starting material, the solvent was concentrated to dryness under vacuum to yield a solid residue [compound (VI)]. To the residue was then added compound (I) (20.0 g, 0.025 mol) in andydrous toluene which contains 0.6 equiv of DMAP and 3 equiv of DCG. The mixture was stirred at room temperature for 2 hr. When the TLC showed the disappearance of starting material, the reaction mixture was quenched with water and the organic layer was washed with water and brine, dried with anhydrous a₂S0₄, filtered and concentrated in vacuum. The residue was purified by column chromatography to give compound (II) (28 g) in 82.3 % conversion yield (¹H-NMR: 2386-158- C3).

[0094] EXAMPLE 3

[0095] Preparation of intermediate compound (III):

Reaction scheme of Example 3

[0096] To a stirred solution of compound (II) (12 g, 10 mmol) in 100 ml CH₂CI₂ was added Dess-Martin periodinane (12 g, 25 mmol), the mixture was stirred at room temperature overnight. When the TLC showed the disappearance of starting material, the reaction mixture was quenched with water and the organic layer was washed with water, dried with anhydrous Na2S0₄, filtered and concentrated in vacuum. The residue was purified by flash chromatography to give compound (III) (11 g) in 91.0 % conversion yield (¹H-NMR: 2386-160-c4).

[0097] EXAMPLE 4

[0098] Preparation of intermediate compound (IV)

Reaction scheme of Example 4

[0099] To a solution of compound (III) (5.0 g, 5.5 mmol) in MeOH (50 ml) was added p-TsOH (1 g, 6 mmol), the mixture was stirred at room temperature for 3 hr. When the TLC showed the disappearance of starting material, the reaction mixture was quenched with aHC0₃ (0.5 g), the organic was concentrated in vacuum and the residue was purified by column chromatography to give compound (IV) (3g) in 82 % conversion yield. (¹H- NMR: 2386-188-c5).

[00100] EXAMPLE 5

[00101] Preparation of Docetaxel:

Reaction scheme of Example 5

[00102] To a stirred solution of compound (VI) (2.0 g, 0.06mmol) in 20 ml THF at 25°C were added NaHC0₃ (30 equiv) and H₂0₂ (60 equiv). The mixture was stirred at 25°C for 48 hr. When the TLC showed the disappearance of starting material, the reaction mixture was quenched with water and extracted by EtOAc. The organic layer was washed with NaSC solution and brine, dried with anhydrous Na₂S04, filtered and concentrated in vacuum. The residue was purified by flash chromatography to give crude Docetaxel (1.46 g) in 77 % conversion yield. The crude product was recrystalized with acetone/n-Hexane = 1/2 (10 ml / 20 ml). ¹H-NMR: 2028- 167-25 ). See Fig. 4. [00103] EXAMPLE 6

[00104] Preparation of intermediate compound (V)

Reaction scheme of Example 6

Docetaxel

[00105] To a solution of compound (III) (5.0 g, 5.5 mmol) in MeOH (50 ml) was added p-TsOH (0.3 g, 1.8 mmol), the mixture was stirred at room temperature for 3 hr. When the TLC showed the disappearance of starting material, the reaction mixture were added 82.5 mmol of saturated NaHC0₃ (0.7 g) aqueous solution, and 30% H₂0₂ (10 equiv). The mixture was stirred at 25°C for 15 hr. When the TLC showed the disappearance of starting material, the reaction mixture was quenched with water and extracted by DCM (dichloromethane). The organic layer was washed with NaSC>3 solution and brine, dried with anhydrous Na₂S04, filtered and concentrated in vacuum. The residue was purified by flash chromatography to give crude Docetaxel (2.8 g) in 71 % conversion yield. The crude product was recrystalized with acetone/n- Hexane = 1/2 (10 ml / 20 ml). H-NMR: 2028-167-25). See Fig. 5.

[00106] EXAMPLE 7

[00107] Comparison of the process of the present invention with a process using another oxazolidine side chain.

Reaction scheme for Example 7

[00108] The comparative process uses the (4S,5R)-N-Boc-2,2-dimethyl- 4-phenyl-5-oxazolidine carboxylic acid methyl ester side chain, which is a docetaxel side chain precursor in which the N, and O were cyclised with 2- methoxypropene. After attachment of this side chain precursor to the taxane core moiety, this side chain precursor causes problem in that it is difficult to open the side chain oxazolidine ring, which results in low yield of about 45- 50% as well as several by products. After attaching the side chain to the taxane moiety, the subsequent cleavage of the oxazolidine ring, by a force condition such as formic acid at room temperature, resulted in an undesired concomitant removal of the BOC group at the nitrogen atom. Because of this, an additional step for replacing the BOC group on the nitrogen atom needs to added.

