MXPA00008050A - Synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile - Google Patents

Abstract

Process for synthesizing paclitaxel by treating baccatin III with a strong base in a solvent, adding an electrophile to the solution to form a 7-O-protected baccatin III derivative, reacting the 7-O-protected baccatin III derivative with a protected paclitaxel sidechain in a solvent such that the protected paclitaxel sidechain is coupled to the 13-hydroxyl of the 7-O-protected baccatin III, and subsequently deprotecting the protected paclitaxel sidechain and the 7-O protecting group to form paclitaxel, and intermediates used therein.

Description

SYNTHESIS OF BACCATINA III OF PACLITAXEL THROUGH THE PROTECTION OF 7-HYDROXYLENE USANTO A STRONG BASE AND A ELECTOOFILO FIELD OF THE INVENTION The present invention relates to the treatment of baccatine III with a strong base at a low temperature, followed by the addition of one or more electrophiles to give baccatine III 7-O-protected, which is then converted to Taxol® (paclitaxel). Accordingly, the usefulness of baccatine III as a starting material for the synthesis of Taxol is shown.

Background of the Invention Paclitaxel (Taxol), a diterpene taxane compound, is a natural product extracted from the bark of the Pacific yew tree, Taxus Brevifolia. It has been shown to have excellent antitumor activity in animal models in vivo, and recent studies have made clear its unique mode of action, which includes the abnormal polymerization of tubulin and breakage of mitosis during the cell cycle. Taxol has recently been approved for the treatment of intractable advanced ovarian cancer, breast cancer and more recently, Kaposi's sarcoma related to AIDS. The results of the REF .: 1ZL883 clinical studies with paclitaxel are mentioned in scientific journals and have been analyzed by numerous authors, such as Rowins and Doneho er in The Clinical Pharmacology and Use of Ant microtubule Agents in Cancer Chemotherapeutics, Phamac Ther, 52, pp 35-84 (1991 ), Spenser and Faulds, Paclitaxel, A Review of Pharmaceutical and Pharmacodynamic Properties and Therapeutic Potential in the Treatment of Cancer, Drugs, 48 (5), pp 794-847 (1994), KC Nicolau et al, Chemistry and Biology of Taxol , Angew Chem, Jpt Ed Eng, 33, pp 15-44 (1994), FA Holmes, AP Kudelka, JJ Kavanaugh, MH Huber, JAA? Am, and V Valero, "Taxane Anticancer Agents - Basic Science and Current Status", edited by Gunda I Georg, Thomas C Chen, Iwao Oiima, and Dolotrai M Vyas, pp 31-57 American Chemical Society, Wash, DC (1995), Susan G Arbuck and Barbara Blaylock, "Taxol® Science and Applications", edited by Matthew Suffness, pp 379-416, CRC Press Boca Raton, FL (1995) and the referees cited here A semi-synthetic analogue of paclitaxel named Taxotere® (docetaxel) has also been found to have good antitumor activity. Taxol and Taxotere structures are shown below along with the conventional numbering system for molecules belonging to the Taxano class, such numbering system It is also used in this application Taxol® (paclitaxel): R = phenyl; R '= acetyl, 2 Taxotere®: R = t-butoxy; R '= hydrogen With reference to the taxane numbering, the reference to a particular carbon in the taxane structure must be indicated throughout this application by a "C-number", which means the carbon in the taxane according to the previous numbering system. For example, "C-13" refers to the carbon at position 13 in the taxane ring as shown above, which has a side chain coupled thereto. Additionally, the bold numbers that accompany the names of compounds and structures refer to the compounds illustrated in the paclitaxel syntheses and Schemes 1-3 of the prior art, below.

The structural unit of the central main element of paclitaxel is Baccatine III 1, a diterpenoid that has the chemical structure: This is also very similar in structure to 10-deacetylbaccatin III 3 ("10-DAB"), which has the chemical structure: but which lacks an acetate ester in the alcohol of position 10.

Commercial pharmaceutical products containing paclitaxel are available, for example, for the treatment of ovarian and breast cancer, and more recently, Kaposi's sarcoma related to AIDS. Paclitaxel has also shown that it promises results in clinical studies for the treatment of other cancers. As a result, the demand for paclitaxel continues to increase, and increasing amounts of paclitaxel are always needed with each passing year to continue research and clinical studies. Paclitaxel is extracted with difficulty and in low yields from the bark of Tax s brevifolia (approximately 1 kg of the drug is isolated from the bark of 3,000 T. brevifolia trees). Due to the difficulty in extracting adequate yields, alternative sources are necessary to synthesize paclitaxel.

