A process for the preparation of paclitaxel

Abstract

The present invention relates to an improved process for the preparation of Paclitaxel. More particularly, the invention provides a green synthetic process for preparation of Paclitaxel from 10-Deacetybaccatin-III (10-DAB), wherein the reactions at various stages does not involve the use of hazardous solvents and reagents or any tedious purification techniques. The present invention also provides Paclitaxel and its intermediates in high yield and purity, eliminating the use of inorganic salts in work-up, thus making the isolation process for the intermediates and product easy.

Description

[0001] FK24015-04-PAT-WO

[0002] A PROCESS FOR THE PREPARATION OF PACLITAXEL.

[0003] CROSS REFERENCE TO RELATED PATENT APPLICATION(S) This patent application claims the benefit of Indian Patent Application No. 202411086966, filed on

[0004] 11 Nov.2024, which is incorporated by reference herein in its entirety.

[0005] FK24015-04-PAT-WO

[0006] FIELD OF INVENTION

[0007] The present invention relates to an improved process for the preparation of Paclitaxel.

[0008] More particularly, the invention provides a synthetic process for preparation of Paclitaxel from 10- Deacetylbaccatin III (10-DAB), with improved process parameters such as reaction conditions, reaction solvents and isolation solvents, thereby avoiding tedious column chromatography technique. Such a process is industrially advantageous, environment-friendly and economically significant.

[0009] The present invention also provides Paclitaxel and its intermediates in high yield and high purity, thus simplifying the isolation process for the intermediates and the final product.

[0010] BACKGROUND OF THE INVENTION

[0011] Paclitaxel, which is chemically known as (2a,5P,7P,10P,13a)-4,10-Diacetoxy-13-{[(2R,3S)-3- (benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20-epoxytax-l l-en-2- yl benzoate is represented by Formula I,

[0012] Formula I

[0013] Paclitaxel is a microtubule inhibitor indicated for various indications such as subsequent therapy for the treatment of advanced carcinoma of the ovary, adjuvant treatment of node-positive breast cancer, in combination with cisplatin for the first-line treatment of non-small cell lung cancer and second-line treatment of AIDS-related Kaposi’s sarcoma.

[0014] It was isolated as a natural product from the bark of the Pacific yew tree and was named as “Taxol”. It was approved by the FDA in 1992 and was commercialized under the trade name Taxol®. The compound was then developed commercially by Bristol Myers Squibb (BMS).

[0015] The first total synthesis of Paclitaxel is reported in Holton RA, Kim HB, Somoza C et al J. Am. Chem. Soc., 1994, 116(4), 1597-1598. It includes a four-step procedure that converts 10-Deacetylbaccatin III (10-DAB) to Paclitaxel.

[0016] There are many other references, that also describe the synthesis of Paclitaxel from 10- Deacetylbaccatin III: FK24015-04-PAT-WO

[0017] 10-Deacetylbaccatin III , which is generally present at a high level in European Yew tree (Taxus baccata) and can be extracted from the leaves and twigs of the tree. 10-Deacetylbaccatin III has been described to be converted into Paclitaxel following the process as shown below: wherein, R is alkyl, aralkyl, substituted cycloalkyl, PG is a hydroxy protecting group

[0018] Scheme- 1 The hydroxyl group of 10-DAB at ClO-is acetylated to give Baccatin III and next C7- hydroxy group is protected with a protecting group. The C7-0H protected Baccatin III is then condensed at Cl 3- hydroxy group with a derivative of oxazolidine, to form a coupled product of oxazolidine derivative. The coupled product further undergoes cleavage of oxazolidine ring followed by deprotection of the C7-hydroxy protected Paclitaxel to provide Paclitaxel. W02004 / 007473 discloses a synthesis of Paclitaxel from 10-DAB where selective acylation of C10- hydroxy group of 10-DAB is performed using acetic anhydride and cerous chloride (i.e. CeCh), in FK24015-04-PAT-WO tetrahydrofuran. Then the C7-hydroxy group is protected with 2,2,2-Trichloroethoxycarbonyl chloride (Troc-Chloride) in presence of pyridine in dichloromethane at a temperature of -5 to -15°C to give 7-Troc-Baccatin III. Next, the C13-hydroxy group of 7-Troc-baccatin III is coupled with N- benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one at a temperature of -30°C to -50°C. The coupled product is deprotected with zinc and acetic anhydride in tetrahydrofuran.

[0019] The above-mentioned process involves the use of solvents such as tetrahydrofuran and dichloromethane which are not recommendable from an environmental perspective, a high amount of cerous chloride and acetic anhydride, reaction at very low temperature (less than 0 °C), a long workup process using inorganic salts and use of silica gel column chromatography for purification of the products formed at various stages.

[0020] Moreover, the protection of the C7-hydroxy group of 10-Deacetylbaccatin III with 2,2,2- trichloroethylchloroformate is done in pyridine (teratogenic) as base in large volume of dichloromethane in 4-dimethylaminopyridine.

[0021] PCT publication W01993 / 006094 discloses a preparation of Paclitaxel where C7-hydroxy of 10-DAB is silylated to yield 7-0-triethylsilyl Baccatin III, which is condensed with a P-lactam precursor. However, the condensation with the P-lactam side chain requires a very low temperature (-30°C to - 50°C) which makes the process not industrially favorable.

[0022] There are several other references that disclose the synthesis of Paclitaxel using tedious and cumbersome work-up process involving the use of inorganic salts, use of excessive amounts of reagents such as cerous chloride for acylation, or use of hazardous solvents such as dichloromethane, tetrahydrofuran, a teratogenic base such as pyridine and the need to use column chromatographic purification, which affects the overall yield as well as the quality of the final product.

[0023] Therefore, there is a need to formulate an efficient, simple, industrially viable and environmentfriendly synthetic process for the preparation of Paclitaxel resulting in high purity products and high yield which overcome the drawbacks of the processes disclosed in the art.

[0024] The inventors of the present invention surprisingly found an efficient process for the preparation of Paclitaxel which offers at least the following advantages: high yield and high purity of the product formed, replacement of conventional solvents with more ecologically friendly (environment-friendly) solvents, lower amounts of solvents required, no requirement for column chromatography FK24015-04-PAT-WO purification, less effluents, and the option to easily scale up the procedure, thereby providing a process that is suitable for large scale industrial production.

[0025] OBJECT OF THE INVENTION It is one aspect of the present invention to provide an environment-friendly process for the synthesis of Paclitaxel.

[0026] It is another aspect of the present invention to overcome one or more of the above-mentioned drawbacks of the prior art.

[0027] Yet another aspect of the present invention provides an efficient and commercially viable process for the synthesis of Paclitaxel without the use of hazardous reagents and solvents.

[0028] SUMMARY OF THE INVENTION

[0029] In a first aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula I, comprising the steps of: a) acetylating a compound of Formula II, with an acetylating agent in a solvent to obtain a compound of Formula III, FK24015-04-PAT-WO b) protecting the compound of Formula III using a protecting reagent in the presence of a base and a solvent to obtain the compound of Formula IV, wherein PG is a hydroxy protecting group, c) condensing the compound of Formula IV with a compound of Formula V,

[0030] Formula V in the presence of a coupling agent and a base in a solvent to obtain a compound of Formula VI, FK24015-04-PAT-WO d) cleaving the oxazolidine ring of the compound of Formula VI with an acid in a solvent to obtain a compound of Formula VII, wherein PG is a hydroxy protecting group, e) deprotecting the compound of Formula VII in a solvent to provide Paclitaxel of Formula I, f) optionally, purifying the Paclitaxel of Formula I, wherein in step a), the solvent is selected from acetone and 2-methyl tetrahydrofuran; in step b), the solvent is selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate; in step c), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and 2-methyl tetrahydrofuran; in step d) the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate; and in step e), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone.