[00109] The cleavage of oxazolidine ring process is: to 5 ml of HCOOH was added intermediate IM4 (2.0 g, 2.2 mmol), the mixture was stirred at room temperature overnight (about 15 hrs). When the TLC showed the disappearance of starting material, the reaction mixture was quenched with NaHCC>3 (0.5 g) and then with water and extracted by EtOAc, The organic layer was washed with NaS0₃ solution and brine, dried with anhydrous Na₂S0₄, filtered and concentrated in vacuum, and then the residue was purified by column chromatography to give intermediate IM5 (0.7g) in 45.0 % conversion yield. The intermediate IM5 was dissolved in THF and 1.5 mole equivalent of (BOC^O, and 1 mole equivalent of NaHC0₃ were added, the mixture was stirred at room temperature for 5 hours or until the TLC shows the starting material completely disappeared, work up as normal to yield 0.55 g (app. 90% yield) end product.

[00110] The acid processes of the present invention do not need this additional step, as no cleavage of the BOC group occurs during opening of the oxazolidine ring. Also, the ring opening step of the process of the present invention, provides for higher conversion yields (Ex. 6 above: combined with the oxidation for conversion to Decetaxel provides for higher conversion yields (Ex. 4 vs. Ex. 7 above: 82%, versus 45% for the comparative process, See Table 1 below). Moreover, the two step conversion ( Ex. 4 and 5) as well as the direct conversion (Ex. 6) of the compound of formula (III) to Docetaxel also provide higher conversion yields compared to the comparative process (Ex. 7): overall yields of 63.1 %, 71 % and 40.5% respectively. Moreover, the direct conversion process also reduces the number of steps of the overall process by one. Therefore, the process of the present invention makes economically more sense. Table 1

omparatve ate from examples 4, 5, 6 and 7. [00111] The embodiments and examples presented herein are illustrative of the general nature of the subject matter claimed and are not limiting. It will be understood by those skilled in the art how these embodiments can be readily modified and/or adapted for various applications and in various ways without departing from the spirit and scope of the subject matter disclosed claimed. The claims hereof are to be understood to include without limitation all alternative embodiments and equivalents of the subject matter hereof. Phrases, words and terms employed herein are illustrative and are not limiting. Where permissible by law, all references cited herein are incorporated by reference in their entirety. It will be appreciated that any aspects of the different embodiments disclosed herein may be combined in a range of possible alternative embodiments, and alternative combinations of features, all of which varied combinations of features are to be understood to form a part of the subject matter claimed.

Claims

CLAIMS:

1. An acid of the formula (VI):

wherein

R₂ is iert-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₅ is a C -C6 alkyl linear or branched, C1-C20 acyl group, C C₂o halogenated acyl group, C₃-Ci₂cycloalkyl, C1-C12 heterocyclyl, C₂- C₂₀ alkenyl, C₂-C₂o alkynyl, C₆-Ci₂ aryl, C₆-C₂o aralkyi, CrC₂₀ alkyloxy C₆-C₂oalkylaryl, C Ci₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyi, heterocyclyl, alkenyl, alkynyl, aryl, aralkyi, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH,— COOR₆ in which R₆ is a C C₆ alkyl, C1-C12 alkyl linear or branched, C6-C12 aryl, C2-C20 alkenyl, C1-C20 alkoxy, C1-C20 alkyl, C₂-C₂oalkynyl, C₆-C₂o aralkyi, C₆-Ci₂ aryl, C₃-C₈ cycloalkyi, C1-C20 aminoalkyl, C6-C12 aminoaryl, C1-C12 aminoheteroaryl, C1-C2₀ hydroxyalkyi, C6-C12 hydroxyaryl, C1-C12 hydroxyheteroaryl, C1-C12 heterocyclyl, C1-C-12 heteroaryl, C2-C20 alkylheterocyclyl, or C₂-C₂o alkylheteroaryl.