-DAB is currently the starting material for paclitaxel semisynthesis, and can be easily extracted from the needles and twigs of the European Tile tree, Taxus baccata L. However, baccatin III, 10-DAB and others taxane compounds, do not show the degree of antitumor activity shown by paclitaxel. Accordingly, the semi-synthesis of paclitaxel from baccatine III, 10-DAB and other taxane compounds is of great interest and importance.

The structural similarity of 10-DAB to taxol falsely represents, however, the difficulty in converting 10-DAB to taxol, and actually makes this conversion highly problematic. The required differentiation of hydroxyl functions C-7 and C- Likewise, the selective reagent of the C-13 hydroxyl group, which is difficult to access with the side chain of N-benzoylphenyleoserine (β-amidoester) adequately protected and voluminous taxol, can be achieved in practice only with specific protection groups and under specially developed reaction conditions JN Denis et al, A Highly Efficient, Practical Approach to Natural Taxol, J Am Chem Soc 110, pp 5917-5918, 1988 This step in C-13 is a coupling reaction step which, although it is tedious due to its position within the concave region of the hemispherical taxane skeleton and because of the significant tight obstacle around this position and by the Hydrogen binding between the 13-hydroxyl group and the 4-acetoxy group is a key step required in each contemplated synthesis of taxol or biologically active taxol derivative, since the presence of the side chain in C-13 is required for antitumor activity Wam et al, J Am. Chem Soc, 93, pp 2325 (1971) The synthetic methods have been previously described in scientific and patent literature Three different routes for Synthesizing paclitaxel known in the literature is described below. The first two routes use 7-0-TES (triethylsilyl) -baccatine III 4, obtained from the selective silylation and acetylation of 10-DAB.

First Paclitaxel Synthesis Route Paclitaxel The first route, developed by Professor R.A. Holton and described in U.S. Patent No. 5,274,124, which is incorporated by reference herein, reacts the lithium anion of 7-0-TES-baccatine III 4 with a β-lactam to introduce the amino acid side chain of paclitaxel required in the C-13 portion. Baccatine III 7-0-TES-protected 4 can be obtained as described by Greene et al in J. Am. Chem. Soc. 110, pp. 5917 (1988).

Second Path of Synthesis of Paclitaxel Paclitaxel); The second route developed by Bristol-Myers Squibb and described in the Serial Number of United States Patent Application 07 / 995,443 and by D.G.I. Kingston et al., In Tetrahedron Letters 35, p. 4483 (1994), both of which are incorporated by reference herein, couples 7-O-TES-baccatine III 4 with oxazolinecarboxylic acid using DCC or a similar dehydrating agent.

Third Pathway of Paclitaxel Synthesis ita? A third route of synthesizing paclitaxel from 15 10-DAB and coupling 7-0-TROC-baccatine III 6 with a protected β-phenylisoserine side chain 7, was developed by A. Commer? On et al., in Rhone-Poulenc Rorer. A. Commercon et al., Tetrahedron Letters 33, pp. 5185-5188 (1992). This route, however, while producing a significant amount of Taxotere, produces Taxol in much smaller yields.

The use of baccatine III as a starting material would significantly simplify paclitaxel semisynthesis.

Baccatine III is currently synthesized by cell culture and could become available in sufficient quantities to maintain economic and competitive semisynthesis This would eliminate the need for 10-DAB in the semi-synthesis of paclitaxel Detailed description of the invention It is an object of the present invention to provide a new, useful and efficient protocol for the semisynthesis of paclitaxel from protected baccatma III derivatives, which comprises the binding of a paclitaxel side chain to the protected baccatma III derivatives, followed by the subsequent deprotection of protected baccatin III derivatives Another objective of the present invention is the condition of methods of producing baccatma III derived vanes that have a protection group at the C-7 site in the taxane structure, and which after the attachment of a side chain and subsequent deprotection , produces paclitaxel in significant amounts A further objective of the present invention is the condition of a simple, efficient, and cost effective protocol for the semi-synthesis of paclitaxel Accordingly, the present invention comprises a novel method by which baccatma III can be efficiently converted to baccatine III 7-0-protected using several different protection groups after the binding of a paclitaxel side chain to the site C-13, these 7-0-protected baccatine III compounds can then be easily converted to paclitaxel which makes baccatma III a valuable starting material for paclitaxel semisynthesis The present disclosure relates broadly to a chemical process for the efficient production of paclitaxel, intermediates and precursors thereof. More specifically, the present invention relates to the semi-synthesis of paclitaxel by protecting the 7-hydroxyl from the baccatma III of the paclitaxel precursor to give baccatine III 7-O-protected, using strong bases, such as lithium tert-butoxide (LitbuO), lithium hexamethyldisilazane (LiHMDS), potassium hexamethyldisilazane (KHMDS) or sodium hexamethyldisilazane (KHMDS) in DMF or similar known solvents, such as DMAC, NMPO, DMEU and DMPU, and several electrophiles, followed by coupling of a side chain of paclitaxel at position C-13 and subsequent protection of C-7 and replacement of the protecting group with a hydrogen More particularly, the invention uses protective groups such as benzyloxy carbonyl (CBZ) or tert-butoxycarbonyl (BOC) at the C-7 site in the hard taxane nte the coupling of the paclitaxel side chain at position C-13.