[0031] In a second aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula I, comprising the steps of: a) acetylating a compound of Formula II with an acetylating agent in a solvent selected from acetone and 2-methyl tetrahydrofuran to obtain a compound of Formula III, and b) converting the compound of Formula III to Paclitaxel of Formula I.

[0032] In a third aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula

[0033] I, comprising: FK24015-04-PAT-WO a) protecting a compound of Formula III using a protecting reagent in the presence of a base selected from the group consisting of 4-dimethylaminopyridine and imidazole, in a solvent selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate to obtain a compound of Formula IV, and b) converting the compound of Formula IV to Paclitaxel of Formula I.

[0034] In a fourth aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula

[0035] I, comprising: a) condensing a compound of Formula IV with a compound of Formula V, in the presence of a coupling agent and a base in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and 2-methyl tetrahydrofuran to obtain a compound of Formula VI, and b) converting the compound of Formula VI to Paclitaxel of Formula I.

[0036] In a fifth aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula

[0037] I, comprising: a) cleaving the oxazolidine ring of a compound of Formula VI with an acid selected from hydrochloric acid or sulphuric acid, in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate to obtain a compound of Formula VII, b) deprotecting the compound of Formula VII to provide Paclitaxel of Formula I.

[0038] In another aspect, the present invention provides a process for the purification of a compound of Formula VI comprising: a) dissolving the compound of Formula VI in isopropyl alcohol, b) adding n-heptane to the solution obtained in step a), and c) isolating the purified compound of Formula VI.

[0039] In yet another aspect, the present invention provides a process for the purification of Paclitaxel of Formula I comprising: a) providing Paclitaxel in diethyl carbonate and a C1-C3 aliphatic alcohol, b) heating the mixture of step a) at a temperature in the range from 40 - 65 °C, and c) isolating the purified Paclitaxel of Formula I.

[0040] In another aspect, the process of the present invention provides Paclitaxel with a purity of more than 99% by HPLC, preferably more than 99.5% by HPLC, most preferably 99.6% by HPLC. FK24015-04-PAT-WO

[0041] DETAILED DESCRIPTION OF THE INVENTION

[0042] The present invention provides an improved process for the synthesis of Paclitaxel of Formula I which is not only industrially viable and suitable for scale up, but also is environment friendly.

[0043] Besides, having an environment-friendly (green chemistry) approach, this process has additional advantages of fewer and easier work-up steps than work-up processes in the prior art, no use of inorganic salts, no requirement for column chromatography for purification, while still resulting in high yield and high purity of product and intermediates that are obtained at various stages of the synthesis.

[0044] Definitions

[0045] The following definitions are used in connection with the present application unless the context indicates otherwise.

[0046] The term “green synthesis ” refers to “a process for the synthesis of a compound that reduces or eliminates the use or the generation of hazardous substances”. Green synthesis refers to chemical processes that utilize either no solvents, reduced quantities of solvents, or environmentally benign alternative solvents, and generally require fewer reagents, thereby minimizing the ecological impact of the process, compared to syntheses that are known in the art.

[0047] The term “green solvents ” as used throughout the specification refers to solvents that are more environment-friendly than other chemical solvents. The so-called green solvents are less toxic and of lower risk to human health than their conventional alternatives. Examples of such solvents include methanol, ethanol, 2-methyl butanol, glycerol, acetone, ethyl acetate, isopropyl acetate, dimethyl glutarate, glycerol triacetate, ethyl lactate, dimethyl carbonate, diethyl carbonate, glycerol carbonate, 1,3-dioxolane, cyclopentyl methyl ether, isosorbide dimethyl ether, and 2-methyl tetrahydrofuran.

[0048] “Dry acetone” refers to anhydrous acetone with water content not more than 0.1% w / w.

[0049] The term “PMI” or “process mass intensity ” of any process refers to the metric that measures the efficiency and environmental impact of a process by comparing the mass of materials used to the mass of the final product.

[0050] In other words, PMI is used for an estimation of greenness of any process. It comprises the mass of all the material used in a synthetic route relative to the amount of isolated product. Materials FK24015-04-PAT-WO considered in its calculation include reagents, reactants, catalysts, solvents (reaction & purification) and work-up chemicals.

[0051] Thus, the PMI of a process can be calculated by using the following equation:

[0052] PMI = total mass in a process or process step mass of product

[0053] The term “acetylating” as used herein, refers to adding an acetyl group to a substrate. The compound providing the acetyl group is called as “acetylating agent”.

[0054] The term “protecting ” as used herein, refers to temporarily attaching a group to a functional group to decrease the reactivity of that functional group so that the protected functional group does not react under synthetic conditions, to which the molecule is subjected in one or more subsequent steps.

[0055] The temporarily introduced groups that prevent the protected functional group from undergoing reaction are referred as “protecting groups ” and chemicals that are used in the reaction to introduce them in the molecule are termed as “protecting reagents

[0056] A suitable protecting reagent in the processes described herein can be selected from the group consisting of benzylchloroformate, isobutylchloroformate, di-tert-butyl dicarbonate, chloro(triethyl)silane, trimethylsilyl chloride, 2-chloroethyl formate and trichloroethyl chloroformate.

[0057] The protecting groups are removed from the molecule after the desired compound is obtained, under conditions that do not affect the desired compound obtained.

[0058] The term “deprotecting” as used herein, refers to the removal of the protecting groups from the compound.

[0059] A protecting group can be removed (deprotected) under acidic, basic and / or neutral conditions, depending on the chemical nature of the protecting group and the functional group it is protecting. Protection and deprotection processes are well known in the art (see notably “Protective groups in organic synthesis”, Greene T. W. and Wuts P. G. M., Wiley -Interscience, 1999).

[0060] The term “condensing” as used herein, refers to reacting a carboxylic group with a hydroxyl group to form an ester linkage.

[0061] The term “coupling agent” as used herein, refers to a reagent that facilitates formation of a bond between two adjacent groups. The term “coupling agent” as used herein, refers to a chemical reagent that couples together the carboxylic acid functionality of a compound with the hydroxyl functionality FK24015-04-PAT-WO of another compound to form an ester linkage. Those skilled in the art will be familiar with the selection of the coupling agents and will appreciate that many different coupling agents are known in the art, the suitability of one coupling agent or another being dependent on the synthetic scheme planned.

[0062] The term “Lewis acid catalyst” as used herein, refers to a substance that accepts a pair of nonbonding electrons and acts as catalyst in a reaction.

[0063] The term “cleaving” as used herein, refers to opening of a ring.

[0064] The term “work-up ” as used herein, refers to a process of isolating a product from the mixture, which generally contains catalyst, impurities, and / or unreacted starting materials.

[0065] The term “isolating” as used herein, refers to a process of obtaining a compound from a reaction mixture, for example by filtration, decantation, extraction, distillation, evaporation, centrifugation, or a combination thereof.