2. The acid of claim 1 , in the form of a salt, ester, anhydride, mixed anhydride, or halide.

3. A process for preparing a compound of formula (VI):

(VI)

said process comprising reacting a compound of formula (VII):

(VII)

with a compound of formula (VIII):

(VIII)

wherein

R₂ is iert-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₃ is OR₅ or N0₂;

R4 is OR₅ or R₅ is a Ci-C₆ alkyl linear or branched, C C₂o acyl group, d- C₂o halogenated acyl group, C₃-C-i₂cycloalkyl, C1-C12 heterocyclyl, C₂- C20 alkenyl, C2-C20 alkynyl, C₆-Ci₂ aryl, C6-C20 aralkyl, C1-C20 alkyloxy C6-C₂₀alkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH,— COOR₆ in which R₆ is a C C₆ alkyl, Ci-d₂ alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂o alkenyl, Ci-C₂₀ alkoxy, C1-C20 alkyl, C2-C₂oalkynyl, C₆-C₂₀ aralkyl, C₆ ^LC-i2 aryl, C₃-C₈ cycloalkyl, Ci-C₂₀ aminoalkyl, C₆-Ci₂ aminoaryl, Ci-Ci₂ aminoheteroaryl, CrC₂₀ hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C1-C12 hydroxyheteroaryl, C1-C12 heterocyclyl, Ci-Ci₂ heteroaryl, C₂-C2o alkylheterocyclyl, or C2-C20 alkylheteroaryl.

4. The process of claim 3, wherein R₂ is terf-butoxycarbonyl (i-BOC).

5. The process of claim 3, wherein R₃ is OCH₃.

6. The process of claim 3, wherein R4 is OCH₃.

7. A process for preparing a compound of formula (VI):

(VI) said process comprising reacting (2S,3R)-/V-Boc-3-phenylisoserine methyl ester:

in anhydrous toluene under nitrogen, with 4-Methoxy benzaldehyde:

and 4-dimethylaminopyridine (DMAP).

8. A compound of formula (II), (III), or (IV):

(IV) wherein

Ri is a suitable protecting group for a hydroxyl group;

R₂ is terf-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₃ is OR₅ or N0₂;

R₅ is a Ci-C₆ alkyl linear or branched, C1-C20 acyl group, C C₂o halogenated acyl group, C₃-Ci₂cycloalkyl, C1-C12 heterocyclyl, C₂- C₂₀ alkenyl, C₂-C₂o alkynyl, C₆-Ci₂ aryl, C₆-C₂o aralkyl, C C₂₀ alkyloxy C₆-C₂₀alkylaryl, Ci-Ci₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR₆ in which R₆ is a CrC₆ alkyl, Ci-Ci₂ alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂₀ alkenyl, CrC₂₀ alkoxy, C1-C20 alkyl, C₂-C₂₀alkynyl, C₆-C₂₀ aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, Ci-C₂₀ aminoalkyl, C₆-Ci₂ aminoaryl, C1-C12 aminoheteroaryl, Ci-C₂o hydroxyalkyl, C6-Ci₂ hydroxyaryl, Ci-Ci₂ hydroxyheteroaryl, C1-C12 heterocyclyl, Ci-Ci₂ heteroaryl, C₂-C₂₀ alkylheterocyclyl, or C2-C₂₀ alkylheteroaryl.

9. The compound of claim 8, wherein said suitable protecting group for a hydroxyl group is chosen from Ci-C₂5 ethers, Ci-C₂₅ substituted methyl ethers, Ci-C₂5 substituted ethyl ethers, Ci-C₂5 acyl groups, C1-C25 halogenated acyl groups, Ci-C₂5 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, d- C₂₅ carbonates, and C-i-C₂₅ sulfonates.

10. The compound of claim 8, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1-(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

11. The compound of claim 8, wherein Ri is diphenylmethylchlorosilane (DPMS).

12. The compound of claim 8, wherein R₂ is fert-butoxycarbonyl (f-BOC).

13. The compound of claim 8, wherein R₃ is OCH₃.

14. A process for p I):

(II)

said process comprising reacting 4-dimethyiaminopyridine (DMAP) and Ν,Ν'- dicyclohexylcarbodiimide (DCC) with a compound of formula (I):

(I)

and a compound of formula (VI):

(VI)

wherein

R-i is a suitable protecting group for a hydroxyl group;

R₂ is feri-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₅ is a C1-C6 alkyl linear or branched, C1-C20 acyl group, C C20 halogenated acyl group, C3-Ci2cycloalkyl, C1-C12 heterocyclyl, C2- C20 alkenyl, C₂-C₂o alkynyl, C6-C 2 aryl, C6-C20 aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR6 in which R₆ is a Ci-C₆ alkyl, C1-C12 alkyl linear or branched, C₆-Ci2 aryl, C2-C20 alkenyl, C1-C20 alkoxy, C1-C20 alkyl, C2-C2oalkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, C1-C2₀ aminoalkyl, C₆-C₁₂ aminoaryl, C Ci₂ aminoheteroaryl, C-1-C20 hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C1-C12 hydroxyheteroaryl, Ci-Ci₂ heterocyclyl, C₁-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl.