The general process described herein comprises the production of 7-0-protected baccatine III derivatives, such as 7-0-CBZ- or 7-0-BOC-baccatine III, the coupling of a side chain at C-13, and the subsequent deprotection of the 7-0-protected baccatine III intermediate product having a C-13 side chain to paclitaxel. An advantageous base particularly for producing 7-O-protected baccatine III is LitbuO, an economical base which provides a good performance and significantly cleaner product. Other useful electrophiles include those of the general formula 0 wherein R is alkyl, aryl, R'O-, 0R '2N-, RS, and X is halogen, imidazoyl, benztriazole, N- (benzyloxycarbonyloxy) succinimide, ORY or -OOCOR in a solvent, such as DMF.

As stated, the 7-hydroxyl of baccatin III is protected with a conventional hydroxy protecting group. Conventional hydroxy protecting groups are parts which can be employed to block or protect a hydroxy function and these are well known in the art. Preferably, the protection groups are those which can be eliminated by methods which do not result in appreciable destruction for the remaining molecule. Examples of such easily separable hydroxy protecting groups, such as benzyloxycarbonyl, triethylsilyl, 2,2,2-trichloroethoxycarbonyl, and tert-butoxycarbonyl, among others are suitable. Other suitable protection groups which can be used are found in Chapter 2 of "Protective Groups in Organic Synthesis", Second Edition, by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley &Sons, Inc.).

The specific examples which are mentioned below illustrate the synthesis of representative compounds of the present invention and are not construed as limiting the invention in sphere or scope. The methods can be adapted to variations to produce intermediates and compounds comprised by this invention, but not specifically described. In addition, variations of the methods for producing the same compounds in a slightly different manner will also be apparent to one skilled in the art.

The abbreviations used herein are conventional abbreviations widely employed in the art. A part of which are: Ac acetyl AcOH acetic acid Bz benzoyl BOC tert-butoxycarbonyl BOC20 di-tert-butylcarbonate CBZ benzyloxycarbonyl CBZ-C1 benzyloxycarbonyl chloride DCC dicyclohexylcarbodiimide DCU N, N-dicyclohexylurea DMAC N, N-dimethylacetamide DMAP 4-dimethylaminopyridine DMEU N, N '-dimethylethylene-urea DMF dimethylformamide DMPU N, N' -dimethylpropylene-urea EtOAc ethyl acetate h ipa hour (s) isopropyl alcohol KHMDS hexamethyldisilazane potassium LiHMDS lithium hexamethyldisilazane or lithium bis (trimethylsilyl) amide LitbuO lithium tert-butoxide MeOH methanol min minutes MTBE tert-butylmethyl ether NaHMDS hexamethyldisilazane sodium NMPO N-methyl-2-pyrrolidinone Ph phenyl rt room temperature tBu tertiary butyl TES triethylsilyl THF tetrahydrofuran TFA trifluoroacetic acid TROC 2,2, 2-trichloromethoxycarbonyl A. Production of 7-0-anion As a starting point in the semi-synthesis of paclitaxel according to the exemplary embodiment of the present invention, baccatin III is reacted with one or more strong bases to give a suitable 7-O-anion for the reaction with an electrophilic / reactive of protection. The process of preparing the 7-O-anion is illustrated in Scheme 1.

Scheme 1 As illustrated in Scheme 1, treatment of a solution of baccatine III 1 in DMF with LitbuO at low temperature produces 7-O-anion 8. DMF is the preferred solvent, since the reaction is slow in the THF used Commonly . Other solvents which may be used include DMAC, NMPO, DMEU and DMPU. Epimer 9 is the favored configuration under these conditions, but surprisingly only 7-0-anion 8 reacts with the electrophile. Although LitbuO is the favored base which gives a cleaner product with a significant yield, other bases can also be used, such as LiHMDS, NaHMD ?, and KHMDS.

B. Production of 7-O-Protected Baccatine III and Paclitaxel Synthesis from the Same.

Using the 7-O-anion 8 prepared in Scheme 1, 7-O-protected baccatine III can be prepared and an oxazoline side chain can be esterified at C-13 according to Scheme 2 and then converted to paclitaxel.