[0066] Various processes for preparation of Paclitaxel are known in the art. However, in recent era, where “green” synthesis is gaining considerable value as a reliable, sustainable, and environment-friendly protocol for synthesizing a wide range of chemicals and materials, the process known for Paclitaxel in the prior arts with the traditional process of synthesis, are not favorable to the sustainability of environment.

[0067] The inventors of the present invention have very well realized the importance of green synthesis and had strived towards developing an environment- friendly synthesis of Paclitaxel that avoids the use of harmful chemicals and potentially hazardous solvents besides maintaining its low cost and great efficiency for large-scale industrial production. The process disclosed in the present application is “green” as it is inclined towards prevention and minimization of waste, reduction of pollutants, and the use of safer or non-toxic solvents and reagents.

[0068] The inventors have successfully developed the synthesis of Paclitaxel from 10-Deacetylbaccatin III (10-DAB) using green solvents (environment-friendly solvents) at different stages of the synthesis of Paclitaxel.

[0069] The process developed by the inventors is simple and does not require a high amount of catalyst such as cerous chloride during the acetylation step and eliminates the use of inorganic salts in the work-up process during the synthesis at various stages. FK24015-04-PAT-WO

[0070] The starting compound of the synthesis i.e., 10-Deacetylbaccatin III (10-DAB) may be obtained by any of the process known in the art such as those described in US 5,393,895, US 5,736,366, US 6,124,482 and US 5,453,521. In a first aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula I, comprising the steps of: a) acetylating a compound of Formula II, with an acetylating agent in a solvent to obtain a compound of Formula III, b) protecting the compound of Formula III using a protecting reagent in the presence of a base and a solvent to obtain a compound of Formula IV, FK24015-04-PAT-WO wherein PG is a hydroxy protecting group, c) condensing the compound of Formula IV with a compound of Formula V,

[0071] Formula V in the presence of a coupling agent and a base in a solvent to obtain a compound of Formula VI, wherein PG is a hydroxy protecting group, d) cleaving the oxazolidine ring of the compound of Formula VI with an acid in a solvent to obtain a compound of Formula VII, FK24015-04-PAT-WO e) deprotecting the compound of Formula VII in a solvent to provide Paclitaxel of Formula I, f) optionally, purifying Paclitaxel of Formula I, wherein in step a), the solvent is selected from acetone and 2-methyl tetrahydrofuran; in step b), the solvent is selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate; in step c), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and 2-methyl tetrahydrofuran; in step d) the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate; and in step e), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone.

[0072] In a second aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula I, comprising the steps of: a) acetylating the compound of Formula II with an acetylating agent in a solvent selected from acetone or 2-methyl tetrahydrofuran to obtain a compound of Formula III, b) converting the compound of Formula III to Paclitaxel of Formula I.

[0073] In an embodiment of the above-described processes, the acetylation is performed using an acetylating agent. The acetylating agent is selected from the group consisting of acetic anhydride and acetyl chloride, preferably the acetylating agent is acetic anhydride.

[0074] Preferably the solvent used in the acetylation step is acetone or 2-methyl tetrahydrofuran. Both acetone and 2-methyl tetrahydrofuran are non-toxic and non-hazardous solvents to the environment. Preferably, the solvent used in the acetylation is acetone, more preferably dry acetone.

[0075] In a preferred embodiment a Lewis acid catalyst is present during the acetylation.

[0076] The Lewis acid catalyst is selected from the group consisting of cerous chloride (CeCh), zinc chloride (ZnCh), titanium chloride (TiCI-i), scandium(III)trifluoromethanesulfonate (Sc(OTf)3), aluminum chloride (AlCh), ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3), ytterbium(III) chloride(YbC13), ytterbium(III)nitrate (Yb(NO3)3), lanthanide trifluoromethanesulfonates (La(OTf)3) FK24015-04-PAT-WO and lutetium(III) trifluoromethanesulfonate (Lu(OTf)3). The preferred Lewis acid catalyst for acetylation is cerous chloride.

[0077] In an embodiment, the amount of cerous chloride and acetic anhydride used in the reaction is reduced and this improves the impurity profile of the compound of Formula III.

[0078] In a preferred embodiment, 10-DAB is reacted with 5 to 6 mole equivalent of acetic anhydride and 0.080 to 0.088 mole equivalent of cerous chloride in acetone.

[0079] This is significantly less than what is reported in the art (for e.g. in W02004 / 007473 or in CN101863862). Thereby the amount of free acetic acid generated during acetylation of ClO-hydroxy group of 10-DAB, is reduced.

[0080] In a preferred embodiment of the process, following the step of acetylation, the residual acetic acid is easily removed with water washing without using inorganic salts for neutralization, resulting in a limited amount of inorganic salt in the resulting product.

[0081] The inventors have surprisingly found that the use of a lower amount of Lewis acid catalysts, such as cerous chloride and a lower amount of acetylating agent, such as acetic anhydride, in this step results in a lower amount of the impurity 7-acetyl paclitaxel in the final product. Additionally, this results in a lower amount of unreacted 10-DAB in the final product, and a lower amount of total impurities. It is proposed that this improvement is due to the reduced formation of acetic acid during step a), according to the invention, resulting in lower amounts of 7,10-diacetyl impurity of Baccatin III.

[0082] 7, 10-diacetyl impurity

[0083] 7-acetyl paclitaxel is a potent impurity of Paclitaxel. It is generated when 7,10-diacetyl impurity of

[0084] Baccatin III is converted to 7-acetyl Paclitaxel in further stages and does not get deprotected at step e) and therefore, remains as 7-acetyl Paclitaxel impurity in Paclitaxel.

[0085] Table 1 demonstrates the effect of a reduced amount of reagents on the purity profile of compound of Formula (III): FK24015-04-PAT-WO

[0086] Table 1

[0087] In a preferred embodiment of the process, following the step of acetylation the residual acetic acid is effectively removed with sufficient washing with water. This saves time required for the work-up and avoids use of inorganic salts which otherwise affects the product assay accuracy and impact the next stages of the synthesis.

[0088] The compound of Formula III can be optionally purified with ethyl acetate and heptane to provide the compound of Formula III in high purity, preferably purity is more than 99 % by HPLC.

[0089] In a third aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula I, comprising: a) protecting the compound of Formula III using a protecting reagent in the presence of base selected from 4-dimethylaminopyridine and imidazole, and a solvent selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate, to obtain the compound of Formula IV, b) converting the compound of Formula IV to obtain Paclitaxel of Formula I.

[0090] The protecting group (PG) is selected from the group consisting of carbobenzyloxycarbonyl (CBZ), isobutoxycarbonyl (i-BOC), t-butoxycarbonyl (t-BOC), triethylsilyl (TES), trimethylsilyl (TMS), 2- chloroethoxy, 2,2,2- trichloroethoxycarbonyl (Troc), preferably 2,2,2- trichloroethoxycarbonyl(Troc). FK24015-04-PAT-WO

[0091] The protecting reagent in step a) of this embodiment and in step b) of the process according to the first described embodiment is selected from the group consisting of benzylchloroformate, isobutylchloroformate, di-tert-butyl dicarbonate, chloro(triethyl)silane, trimethylsilyl chloride, 2- chloroethyl chloroformate and 2,2,2-trichloroethyl chloroformate.

[0092] The protection of the C7-hydroxy group of the compound of Formula III is also performed in environment-friendly solvents in place of harmful solvents that are reported in processes disclosed in the art.