1 5. The process of claim 14, wherein said suitable protecting group for a hydroxyl group is chosen from C1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, C-p C25 carbonates, and C1-C25 sulfonates.

16. The process of claim 14, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1 -(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethyiisopropylsiiyi, dimethylthexyisilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

17. The process of claim 14, wherein Ri is diphenylmethylchlorosilane (DPMS).

18. The process of claim 14, wherein R₂ is ferf-butoxycarbonyl (f-BOC).

19. The process of claim 14, wherein R₃ is OCH₃.

20. A process for preparing a compound of formula (III):

wherein

Ri is a suitable protecting group for a hydroxyl group;

R₂ is ferf-butoxycarbonyl (ί-BOC) or benzoyl (Bz);

R₃ is OR₅ or N0₂;

R5 is a C-1-C6 alkyl linear or branched, C1-C20 acyl group, Ci- C2₀ halogenated acyl group, C₃-Ci₂cycloalkyl, C1-C12 heterocyclyl, C₂- C₂o alkenyl, C₂-C₂₀ alkynyl, C₆-Ci₂ aryl, C₆-C₂o aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR₆ in which R₆ is a C C6 alkyl, C-1-C12 alkyl linear or branched, C₆-Ci2 aryl, C₂-C₂o alkenyl, Ci-C₂₀ alkoxy, C1-C₂0 alkyl, C₂-C₂oalkynyl, C6-C20 aralkyl, C6-C12 aryl, C₃-Cs cycloalkyl, C1-C20 aminoalkyl, C6-Ci₂ aminoaryl, C Ci₂ aminoheteroaryl, CrC₂₀ hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C Ci₂ hydroxyheteroaryl, C C-i₂ heterocyclyl, Ci-Ci₂ heteroaryl, C2-C20 alkylheterocyclyl, or C2-C20 alkylheteroaryl.

21. The process of claim 20, wherein said oxidizing agent is chosen from N-methylmorpholine N-oxide (NMO)/Tetrapropylammonium perruthenate (TPAP) and Dess-Martin periodinane.

22. The process of claim 20, wherein said suitable protecting group for a hydroxyl group is chosen from C1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, C C25 carbonates, and C1-C25 sulfonates.

23. The process of claim 20, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxy methyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1 -(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

24. The process of claim 20, wherein Ri is diphenylmethylchlorosilane (DPMS).

25. The process of claim 20, wherein R₂ is terf-butoxycarbonyl (f-BOC).

26. The process of claim 20, wherein R₃ is OCH₃.

27. A process of preparing a compound of formula (IV):

(IV) said process comprising reacting p-toluenesulfonic acid (pTsOH) with a compound of formula (III):

(Ill)

wherein

Ri is a suitable protecting group for a hydroxyl group;

R₂ is terf-butoxycarbonyl (f-BOC);

R₃ is OR₅ or N0₂;

R₅ is a C1-C6 alkyl linear or branched, C1-C20 acyl group, Ci- C20 halogenated acyl group, C3-Ci2cycloalkyl, C1-C12 heterocyclyl, C₂- C20 alkenyl, C2-C20 alkynyl, C6-Ci₂ aryl, C₆-C₂o aralkyl, CrC₂₀ alkyloxy C6-C₂oalkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C2-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR6 in which R₆ is a C1-C6 alkyl, C Ci₂ alkyl linear or branched, C₆-Ci₂ aryl, C₂-C₂o alkenyl, CrC₂₀ alkoxy, C1-C20 alkyl, C₂-C₂oalkynyl, C6-C20 aralkyl, C6-C12 aryl, C3-C8 cycloalkyl, C1-C20 aminoalkyl, C₆-Ci₂ aminoaryl, Ci-Ci₂ aminoheteroaryl, CrC₂₀ hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C1-C12 hydroxyheteroaryl, C1-C12 heterocyclyl, C1-C12 heteroaryl, C₂-C2o alkylheterocyclyl, or C^C^ alkylheteroaryl.