Scheme 2 i Zn. Acetic acid: TFA. acetic acid, water 18 3 TEA 1 H, Pd / C 2 TFA acetic acid, water paclitaxel I formic acid: TFA acetic acid, water r ** ~ - As illustrated in Scheme 2, the addition of a protection group P, which is advantageously delivered by electroflixes such as, for example, TR0C-C1, CBZ-C1, CBZ20, B0C-C1 or BOC20, results in the formation of the derivatives of baccatine III 7-0-TROC-protected, 7-O-CBZ-protected and 7-0-BOC-protected 6, 10, and 11, respectively This reaction is rapid and gives little byproduct 7, 13-b? s-protected Other protecting groups, for example, acyl halides, dialkyl phosphates and carbonates, such as diethylchlorophosphate, isobutyl chloroformate dbuOOC), acetate (Ac), adamantyl fluoroformate (AdOOC), chloroformate of aillo (AlilOCC), vmilo chloroformate (vinilOOC), acetylimidazole and TR0C-C1 work well in the formation of bacccatma III 7-O-protegda derivatives 12, 13, 14, 15, 16 and 17 They can also be formed simple esters, such as acetate, with the use of acetylimidazole. The reaction of the derivatives of baccatma III 7-O-proteg 6, 10, and 11 with oxazoline 5, a protected paclitaxel side chain, in toluene with DCC and DMAP gave the products having a side chain at C-13 7-O-Proteg? Da 18, 19 and 20 These paclitaxel precursors 18, 19 and 20 can all be converted to paclitaxel 2 by removal of the 7-0 protection groups by ordinary method, and by acid hydrolysis of the protected side chain to β-phenylisoserma C. Production of 7-O-protected Baccatine III and Paclitaxel Synthesis from the Same - Alternative Synthesis As illustrated in Scheme 3, the protected 7, 6, 10, and 11 Baccatine III derivatives, prepared according to the steps illustrated in Scheme 2, may alternatively be coupled with BMOP 24 in LitbuO, which is it is esterified at C-13 and then treated with acid to produce 7-O-protected paclitaxel precursors 21, 22, and 23. These paclitaxel precursors 21, 22, and 23, can then be converted to paclitaxel 2 by elimination of 7-0 protection groups by ordinary method, and by acid hydrolysis of the protected side chain to phenylisoserine.

Scheme 3 6. P = TROC 21. P - TROC 10. P = CBZ 22. P = CBZ 11. P - BOC Zn.acetic acid, MeOH Pd / C al, EtOH paclitaxel TFA, acetic acid It is believed that one of ordinary skill in the art can, using the above description, carry out the described processes and prepare the full scope of the intermediates and compounds of the present invention. The following examples also exemplify the procedure general for the preparation procedures inherent in the synthesis of paclitaxel from Baccatina III.

Example 1 Synthesis of 7-0-Acyl-Baccatine III derivatives from Baccatine III Baccatine III 1 is dissolved in DMF. The resulting solution is cooled to -40 ° C, and LiHMDS (1M solution in THF) is added. After 5 minutes, the appropriate electrophile is added. The reaction is stirred at -30 ° C, and an additional base or electrophilic is added to bring the reaction to completion. The reaction is then cooled rapidly with acetic acid and poured into MTBE. The MTBE solution is washed 3 times with water, the organic layer is concentrated, and then the resulting residue is isolated by chromatography on silica gel (ethyl acetate / hexanes) or crystallized to give the title compound. to. 7-O-TROC-baccatine III (6) Using the general procedure, baccatin III (0.150 g, 0.26 mmol) was reacted with LiHMDS (0.52 mL, 2.0 equivalents) and TR0C-C1 (43 μL, 1.2 equivalents) in 2 mL of DMF to produce 80 mg (41%) of 7-O-TROC-baccatine III after chromatography on silica gel. b. 7-O-CBZ-baccatine III (10) Baccatin III (0.25 g, 0.43 mmol) was dissolved in 4 mL of anhydrous DMF. The solution was cooled to -40 ° C and 150 mol% of LiHMDS (1M in THF, 0.64 mL) was added slowly for 1 minute. After 5 minutes, CBZ20 (150% mol, 0.185 g) was added as a solution in DMF (0.5 mL), and the reaction was allowed to stir at -35 to -30 ° C. An additional base was added after 40 minutes (0.1 mL), and CBZ20 (40 mg) in one hour. After 3 hours, 1.5 mL of acetic acid was added and the reaction mixture was poured into 25 mL of MTBE. The organic layer was washed with 3 x 15 mL of water, and then concentrated to an oil. The product was crystallized with MTBE / heptane to give 228 mg of 7-O-CBZ-baccatine III, 82%.