[0093] In a preferred embodiment, the solvent in the protecting step described above is dry acetone.

[0094] The processes reported in the art involve the use of pyridine base for the protection of C7-hydroxy group of acetylated 10-DAB of Formula III.

[0095] The inventors have found that the use of pyridine can be avoided, with the process according to the invention, wherein it has been demonstrated for the first time, that the use of 4-dimethylaminopyridine or imidazole as base are suitable for the successful reaction. Both 4-dimethylaminopyridine and imidazole are non-toxic and are solid as compared to pyridine which is a liquid and is known to have a teratogenic effect.

[0096] The most preferred base for conversion of the compound of Formula III to the compound of Formula IV is 4-dimethylaminopyridine.

[0097] In a preferred embodiment, the compound of Formula III is protected using 2,2,2-trichloroethyl chloroformate (Troc chloride) as protecting agent, in dry acetone in the presence of 4- dimethylaminopyridine at a temperature of 25 °C to 30 °C. Preferably, the reaction mixture is cooled to 0 °C to 5 °C and stirred for 2 to 4 hours. The reaction mass is evaporated, and water is added. The solid obtained is filtered and preferably washed with water and n-heptane.

[0098] The inventors have found that an unspecified (unknown) impurity is formed in an amount of -3.37% (detected by HPLC), when the process reported in the prior art is followed using dichloromethane and pyridine as base during the reaction.

[0099] Surprisingly, the use of 4-dimethylaminopyridine or imidazole as base instead of pyridine in the step of protecting compound of Formula III of the process according to the invention, reduces the amount of this unspecified (unknown) impurity and limits the impurity to less than 1.5% by HPLC, preferably less than 1.2% by HPLC. FK24015-04-PAT-WO

[0100] It is further preferred that the process of preparing compound of formula IV starting with protecting a compound of Formula III, does not involve the addition of inorganic salts. It is preferred that the compound of Formula IV is isolated without using inorganic salts. Instead, water is added in the reaction mass, whereby the product, i.e., the compound of Formula IV is obtained as solid, which is filtered and dried.

[0101] On the contrary, in the prior art process, the compound of Formula IV is isolated using inorganic salts. This results in a low purity of said compound of Formula IV, a significant portion of the material's weight is composed of impurities such as unreacted starting materials, byproducts, or inorganic salts from the isolation process. This may impact on the next stage reaction.

[0102] The compound of Formula IV is then optionally purified with a mixture of ethyl acetate and n-heptane providing the compound of Formula IV with purity more than 98% by HPLC.

[0103] In a fourth aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula I, comprising: a) condensing the compound of Formula IV with a compound of Formula V,

[0104] Formula V in the presence of a coupling agent and a base in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate, and 2-methyl tetrahydrofuran to obtain the compound of Formula VI, and b) converting the compound of Formula VI to Paclitaxel of Formula I.

[0105] In a preferred embodiment, the solvent is ethyl acetate.

[0106] The coupling agent may be selected from the group consisting of N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC.HC1), N,N-di cyclohexylcarbodiimide (DCC), N,N’- diisopropylcarbodiimide (DIC), di-2-pyridyl carbonate (DPC), hexafluorophosphate benzotriazole tetramethyl uronium (HBTU) , (2-(lH-benzotriazole-l-yl)-l,l,3,3tetramethyluronium tetrafluoroborate (TBTU), 2( 1 H-7-azabenzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium tetrafluoroborate (TATU) and l-[(l-(cyano-2ethoxy-2-oxoethylideneaminooxy)- FK24015-04-PAT-WO dimethylaminomorpholinomethylene)]-methanaminium hexafluorophosphate (COMU), preferably it is N,N-dicyclohexylcarbodiimide (DCC).

[0107] The prior art literature discloses the use of solvents such as dichloromethane, tetrahydrofuran and the like, for this stage. However, the use of ethyl acetate provides the process with clear advantages of becoming more environment- friendly, less toxic, and less expensive due to lower disposal cost of used solvents.

[0108] Preferably, the base used for the condensation step is 4- dimethylaminopyridine or 2- dimethylaminopyridine.

[0109] In a more preferred embodiment, the compound of Formula IV is condensed with the compound of Formula V in ethyl acetate and in presence of 4-dimethylaminopyridine and N,N- dicyclohexylcarbodiimide at a temperature range of 20°C to 30°C, preferably at 20-25°C, to provide the compound of Formula VI.

[0110] In a further aspect, the present invention provides a process for the purification of compound of Formula VI. This purification process comprises the following steps: a) dissolving a compound of Formula VI in isopropyl alcohol and b) adding n-heptane to the solution obtained at step a), c) isolating the purified compound of Formula VI.

[0111] Isopropyl alcohol and n-heptane are solvents which are more environment- friendly than those reported in the literature for purifying Paclitaxel, which are a mixture of toluene and hexane. Accordingly, the purification process of the compound of Formula VI employing isopropyl alcohol and n-heptane provides the clear advantages of being environment-friendly, less toxic, and less expensive due to lower disposal cost of used solvents.

[0112] In a preferred embodiment of the purification process described above, the compound of Formula VI is dissolved in isopropyl alcohol at a temperature range from 50 to 90°C, preferably at a temperature range from 60 to 80°C, more preferably at a temperature range from 70 to 90°C. n-Heptane is added to the mixture of step a); the reaction mixture is stirred and cooled to 20°C to 25°C. A solid is precipitated which is filtered. The solid is washed with n-heptane and dried to get the purified coupled product.

[0113] In a more preferred embodiment, the compound of Formula VI is obtained after purification in high yield and high purity. FK24015-04-PAT-WO

[0114] The purity of compound of Formula VI is more than 97% by HPLC, preferably more than 98% by HPLC, more preferably more than 99% by HPLC.

[0115] The yield of compound of Formula VI even after purification is high. In a preferred embodiment, the compound of Formula VI is obtained in more than 90% yield, preferably more than 95% yield, more preferably more than 98% yield, most preferably 98.5% yield.

[0116] In a fifth aspect, the present invention relates to a process for the preparation of Paclitaxel of Formula

[0117] I, comprising: a) cleaving the oxazolidine ring of a compound of Formula VI with an acid selected from hydrochloric acid or sulphuric acid, in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate, to obtain compound of Formula VII, and wherein PG is a hydroxy protecting group, b) deprotecting the compound of Formula VII to provide Paclitaxel of Formula I.

[0118] The process of the invention for cleaving the oxazolidine ring employs an acid selected from hydrochloric acid or sulphuric acid. The preferred acid is hydrochloric acid.

[0119] It is observed that at this stage, the highest unknown impurity (HIUI) increases with increasing the amount of acid. However, if a catalytic amount of acid is used, formation of a highest unknown impurity is reduced to an acceptable limit accompanying the compound of Formula VII as shown in Table 2 below: FK24015-04-PAT-WO

[0120] Table 2

[0121] In a preferred embodiment, the oxazolidine ring of the compound of Formula VI is cleaved using a catalytic amount of acid, preferably the amount of acid used in the reaction is 0.05 to 0.08% w / w based on weight of the compound of Formula VI, more preferably the amount of acid used in the reaction is 0.06 to 0.08% w / w based on weight of the compound of Formula VI, most preferably the amount of acid used in the reaction is 0.08% w / w based on the weight of the compound of Formula VI.

[0122] In a preferred embodiment, the oxazolidine ring of the compound of Formula VI is cleaved using hydrochloric acid in ethyl acetate.