28. The process of claim 27, wherein said suitable protecting group for a hydroxyl group is chosen from Ci-C₂₅ ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, C-1-C25 esters, d- C25 carbonates, and C1-C25 sulfonates.

29. The process of claim 27, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxy methyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1-(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

30. The process of claim 27, wherein R-i is diphenylmethylchlorosilane (DPMS).

31. The process of claim 27, wherein R₂ is tert-butoxycarbonyl (t-BOC).

32. The process of claim 27, wherein R₃ is OCH₃.

33. A process of preparing a compound of formula (V)

(V)

wherein

R₂ is feri-butoxycarbonyl (i-BOC).

34. The process of claim 33, wherein said oxidizing agent is hydrogen peroxide (H₂0₂) and sodium bicarbonate (NaHC0₃).

35. A process of preparing a compound of formula (V):

said process comprising reacting p-toluenesulfonic acid (pTsOH) with a compound of formula (III), followed by oxidation with hydrogen peroxide (H₂0₂) and sodium bicarbonate (NaHC0₃):

wherein

Ri is a suitable protecting group for a hydroxyl group;

R2 is ferf-butoxycarbonyl (f-BOC);

R₃ is OR₅ or N0₂;

R₅ is a C-i-Ce alkyl linear or branched, C C₂o acyl group, d- C₂o halogenated acyl group, C₃-Ci₂cycloalkyl, Ci-Ci₂ heterocyclyl, C₂- C20 alkenyl, C2-C20 alkynyl, C6-C12 aryl, C₆-C₂o aralkyl, Ci-C₂₀ alkyloxy C₆-C₂oalkylaryl, Ci-C-|₂ heteroaryl, C2-C20 alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN , CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COO 6 in which R₆ is a Ci-C₆ alkyl, C1-C12 alkyl linear or branched, C₆-Ci2 aryl, C₂-C₂o alkenyl, C1-C20 alkoxy, C1-C20 alkyl, C₂-C₂oalkynyl, C6-C20 aralkyl, C₆-Ci₂ aryl, C₃-C₃ cycloalkyl, C1-C20 aminoalkyl, C6-Ci₂ aminoaryl, C_rCi₂ aminoheteroaryl, Ci-C₂₀ hydroxyalkyl, C₆-Ci₂ hydroxyaryl, Ci-Ci₂ hydroxyheteroaryl, C1-C12 heterocyclyl, C C₁₂ heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂₀ alkylheteroaryl.

36. The process of claim 35, wherein said suitable protecting group for a hydroxyl group is chosen from C1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, Ci-C₂5 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, Ci- C₂5 carbonates, and C1-C25 sulfonates.

37. The process of claim 35, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1 -(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

38. The process of claim 35, wherein Ri is diphenylmethylchlorosilane (DPMS).

39. The process of claim 35, wherein R₃ is OCH₃.

40. A process of preparing paciitaxel, docetaxel and derivatives thereof comprising the steps of:

(a) attaching a compound of formula VI):

(VI)

to the C-15 hydroxyl position of the compound of formula (I):

(I)

to obtain a compound of formula (II):

(ii);

(in);

(IV),

and

(f) when R₂ is terf-butoxycarbonyl (i-BOC), oxidizing the compound of formula (IV) with an oxidizing agent to obtain a compound of formula (V):

(V),

wherein

Ri is a suitable protecting group for a hydroxyl group;

R2 is fert-butoxycarbonyl (f-BOC) or benzoyl (Bz);

R₅ is a C-i-Ce alkyl linear or branched, C1-C20 acyl group, d- C20 halogenated acyl group, C3-Ci2cycloalkyl, C1-C-12 heterocyclyl, C₂- C20 alkenyl, C₂-C₂o alkynyl, C₆-Ci₂ aryl, C₆-C₂o aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C2-C20 alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF₃,— SH,— OCH₂Ph,— OPh,— SCH₃,— SPh,— SCH₂Ph,— COOH, — COOR6 in which R6 is a C C6 alkyl, C1-C12 alkyl linear or branched, C6-C12 aryl, C₂-C₂o alkenyl, C1-C20 alkoxy, C1-C20 alkyl, C₂-C2oalkynyl, C₆-C₂o aralkyl, C₆-Ci₂ aryl, C₃-C₈ cycloalkyl, C1-C20 aminoalkyl, C₆-Ci₂ aminoaryl, C1-C12 aminoheteroaryl, C1-C20 hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C1-C12 hydroxyheteroaryl, CrC₁₂ heterocyclyl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl.