NMR d 8.0-7.2 (m, 10H), 6.35 (s, 1H), 5.54 (d, 1H, J = 6.8), 5.47 (dd, 1H, J = 7.2, 10.8), 5.12 (dd, 2H, J = 12.2, 21.2), 4.88 (d, 1H, J = 8.6), 4.76 (t, 1H, J = 8.1), 4.03 (d, 1H, J = 7.2), 3.93 (d, 1H, J = 7.2), 2.65-2.40 (m, 1H), 2.30-1.70 (m, 5H), 2.20 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.70 (s, 3H), 1.10 (s, 3H), 0. 90 (s, 3H). c. 7-O-BOC-baccatine III (11) Using the general procedure, baccatin III (2.076 g, 54 mmol) was reacted with LiHMDS (5.6 mL, 1.5 equivalents) and B0C20 (1.36 g, 1.5 equivalents) in 24 mL of DMF to produce 1.6 g (75%) of 7-O-BOC-baccatine III after chromatography on silica gel.

NMR d 8.00-7.30 (m, 5H), 6.43 (s, 1H), 5.55 (d, 1H, J = 7.2), 5.30 (dd, 1H, J = 6.8, 10.4), 4.85 (d, 1H, J = 8.6), 4.75 (t, 1H, J = 8.1), 4.20 (d, 1H, J = 8.6), 4.07 (d, 1H, J = 7.3), 3.89 (d, 1H, J = 6.8), 2.60-2.48 (m, 1H), 2.21-2.00 (m, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H), 1.90-1.78 (ra, 1H), 1.68 (s, 3H) ), 1.60-1.50 (m, 1H), 1.36 (s, 9H), 1.05 (s, 3H), 0.97 (s, 3H). d. 7-O-diethylphosphoryl-baccatine III (12) Using the general procedure, baccatine III (0.150 g, 0.26 mmol) was reacted with LiHMDS (0.52 mL, 2 equivalents) and chlorodiethylphosphate (45 μL, 1.2 equivalents) in 2 mL of DMF to yield 110 mg (59%) of 7-O-diethylphosphoryl-baccatine III after chromatography on silica gel.

"M" "- ^ ° e 7-0-? sobutox? carbon? l-baccatma III (13) Using the general procedure, baccatma III (0 150 g, 0 26 mmol) was reacted with LiHMDS (0 52 mL, 2 equivalents) and isobutylchloroformate (66 μL, 2 equivalents) in 2 mL of DMF to yield 153 g (87 %) of 7-O-? sobutox? carbon? l-baccatma III after chromatography on silica gel f 7-O-acet? l-baccatma III (14) The LiHMDS in THF (1M, 1 mL, 1 mmol) was added for 1 minute to a stirred solution of baccatma III (700 mg, 1 19 mmol) in dry THF and DMF at -45 ° C under argon After 5 minutes, a solution of acetylimidazole (264 3 mg, 2 4 mmol) in dry DMF (15 mL) was added in one minute and stirring was continued for 3 minutes. The reaction was slowly heated from -45 ° C to -35 ° C during 5 minutes and maintained for 10 minutes between -35 ° C and -33 ° C HPLC indicated the absence of starting material. The reaction was quickly cooled with AcOH (100 μL) and diluted with 15 mL of MTBE, which then it was washed with water (5 x 10 mL) and evaporated to give a white solid (772 mg). This solid was dissolved in 3 mL of toluene at 65 ° C, to which was added heptane (12 mL).

The resulting mixture was stirred at 65 ° C to 29 ° C for 45 minutes and at room temperature for 45 minutes to give 7-0-acetyl-baccatine III (582 mg) as a crystalline material with a yield of 77.6%. g. 7-O-adamantyloxycarbonyl-baccatine III (15) Using the general procedure, baccatine III (0.150 g, 0.26 mmol) was reacted with LiHMDS (0.52 mL, 2 equivalents) and adamantyl fluoroformate (101 mg, 2 equivalents) in 2 mL of DMF to produce 120 mg (64%) ) of 7-O-adamantyloxycarbonyl-baccatine III after chromatography on silica gel. h. 7-0-allyloxycarbonyl-baccatine III (16) Using the general procedure, baccatin III (0.200 g, 0.34 mmol) was reacted with LiHMDS (0.68 mL, 2 equivalents) and allyl chloroformate (45 μL, 1.25 equivalents) in 2 mL of DMF to produce 120 mg (65%) ) of 7-O-allyloxycarbonyl-baccatine III after chromatography on silica gel. i. 7-O-vinyloxycarbonyl-baccatine III (17) Using the general procedure, baccatin III. (0.116 g, 0.198 mmol) was reacted with LiHMDS (0.2 mL, 1 equivalent) and vinyl chloroformate (25 μL, 1.5 equivalents) in 2 mL of DMF to yield 79 mg (61%) of 7-O-vinyloxycarbonyl- baccatin III after chromatography on silica gel.