[0123] The cleavage of the oxazolidine ring of the compound of Formula VI is preferably carried out at a temperature of 15 to 25 °C.

[0124] The product may be purified using a mixture of ethyl acetate and n-heptane.

[0125] The inventors of the present invention have found that using a catalytic amount of acid not only can improve the impurity profile in terms of high unknown impurity, but it also can reduce the amount of p-anisaldehyde by-product in the compound of Formula VII, preferably it reduces the p-anisaldehyde by-product in the compound of Formula VII by more than 50% as compared to prior art.

[0126] The deprotection of the compound of Formula VII to Paclitaxel can be performed with activated zinc.

[0127] Activated zinc is prepared by heating zinc powder in a solution of ammonium chloride at a temperature of 85°C to 95° or in dilute HC1 at a temperature in the range of 20-30°C, followed by cooling the solution.

[0128] In a preferred embodiment, the deprotection of the compound of Formula VII to obtain Paclitaxel may be performed using activated zinc in presence of an acid in a solvent. FK24015-04-PAT-WO

[0129] The deprotection is performed in an acid selected from acetic acid, trifluoroacetic acid and formic acid, preferably acetic acid.

[0130] Ammonium chloride can be added during the deprotection reaction to keep the zinc activated, for the reaction to occur effectively.

[0131] The deprotection is performed in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone, preferably acetone.

[0132] In a preferred embodiment, the compound of Formula VII is deprotected using activated zinc and acetic acid in presence of ammonium chloride at a temperature in the range of 20-30°C in acetone.

[0133] In a more preferred embodiment, the compound of Formula VII in the mixture of acetone, water, acetic acid and methanol is deprotected using activated zinc and acetic acid in presence of ammonium chloride at a temperature in the range of 20-30°C.

[0134] The reaction mixture is stirred for 4-6 hours, preferably for 5 hours, or preferably for 6 hours, the solid residue is filtered and washed with acetone. Water is added to the filtrate and a precipitate is obtained which is filtered, washed with water and is purified in n-heptane-ethyl acetate mixture, filtered and dried to get Paclitaxel.

[0135] Paclitaxel is thus isolated from the reaction mass without use of inorganic salts in the work-up, which would have otherwise resulted in lower assay of Paclitaxel.

[0136] Paclitaxel obtained after deprotection of the compound of Formula VII, is optionally purified using one or more solvents that are selected from the consisting of acetone, methanol, ethanol, isopropyl alcohol, n-heptane, diethyl carbonate and mixtures thereof.

[0137] In yet another aspect, the present invention provides a process for the purification of Paclitaxel of Formula I comprising: a) providing Paclitaxel in diethyl carbonate and a C1-C3 aliphatic alcohol, b) heating the mixture of step a) at a temperature 40- 65 °C, and c) isolating the purified Paclitaxel of Formula I.

[0138] In step a), the C1-C3 aliphatic alcohol is selected from methanol, ethanol, isopropyl alcohol and mixtures thereof. FK24015-04-PAT-WO

[0139] The purification process of Paclitaxel using green solvents efficiently provides Paclitaxel with a purity which is comparable to the purity of Paclitaxel that is obtained by a purification process using solvents that are not considered green.

[0140] In yet another aspect, the process of the present invention provides Paclitaxel with purity more than 99.0% by HPLC, preferably more than 99.5% by HPLC, more preferably 99.6% by HPLC, where the impurities are within the permissible limit as provided by regulatory guidelines.

[0141] The Paclitaxel obtained by the process of present invention contains 7-Epi Paclitaxel impurity not more than 0.40 % by HPLC, 10-Deacetyl-7-Epi Paclitaxel impurity not more than 0.40 % by HPLC and 10-Deacetyl Paclitaxel impurity not more than 0.20% by HPLC.

[0142] The impurities are represented as below:

[0143] 7-Epi Paclitaxel 10-Deacetyl-7-Epi Paclitaxel

[0144] 10-Deacetyl Paclitaxel

[0145] In a preferred embodiment, 7-Epi Paclitaxel impurity, 10-Deacetyl-7-Epi Paclitaxel impurity and 10- Deacetyl Paclitaxel impurity each are present in an amount which is not more than 0.10% by HPLC, in the final product (i.e. Paclitaxel).

[0146] The inventors of the present invention developed a process wherein the process involves use of less hazardous solvents for all the steps of synthesis starting from 10-DAB to Paclitaxel. Surprisingly the process is not only environment-friendly, but also efficient and provides several advantages compared to those reported in the art, for instance, FK24015-04-PAT-WO

[0147] Avoids use of inorganic salts during work-up: the intermediate products are isolated from water in most stages, avoiding cumbersome work-up that employs use of inorganic salts.

[0148] No use of column chromatographic during the process: Paclitaxel is obtained through solvent purification in high yield and purity. This further makes the entire process greener by eliminating the need for detoxification and disposal of used silica gel and avoiding the hazards related to dumping.

[0149] No need of sub-zero temperature: provides a useful, efficient environment-friendly and industrially feasible process by replacing bases such as pyridine, lithium tert-butoxide, lithium hexamethyldisilazane, butyllithium that generally needs reaction temperature to be below 0°C, with a base such as 4-dimethylaminopyridine or imidazole that does not requiring temperature conditions to be below zero and provides good results without generating high amount of undesired side products or impurities.

[0150] 4-dimethylaminopyridine or imidazole, being solid material, is also easily removed during filtration of the precipitated product. This aids in making the work-up process easy and quick. At most stages, water is used for the isolation of the products.

[0151] Better impurity profile: Lower number of impurities generated at various stages leads to easier purification process to get Paclitaxel with high yield and high purity. There is minimization in waste produced as lesser quantity of acids and catalysts is used for reactions as well as there is lesser use of solvents during workups.

[0152] The green potential of different processes can be estimated based on a mathematical term called “PMI” or “Process Mass Intensity” which requires careful analysis of the examples and metrics data generated during the process. This is an effective tool for the assessment of the efficiency and sustainability of a process and a concept to measure and quantify the green chemistry involved in the process. The lower the PMI of the process, the more environment-friendly the synthesis process is.

[0153] Comparative PMI data for all five stages of the synthesis provided in reference example 3 and as per present invention is provided in Table 3 as below: FK24015-04-PAT-WO

[0154] Table 3

[0155] *-PMI values may deviate in a range of ±5_

[0156] The lower PMI of the process of the present invention is thus indicative of a synthesis which involves fundamentals of green chemistry, and which meets the need of the art.

[0157] FK24015-04-PAT-WO

[0158] Embodiments:

[0159] 1. A process for the preparation of Paclitaxel of Formula I, comprising: a) acetylating the compound of Formula II, with an acetylating agent in a solvent to obtain a compound of Formula III, b) protecting the compound of Formula III using protecting reagent in the presence of a base and a solvent to obtain the compound of Formula IV, FK24015-04-PAT-WO c) condensing the compound of Formula IV with a compound of Formula V,

[0160] Formula V

[0161] In the presence of a coupling agent and a base in a solvent to obtain compound of Formula VI, wherein PG is a hydroxy protecting group, d) cleaving the oxazolidine ring of the compound of Formula VI with an acid in a solvent to obtain compound of Formula VII, wherein PG is a hydroxy protecting group, e) deprotecting the compound of Formula VII in a solvent to provide Paclitaxel of Formula I, f) optionally, purifying Paclitaxel of Formula I, wherein in step a), the solvent is selected from acetone or 2-methyl tetrahydrofuran; in step b), the solvent is selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate. FK24015-04-PAT-WO in step c), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and 2-methyl tetrahydrofuran; in step d) the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate; and in step e), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone.