41. The process of claim 40, wherein said suitable protecting group for a hydroxyl group is chosen from C1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 stlyl ethers, C1-C25 esters, C C25 carbonates, and C1-C25 sulfonates.

42. The process of claim 40, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxyethyl, 1 -(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, ally), propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

43. The process of claim 40, wherein Ri is diphenylmethylchlorosilane

(DPMS).

44. The process of claim 40, wherein R₂ is fert-butoxycarbonyl (f-BOC).

45. The process of claim 40 wherein R₃ is OCH₃.

46. The process of claim 40, wherein said taxane derivative is paclitaxel or docetaxel.

47. A process of preparing docetaxel and derivatives thereof comprising the steps of:

(a) attaching a compound of formula (VI):

(VI)

to the C-15 hydroxyl position of the compound of formula (I):

(I)

to obtain a compound of formula (II):

(M);

(d) oxidizing the compound of formula (II) with an oxidizing agent to obtain a compound of formula

and,

Rt is a suitable protecting group for a hydroxyl group;

R₂ is ferf-butoxycarbonyl (i-BOC);

R₅ is a C1-C6 alkyl linear or branched, C1-C20 acyl group, C C₂o halogenated acyl group, C₃-Ci₂cycloalkyl, Ci-Ci₂ heterocyclyl, C₂- C20 alkenyl, C₂-C₂o alkynyl, C₆-Ci₂ aryl, C₆-C₂o aralkyl, C1-C20 alkyloxy C₆-C₂oalkylaryl, C1-C12 heteroaryl, C₂-C₂o alkylheterocyclyl, or C₂-C₂o alkylheteroaryl,

said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, heteroaryl, alkylheterocyclyl, and alkylheteroaryl are unsubstituted or substituted with at least one substituent, each of said substituent(s) being chosen from F, CI, Br, I, OH, SH, NH₂, N0₂, CN, CF_3>— SH,— OCH₂Ph,— OPh,— SCH₃₍— SPh,— SCH₂Ph,— COOH, — COOR6 in which R6 is a C C6 alkyl, C-1-C12 alkyl linear or branched, C6-Ci₂ aryl, C₂-C₂₀ alkenyl, Ci-C₂o alkoxy, C1-C20 alkyl, C₂-C₂₀alkynyl, C₆-C₂o aralkyl, C₆-C₁₂ aryl, C₃-C₈ cycloalkyl, CrC₂₀ aminoalkyl, C₆-Ci₂ aminoaryl, C-i-Ci₂ aminoheteroaryl, C1-C2₀ hydroxyalkyl, C₆-Ci₂ hydroxyaryl, C d₂ hydroxyheteroaryl, Ci-Ci₂ heterocyclyl, C Ci₂ heteroaryl, C₂-C₂o alkylheterocyclyl, or C2-C20 alkylheteroaryl.

48. The process of claim 47, wherein said suitable protecting group for a hydroxyl group is chosen from C-1-C25 ethers, C1-C25 substituted methyl ethers, C1-C25 substituted ethyl ethers, C1-C25 acyl groups, C1-C25 halogenated acyl groups, C1-C25 substituted benzyl ethers, C1-C25 silyl ethers, C1-C25 esters, d- C25 carbonates, and C1-C25 sulfonates.

49. The process of claim 47, wherein said suitable protecting group for a hydroxyl group is chosen from diphenylmethylchlorosilane (DPMS), Tosyl, methyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 2-(trimethylsilyl)ethoxymethyl, dioxanyl, 1 -ethoxy ethyl, 1-(2- chloroethoxy)ethyl, 2,2,2-trichloroethyl, t-butyl, allyl, propargyl, benzyl, p- methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, benzylformate, methylcarbonyl, ethylcarbonyl, methoxymethyl arbonyl, trichloroethoxycarbonyl, benzylcarbonyl, benzyloxycarbonyl. allylsulfonyl, methanesulfonyl, and p-toluenesulfonyl.

50. The process of claim 47, wherein R is diphenylmethylchlorosilane (DPMS).

51. The process of claim 47, wherein said oxidation is with hydrogen peroxide (H₂0₂) and sodium bicarbonate (NaHC0₃).

52. The process of claim 47 wherein R₃ is OCH₃.

53. The process of claim 47, wherein said taxane derivative is docetaxel.