Example 2 General Procedure for the Coupling of Oxazoline to Compounds Derived from 7-Acyl-Baccatine III The 7-O-acyl-baccatine III compound is added to dry toluene. DCC, DMAP and oxazolinecarboxylic acid are added and the reaction mixture is stirred at room temperature until the HPLC determines that no starting material remains. The reaction is quenched with AcOH, diluted with EtOAc, and filtered to remove the DCU. The organic solution is washed with 10% KH2P04, 10% NaHCO3, and water, concentrated, and the desired product is isolated by crystallization or chromatography on silica gel. to. 7-0-TROC-13-0-oxazolinoylbaccatine III (18) Following the general procedure, 7-0-TROC-baccatine III 6 (80 mg, 0.105 mmol) was combined with oxazolinecarboxylic acid 5 (34 mg, 0.126 mmol), DMAP (15 mg, 0.126 mmol) and DCC (26 mg, 126 mmoles) in toluene (2 ml) to produce 7-0-TROC-13-0-oxazolinoylbaccatine III (82 mg, 77%) after chromatography (hexane / EtOAc 5: 2). b. 7-0-CBZ-13-0-oxazolinoylbaccatine III (19) Following the general procedure, 7-0-CBZ-baccatine III 10 (262.2 mg, 0.36 mmol) was combined with oxazolinecarboxylic acid 5 (117 mg, 0.44 mmol), DMAP (47.2 mg, 0.39 mmol) and DCC (113 mg, 0.55 mmoles) in toluene (5 mL) to produce 7-0-CBZ-13-0-oxazolinoylbaccatin III (295 mg, 83.6%) after chromatography (hexane / EtOAc 65:35). c. 7-0-BOC-13-0-oxazolinoylbaccatine III (20) Following the general procedure, 7-O-BOC-baccatine III 11 (0.5 g, 0.73 mmol) was combined with oxazolinecarboxylic acid 5 (234 mg, 0.88 mmol), DMAP (94.3 mg, 0.77 mmol) and DCC (190.7 mg, 0.93 mmol) in toluene (5.1 mL) to produce 7-0-BOC-13-0-oxazolinoylbaccatine III (641 mg, 94%) after crystallization with isopropyl alcohol .

Example 3 Synthesis of Paclitaxel from 7-O-Protected Paclitaxel Precursors to. Paclitaxel from 7-0-CBZ-13-0-oxazolinoylbaccatine III (19) - First Method The 7-0-CBZ-13-0-oxazolinoylbaccatine III 19 (100 mg, 0.1 mmol) was dissolved in a solution of TFA (50 μL), AcOH (1.05 mL) and water (0.268 mL). This mixture was stirred at room temperature for 5 hours until no starting material was detected. The solution was quenched with NaOAc (59 mg) in water (0.21 mL) and stirred for 3 minutes. CH2C12 (10 mL) and water (3 mL) were added and stirring was continued for 3 minutes. The phases were separated and the water layer was extracted with CH2C12 (5 mL). The combined organic layers were washed with water (2 x 5 mL), concentrated to 1.5 mL and treated with TEA (193 [mu] L).