[0162] 2. A process for the preparation of Paclitaxel of Formula I, comprising the steps of: a) acetylating the compound of Formula II with an acetylating agent in solvent selected from acetone or 2-methyl tetrahydrofuran to obtain a compound of the Formula III, and b) converting the compound of Formula III to Paclitaxel of Formula I.

[0163] 3. The process according to embodiment 1 or 2, wherein the acetylation is performed using an acetylating agent selected from acetic anhydride and acetyl chloride.

[0164] 4. The process according to embodiment 3, wherein the acetylation is affected in presence of a Lewis acid catalyst.

[0165] 5. The process according to embodiment 4, wherein the Lewis acid is selected from the group consisting of cerous chloride, zinc chloride, titanium chloride, scandium (Ill)trifluoromethanesulfonate, aluminum chloride, ytterbium(III) trifluoromethanesulfonate, FK24015-04-PAT-WO yterbium(III) chloride, yterbium(III)nitrate, lanthanide trifluoromethanesulfonate and lutetium(III) trifluoromethanesulfonate.

[0166] 6. A process for the preparation of Paclitaxel of Formula I, comprising: a) protecting the compound of Formula III using a protecting reagent in the presence of base selected from 4-dimethylaminopyridine or imidazole and a solvent selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate to obtain the compound of Formula IV, and wherein PG is a hydroxy protecting group, b) converting the compound of Formula IV to Paclitaxel of Formula I.

[0167] 7. The process according to embodiment 1 or 6, wherein the protecting reagent is selected from the group consisting of benzylchloroformate, isobutylchloroformate, di-tert-butyl dicarbonate, chloro(triethyl)silane, trimethylsilyl chloride, 2-chloroethyl formate and trichloroethyl chloroformate. 8. A process for the preparation of Paclitaxel of Formula I, comprising: a) condensing the compound of Formula IV FK24015-04-PAT-WO wherein PG is a hydroxy protecting group, with a compound of Formula V,

[0168] Formula V in the presence of a coupling agent and a base in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate, and 2-methyl tetrahydrofuran to obtain the compound of Formula VI, wherein PG is a hydroxy protecting group b) converting the compound of Formula VI to Paclitaxel of Formula I.

[0169] 9. The process according to embodiment 1 or 8, wherein the coupling agent is selected from the group consisting of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N,N- dicyclohexylcarbodiimide, N,N’ -diisopropylcarbodiimide, Di-2-pyridyl carbonate, hexafluorophosphate benzotriazole tetramethyl uronium, 2-(lH-benzotriazole-l-yl)- 1 , 1 ,3,3tetramethyluronium tetrafluoroborate, 2(lH-7-azabenzotriazole- 1 -yl)-l , 1,3,3- tetramethyluronium tetrafluoroborate and l-[(l-(cyano-2ethoxy-2- oxothylideneaminooxy)dimethylaminomorpholinomethylene)] methanaminium hexafluorophosphate.

[0170] 10. The process according to embodiment 1 or 8, wherein the base is 4- dimethylaminopyridine or 2- dimethylaminopyridine.

[0171] 11. A process for the preparation of Paclitaxel of Formula I, comprising: FK24015-04-PAT-WO a) cleaving the oxazolidine ring of a compound of Formula VI wherein PG is a hydroxy protecting group; with an acid selected from hydrochloric acid or sulphuric acid, in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate to obtain compound of Formula VII, wherein PG is a hydroxy protecting group, b) deprotecting the compound of Formula VII to provide Paclitaxel of Formula I.

[0172] 12. The process according to embodiment 11, wherein the acid is used in an amount of 0.05 to 0.08% w / w based on weight of the compound of Formula VI.

[0173] 13. The process according to embodiment 1 or embodiment 11, wherein the deprotection is performed with activated zinc in the presence of an acid in a solvent.

[0174] 14. The process according to embodiment 13, wherein an acid is selected from acetic acid, trifluoroacetic acid and formic acid. 15. The process according to embodiment 13, wherein a solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone.

[0175] 16. The process according to any of embodiments 1, 6, 8 or 11, wherein PG is selected from the group consisting of carbobenzyloxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, triethylsilyl, trimethylsilyl, 2-chloroethoxy and 2,2,2- trichloroethoxycarbonyl. FK24015-04-PAT-WO

[0176] 17. The process according to any of embodiments 1, 6, 8 or 11, wherein PG is 2,2,2- trichloroethoxy carbonyl.

[0177] 18. A process for the purification of compound of Formula VI comprising: a) dissolving compound of Formula VI in isopropyl alcohol; b) adding n-heptane to the solution obtained at step a), and c) isolating the purified compound of Formula VI.

[0178] 19. A process for the purification of Paclitaxel of Formula I comprising: a) providing Paclitaxel in diethyl carbonate and a C1-C3 aliphatic alcohol, b) heating the mixture of step a) at a temperature 40 to 65°C, and c) isolating the purified Paclitaxel of Formula I.

[0179] 20. The process according to embodiment 19, wherein the C1-C3 aliphatic alcohol is selected from methanol, ethanol, isopropyl alcohol and mixtures thereof.

[0180] 21. Paclitaxel having purity more than 99% by HPLC, preferably more than 99.5% by HPLC, most preferably 99.6% by HPLC, obtainable by the process according to any of the preceding embodiments.

[0181] FK24015-04-PAT-WO

[0182] Abbreviations:

[0183] 10-D AB : 10-Deacetybaccatin III

[0184] Baccatin III: (2P,5a,7a, 1 Oa, 13 P)-4, 10-Diacetoxy- 1 ,7, 13 -trihydroxy-9-oxo-5,20-epoxytax- 11 -en-2-yl benzoate

[0185] 7-Troc-Baccatin III : 7-O-(2,2,2-Trichloroethoxycarbonyl) Baccatin III

[0186] 7-Troc Paclitaxel: lS)-4a,10P-Bis(acetoxy)-2a-(benzoyloxy)-5P,20-epoxy-l,7P,13a-trihydroxytaxa- 1 l-ene-9-one

[0187] CBZ: carbobenzyloxy carbonyl i-BOC: isobutoxycarbonyl t-BOC: t-butoxycarbonyl

[0188] TES: tri ethylsilyl

[0189] TMS: trimethylsilyl

[0190] Troc: 222- trichloroethoxycarbonyl

[0191] EDC. HC1: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0192] DCC: N N-dicyclohexylcarbodiimide

[0193] DIC: NN’ -Diisopropylcarbodiimide

[0194] DPC: di-2-pyridyl carbonate

[0195] HBTU: hexafluorophosphate benzotriazole tetramethyl uronium

[0196] TBTU : 2-( 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethy luronium tetrafluoroborate

[0197] T ATU : 2( 1 H-7-azabenzotr iazole- 1 -y 1) - 1 , 1 , 3 , 3 -tetramethy luronium tetrafluoroborate

[0198] COMU: l-[(l-(cyano-2ethoxy-2-oxothylideneaminooxy) dimethylamino morpholino methylene)] methanaminium hexafluorophosphate.

[0199] CeC13 : cerous chloride

[0200] NH4C1: ammonium chloride

[0201] ZnC12: zinc chloride

[0202] TiC14: titanium chloride FK24015-04-PAT-WO

[0203] A1C13 : aluminum chloride

[0204] YbC13: ytterbium (III) chloride

[0205] Sc(OTf)3 : scandium(III)trifluoromethanesulfonate Lu(0Tf)3: lutetium(III) trifluoromethanesulfonate

[0206] Yb(OTf)3): ytterbium(III) trifluoromethanesulfonate

[0207] Yb(NO3)3 :ytterbium(III)nitrate

[0208] La(OTf)3: lanthanide trifluoromethanesulfonate

[0209] HC1: Hydrochloric acid HPLC: High-performance liquid chromatography

[0210] HIUI: Highest unknown individual impurity

[0211] PMI: process mass intensity

[0212] Ph: Phenyl

[0213] Ac: Acetyl Bz: Benzyl

[0214] FK24015-04-PAT-WO

[0215] Detailed experimental parameters suitable for the synthesis of Paclitaxel are provided by the following examples, which are intended to be illustrative and not limiting of all possible embodiments of the invention.

[0216] EXPERIMENTAL DETAILS

[0217] Throughout the following the term ‘room temperature’ refers to a temperature in the range of 20- 30°C.

[0218] Reference Example 1: Synthesis of Paclitaxel, according to the process of CN103130753

[0219] Step 1: Synthesis of (2p,5a,7a,10a,13P)-4,10-Diacetoxy-l,7,13-trihydroxy-9-oxo-5,20-epoxytax- ll-en-2-yl benzoate (Baccatin III)

[0220] To a clean and dry flask, tetrahydrofuran (1500 ml) and 10-Deacetyl Baccatin III (10.0 g) were added and stirred. Cerrous chloride (0.68 g) and acetic anhydride (2.8 g) were added and the reaction mixture was stirred for 5 hrs at 0° to 5°C. After completion of the reaction, ethyl acetate (1000 ml) was added and the reaction mixture was successively washed with sodium bicarbonate solution (20 g in 400 ml water), followed by sodium chloride solution (20 g in 300 ml water). The organic layer was evaporated to get Baccatin III (10.1g). (Yield 93.8%)

[0221] Step II: Synthesis of 7-O-(2, 2, 2-Trichloroeth oxy carbonyl) baccatin III

[0222] Baccatin III (5 g) was added into dichloromethane (40 ml) under stirring and funnel was washed with dichloromethane (5 ml). Anhydrous pyridine (9.78 g) was added into reaction mixture and stirred for 5 minutes at 22°C to 23 °C, followed by cooling to 0°C. Troc chloride (2.7 g) was added slowly to the reaction mixture at 0°C to 2°C and the reaction mixture was stirred for 1 hour at 1°C to 3 °C. The reaction mixture was washed with water and the organic part was washed with 4% hydrochloric acid (50 ml) followed by saturated brine solution (50 ml, 10 g in 50 ml water) twice. The organic part was evaporated and dried. Thin Layer Chromatography (TLC) analysis of the resulting product indicates that approximately -10-15% reaction has been completed at this stage.

[0223] Step III: Synthesis of 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl -carbonyl]- baccatin III)

[0224] Dichloromethane (100 ml), 7-O-(2,2,2-Trichloroethoxycarbonyl) baccatin III (5 g, prepared using reference example 2, step II) was stirred for 9 minutes at 23°C to 24°C. 4-dimethylaminopyridine (0.8 g) and (4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (7.95 g) were added into the reaction mixture . After adding di cyclohexyl carbodiimide (4.05 g) in di chloromethane FK24015-04-PAT-WO

[0225] (15 ml) to the resulting mixture, the mixture was stirred for 2 hours at 24°C to 26°C. The reaction mixture was filtered and solid obtained was washed with dichloromethane (20 ml) twice. The filtrate obtained was successively washed with water, 4% HC1 solution and brine solution (5 g sodium chloride in 50 ml water). After stirring the organic part with sodium sulphate (5 g), it was evaporated to dryness at 45°C to give 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl -carbonyl]- baccatin III (12.57 g).

[0226] Step IV: Synthesis of (lS)-4a,10P-Bis(acetoxy)-2a-(benzoyloxy)-5p,20-epoxy-l,7p,13a- trihydroxytaxa-ll-ene-9-one (7-Troc Paclitaxel)

[0227] A mixture of 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl-carbonyl]-baccatin III (5 g) and formic acid (40 ml) was stirred for 1 hr at 25°C to 26°C till the reaction was completed, water (83 ml) was added slowly and the reaction mixture was stirred for complete crystallization. It was filtered after 1 hr of stirring and the solid obtained was dried for 10 hrs at 55°C to obtain 4.36 g of product which contains 7-Troc Paclitaxel and p-anisaldehyde, as an impurity.

[0228] Step V: Synthesis of (2a,5p,7p,10p,13a)-4,10-Diacetoxy-13-{[(2R,3S)-3-(benzoylamino)-2- hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (Paclitaxel)

[0229] 7-Troc Paclitaxel (40 g) was dissolved in acetic acid (455 ml) and methanol (230 ml). Activated zinc (47 g) was added and stirred for 1.5 to 2 hours below 70°C. The reaction mixture was filtered and added to a mixture of disodium hydrogen phosphate solution (1.8 kg in 2.8 L water) and dichloromethane (1500 ml) and stirred for 15 to 30 minutes. The organic layer was separated and washed successively with sodium bicarbonate solution (35 g in 420 ml water) and sodium chloride solution (70 g in 350 ml water). The organic layer was evaporated, followed by the addition of hexane (630 ml) and stirring. The resultant mass was filtered and dried at 45 to 50°C for 8 tolO hours to get Paclitaxel (Yield: 97%, Purity: 87% by HPLC).

[0230] Step VI: Purification of Paclitaxel

[0231] Paclitaxel (10 g) was subjected to column chromatography over silica gel as the stationary phase, using mixture of ethyl acetate and hexane (2:1) as eluent. The pure fraction, as confirmed by thin layer chromatography (TLC), was collected and evaporated to dryness under reduced pressure at 40 to 45 °C to yield Paclitaxel (Yield: 73%, Purity: 98% by HPLC). FK24015-04-PAT-WO

[0232] Reference Example 2: Synthesis of Paclitaxel via Traditional Solvent System (for Green Chemistry Comparison)

[0233] Step I: Synthesis of (2p,5a,7a,10a,13P)-4,10-Diacetoxy-l,7,13-trihydroxy-9-oxo-5,20-epoxytax- ll-en-2-yl benzoate (Baccatin III)

[0234] 10-DAB (50 g, 0.092 mole) was dissolved in tetrahydrofuran (500 ml), acetic anhydride (53.8 g, 0.52 mole) followed by addition of cerous chloride (4 g, 0.016 mole) and the reaction mixture was stirred for 2 to 3 hours at 25°-30°C. After completion of reaction, the reaction mixture was stirred for 30 minutes after adding water. Dichloromethane was added to the reaction mixture and the reaction mixture was added into disodium hydrogen phosphate solution. The organic layer was separated after stirring for 20-30 minutes and evaporated under reduced pressure to get solid residue which on purification with dichloromethane -hexane mixture (1:1.5) and drying at 55° to 60°C for 7 to 8 hours under reduced pressure yielded Baccatin III (51.5 g) (Purity: 97.6% by HPLC).