At room temperature, the reaction mixture was quenched with concentrated H2SO4 (0.162 mL) in water (1444 mL) and extracted with CH2C12 (10 mL). The organic phase was washed with water (2 x 5 mL), dried over Na 2 SO 4, and evaporated to give pure 7-O-CBZ-paclitaxel 22 (102.3 mg, 100%). Then 7-O-CBZ-paclitaxel was converted to paclitaxel by hydrolysis of this compound (65 mg, 0.08 mmol), this was carried out using TFA (38.1 μL, 0.5 mmol), AcOH (0.8 mL), and water ( 0.203 mL) for 5 hours, followed by TEA (146.2 μL) for 1 hour to give pure paclitaxel (66.1 mg) with a yield of 99.5%. b. Paclitaxel from 7-0-CBZ-13-0-oxazolinoylbaccatine III (19) - Alternate Method The 7-0-CBZ-13-0-oxazolinoylbaccatine III 19 (120 mg, 0.12 mmol) in EtOH (20 mL) was hydrogenated with 10% Pd / C (20 mg) and H2 (30 psi) to give 13- O-oxazolinoyl-baccatine III (99.6 mg), with a yield of 96.3%. Hydrolysis of this compound (65 mg, 0.08 mmolee) was carried out using TFA (38.1 μL, 0.5 mmol), AcOH (0.8 mL), and water (0.203 mL) for 5 hours, followed by TEA (146.2 μL) during 1 hour to give pure paclitaxel (66.1 mg) with a yield of 99.5%. c. Paclitaxel from 7-0-BOC-13-0-oxazolinoylbaccatine III (20) - First Method A solution of 7-0-BOC-13-0-oxazolinoylbaccatin III (100 mg, 0.11 mmol) and water (0.3 mL) in AcOH (2.36 mL) was stirred at 75 ° C. The reaction mixture after 20 hours was diluted with methylene chloride (15 mL) and washed with water (3 x 15 mL). The organic phase was concentrated and purified on silica gel using hexane-EtOAc (3: 7) to give paclitaxel (63 mg) in 69.1% yield. d. Paclitaxel from 7-0-BOC-13-oxazolinoylbaccatine III (20) - Second Method A trifluoroacetic acid (0.472 mL, 6.13 mmol) was added to a biphasic mixture of 7-0-BOC-13-oxazolinoylbaccatine III (900 mg, 0.96 mmol) in CH2C12 (18 mL) and water (2.7 mL) at room temperature. it stirred for 19 hours. Since no starting material was detected by HPLC, the reaction was quenched with aqueous NaOAc solution and the phases were separated. The 2 '-OBZ-7-BOC-paclitaxel contained in the methylene chloride phases was treated with TEA (1.8 mL, 12.9 mmol). After 23 hours at room temperature, the reaction mixture was rapidly cooled with H 2 SO 4 diluted at 15 ° C. The phase organic material obtained after separation was washed with water (2 x 10 mL) and evaporated to a foamy solid, which on crystallization with IPA-hexane gave 7-0-BOC-paclitaxel (782 mg) with a yield of 85.2 %. To 7-0-BOC-paclitaxel (500 mg, 0.52 mmole) cold formic acid (99%, 5 mL, 10 ° C) was added in a flask at 7 ° C and the resulting solution was stirred at 7-10 ° C. for 45 minutes. The reaction mixture was diluted with methylene chloride (40 mL) and washed with water (4 x 10 mL). Evaporation of the organic phase gave a foamy solid, which was crystallized with IPA to give paclitaxel (284.7 mg) with a yield of 63.3%. and. Paclitaxel from 7-0-BOC-13-0-oxazolinoylbaccatine III (20) - Third Method The 7-0-BOC-13-0-oxazolinoylbaccatine III 20 (450 mg, 0.54 mmol) was treated with TFA (0.273, 3.54 mmol), AcOH (5.71 mL) and water (1048 mL) at room temperature for 7 hours, followed by ASD (1.01 mL, 7.25 mmol) for 0.5 hour to give paclitaxel (310 mg) with a yield of 64.7% after crystallization with IPA.

Example 4 General Procedure for the Coupling of the BMOP Lateral Chain to the 7-O-Acyl-baccatine Compounds A solution of 7-0-acyl-baccatine III in THF at -55 ° C is treated with LiHMDS (1M in THF). A solution of BMOP in THF is added and the reaction is stirred at 0 ° C for 3 hours. Water is added to rapidly quench the reaction, and the mixture is poured into EtOAc. The organic layer is washed with water and brine, dried over Na 2 SO 4, and concentrated. The resulting product is redissolved with aqueous NaOAc solution, diluted with CH2C12, and washed with water, 10% NaHCO3 and brine. Then the organic layer is dried over Na 2 SO 4, and purified by chromatography on silica gel to give 7-O-protected paclitaxel. to. 7-O-TROC-paclitaxel (21) Following the general procedure, 7-O-TROC-baccatine III 6 (158.4 mg, 0.21 mmol) in 4.6 mL of THF was reacted with BMOP 24 (137 mg, 0.40 mmol) and LiHMDS (0.25 mL, 0.25 mmol) to produce 139.5 mg (79%) of 7-O-TROC-baccatine III. b. Paclitaxel from 7-O-TROC-paclitaxel (21) The 7-O-TROC-paclitaxel 21 (130 mg, 0.13 mmol) was reacted with Zn powder (150 mg, 2.29 mmol) in AcOH-MeOH (1: 1, 5 mL) at 60 ° C for 2.5 hours. The reaction mixture was cooled and filtered and the organic solvent was evaporated. The resulting residue was purified by column chromatography to produce paclitaxel (88.3 mg) in a yield of 81.9%. c. 7-O-CBZ-paclitaxel (22) Following the general procedure, 7-O-CBZ-baccatine III 10 (156.5 mg, 0.22 mmol) in 2 mL of THF was reacted with BMOP 24 (94.7 mg, 0.28 mmol) and LiHMDS (0.24 mL, 0.24 mmol) for produce 139.5 mg (61%) of 7-O-CBZ-paclitaxel. d. Paclitaxel from 7-0-CBZ-paclitaxel (22) The 7-O-CBZ-paclitaxel 22 (115 mg, 0.12 mmol) was hydrogenated (H2 at 30 psi, 20 mg of 10% Pd / C in 20 mL of ethanol absolute) for 3 hours. The reaction mixture was washed with 10 mL of CH2C12. The combined filtrates were concentrated and isolated by chromatography to give 73.4 mg of paclitaxel, 78.1%. and. Paclitaxel directly from 7-O-BOC-baccatine III (11) through 7-O-BOC-paclitaxel (23) Following the general procedure, 7-O-BOC-baccatine III 11 (125 mg, 0.18 mmol) in 2.5 mL of THF was reacted with BMOP 24 (125 mg, 0.37 mmol) and LiHMDS (0.22 mL, 0.22 mmol) for produce 7-O-BOC-paclitaxel without purification, which was not isolated, but was also reacted with TFA (60 μL, 0.78 mmol) and water (0.316 mL) in AcOH (1.25 mL) for 51 hours to produce 57.4 mg (55.2%) of paclitaxel.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (19)

1. A process for preparing paclitaxel, characterized in that you characterize p that acted in or convert taocatine m ai baccatine 7-0-acyl-protected in bugn yield and high quality with an electrofilic protection group of the formula: with a strong base in a solvent of the general formula, R-CONR'2; where R is alkyl, aryl, R'O-, R'2N-, or RS; R is d 6 alkyl, C 1-6 alkenyl, benzyl, or trichloroethyl; Y X is halogen, imidazoyl, benztriazole, N- (benzyloxycarboxylosxy) succinimide, ORY or -OOCOR.

2. A process according to claim 1, characterized in that the solvent is selected from the group consisting of DMF, DMAC, NMPO, DMEU and DMPU.

3. A process according to claim 2, characterized in that the solvent is DMF.

4. A process according to claim 1, characterized in that the strong base has the general formula R-0 M *, wherein R is alkyl or aryl, and M is a metal selected from the group consisting of lithium, sodium, and potassium.

5. A process according to claim 1, characterized in that the strong base is selected from the group consisting of LiHMDS, LitbuO, KHMDS, and NaHMDS; and the solvent is DMF.

6. A process according to claim 5, characterized in that the strong base is LitbuO.

7. A process according to claim 1, characterized in that the electrophilic protection group is selected from the group consisting of CBZ-C1, CBZ20, CBZ-benztriazole, B0C-C1, BOC20, TR0C-C1, diethylchlorophosphate, isobutyl chloroformate, acetylimidazole , adamantyl fluoroformate, allyl chloroformate, and vinyl chloroformate.

A process to synthesize paclitaxel of the formula: characterized in that it comprises the steps of: to. treat a baccatin III solution that has the formula with a strong base in a solvent; b. adding an electrophile to the solution to form a 7-O-protected baccatma III derivative having the formula c. reacting the baccatine III 7-O-β-rotegged derivative with a paclitaxel side chain protected in a solvent, such that the side chain is coupled with the 7-O-protected baccatin III derivative at the C-13 position; Y d. unprotect the protected paclitaxel side chain and remove the 7-0 protection group to form paclitaxel.

9. The process according to claim characterized in that the solvent is DMF.

10. The process according to claim 8, characterized in that the strong base is selected from the group consisting of LitbuO, LiHMDS, KHMDS, and NaHMDS.

11. The process according to claim 8, characterized in that the electrophilic is selected from the group consisting of CBZ-C1, CBZ20, CBZ-benztriazole, BOC-C1, BOC20, diethylchlorophosphate, isobutyl chloroformate, acetylimidazole, adamantyl fluoroformate, chloroformate allyl, and vinyl chloroformate.

12. The process according to claim 8, characterized in that the protected paclitaxel side chain binds to the C-13 hydroxyl of the baccatine III 7 -O-protected derivative using a dehydrating agent.

13. The process according to claim 12, characterized in that the dehydrating agent is DCC.

The process according to claim 12, characterized in that the dehydrating agent is toluene with DCC and DMAP

The process according to claim 8, characterized in that the protected paclitaxel side chain binds to the C-13 hydroxyl of the 7-0-protected baccatma III derivative using a strong base.

The process according to claim 15, characterized in that the strong base is LitbuO or butyl lithium

ID 17 The process according to claim 8, characterized in that the step of deprotecting the protected side chain and eliminating the 7-0 protection group of the baccatma III 7-O-protected derivative is carried out by hydrolysis 20 acid

The process according to claim 8, characterized in that the side chain of paclitaxel is a side chain of β-phenylisosene

19. A paclitaxel derivative of the formula: characterized in that, R is alkyl or aryl; X is halogen, silyl, alkoxy, thio or amino; n is an integer from 1 to 3; with the proviso that when R is alkyl, X is not halogen.