[0235] Step II: Synthesis of 7-O-(2,2,2-Trichloroethoxycarbonyl) baccatin III (7-Troc baccatin III)

[0236] Baccatin III (50 g, 0.85 mole) was dissolved in dichloromethane (500 ml) and anhydrous pyridine (77 g, 0.97 mole) and Troc-chloride (38.7 g, 0.18 mole) was added to it and stirred for 1 to 1.5 hours at 0°C to 5°C. After completion of the reaction, hydrochloric acid solution was added, stirred and the organic layer was isolated. The organic layer was washed with sodium bicarbonate solution, followed by sodium chloride solution. After evaporating under reduced pressure, the residue obtained was purified by dichloromethane-hexane (1:2) mixture , and dried at 55°-60°C for 7 to 8 hours under reduced pressure to get 7 7-Troc baccatin III (62.5 g, Yield: 96%, Purity: 98.5% by HPLC).

[0237] Step III: Synthesis of 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl -carbonyl]- baccatin III

[0238] 7-Troc baccatin III (50 g, 0.065 mole) was added to ethyl acetate (500 ml). 4- dimethylaminopyridine (3.6 g, 0.032 mole) and (4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (31.7 g, 0.078 mole) and N,N-dicyclohexylcarbodiimide (32 g, 0.155 mole) was added to it. The reaction mixture was stirred for 2-2.5 hours at 20°-25°C, filtered and washed with ethyl acetate (750 ml). The filtrate was washed successively with ammonium chloride solution (70 g in 500 ml water) and sodium chloride solution (70 g in 1400 ml water). The organic part was evaporated to dryness and residue obtained was purified by toluene-hexane to get 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3- oxazolidinyl -carbonyl]-baccatin III (72.5 g) (Yield: 96%, Purity: 99% by HPLC). FK24015-04-PAT-WO

[0239] Step IV: Synthesis of (lS)-4a,10P-Bis(acetoxy)-2a-(benzoyloxy)-5p,20-epoxy-l,7p,13a- trihydroxytaxa-ll-ene-9-one (7-Troc Paclitaxel)

[0240] 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl-carbonyl]-baccatin III (20 g) was dissolved in ethyl acetate (400 ml) and hydrochloric acid (1.9 g) was added to it. The reaction mixture was stirred for 6 to 7 hours at 18° to 22°C and washed successively with sodium bicarbonate solution (10 g in 150 ml water) and sodium chloride solution (30 g in 150 ml water). The organic layer was evaporated, followed by addition of hexane (370 ml). The obtained material after stirring for 30 minutes was filtered and dried under vacuum at 55° to 60°C for 8 to 10 hours to give 18.7 g of product which contains 7-Troc Paclitaxel (90-92% by HPLC) and p-ansaldehyde, as an impurity.

[0241] Step V: Synthesis of (2a,5p,7p,10p,13a)-4,10-Diacetoxy-13-{[(2R,3S)-3-(benzoylamino)-2- hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (Paclitaxel)

[0242] 7-Troc Paclitaxel (40 g) was dissolved in acetic acid (455 ml) and methanol (230 ml). Activated zinc (47g) was added and stirred for 1.5 to 2 hours below 70°C. The reaction mixture was filtered and added to a mixture of disodium hydrogen phosphate solution (1.8 kg in 2.8 L water) and dichloromethane (1500 ml) and stirred for 15 to 30 minutes. The organic layer was separated and washed successively with sodium bicarbonate solution (35 g in 420 ml water) and sodium chloride solution (70 g in 350 ml water). The organic layer was evaporated, followed by the addition of hexane (630 ml) and stirring. The resultant mass was filtered and dried at 45 to 50°C for 8 tolO hours to get Paclitaxel (32.2 gm) (Yield: 97%, Purity: 87% by HPLC).

[0243] Step VI: Purification of Paclitaxel

[0244] Paclitaxel (10 g) was subjected to column chromatography over silica gel (166 g) using mixture of ethyl acetate and hexane (2: 1) as eluent. The pure fraction, as confirmed by Thin-layer chromatography (TLC), was evaporated to dryness at reduced pressure at 40 to 45°C to get Paclitaxel (7.3 gm) (Yield: 73%, Purity: 98% by HPLC).

[0245] Step VII: Purification of Paclitaxel

[0246] Paclitaxel (20 g) was dissolved in acetone (600 ml) and filtered through 0.2-micron filter paper. To the filtrate, 1320 ml of n-heptane (filtered through 5-micron filter) was added and stirred for 2 hours. The obtained solid was filtered and dried at 50 to 55°C under reduced pressure get Paclitaxel semisynthetic (16 g) (Yield: 80%, Assay 99.7%). FK24015-04-PAT-WO

[0247] EXAMPLE 3: Synthesis of Paclitaxel

[0248] Step I: Synthesis of (2p,5a,7a,10a,13P)-4,10-Diacetoxy-l,7,13-trihydroxy-9-oxo-5,20-epoxytax- ll-en-2-yl benzoate (Baccatin III), Compound of Formula III

[0249] Dry acetone (6000 mL) was added to 10-DAB (200 g, 0.367 mole) under stirring. Cerous chloride (8 g, 0.04 w / w%) and acetic anhydride (215.2 g, 2.1 mole) were added, and the reaction mixture was stirred at 25°C to 30°C for 6 to 7 hours. Water was added to the reaction mixture and the reaction mixture was evaporated. Water was again added, the reaction mixture was stirred and the solid that was obtained was filtered. After washing with water and n-heptane (600-900 ml), the filtered solid was dissolved in ethyl acetate at 75°C to 85°C and n-heptane was added to the solution and stirred. The precipitate obtained was filtered and dried to provide Baccatin III (Yield: 93%, Purity: 99% by HPLC).

[0250] Step II: Synthesis of 7-O-(2,2,2-Trichloroethoxycarbonyl)baccatin III (7-Troc-baccatin III),, Compound of Formula IV

[0251] Dry acetone (2400 ml) was added to Baccatin III (200 g, 0.341mole), followed by addition of 4- dimethylaminopyridine (104.2 g , 0.853mole), and the reaction mixture was stirred at 25°C to 30°C and cooled to 0°C to 5°C. 2,2,2-Trichloroethyl chloroformate (Troc chloride) (0.718 mole) was added and the mixture was stirred for 3 to 4 hours. The reaction mass was evaporated partially, and water was added. A solid was obtained which was filtered and washed with water and n-heptane. The solid was then added to ethyl acetate and heated to 75°C to 80°C and 1200 ml n-heptane was added to it and the mixture stirred. After cooling to 20°C-30°C, the reaction mixture was stirred for 1 to 2 hours, filtered and dried to give 251g of 7-Troc-baccatin III (Yield: 96%, Purity: 98.6% by HPLC).

[0252] Step III: Synthesis of 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl -carbonyl]- baccatin III , Compound of Formula VI

[0253] 7-Troc-baccatin III (0.262 mole) (200 g) was added to ethyl acetate (1600 ml) under stirring. After adding 14.4 g (0.118 mole) of 4-dimethylaminopyridine and 127.1 g (4S,5R)-3-benzoyl-2-(4- methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (0.315mole) (Compound of Formula V) into it, the reaction mixture was cooled down to 15°C to 20°C. N,N-Dicyclohexylcarbodiimide (DCC) (127.9 g) was added, and the reaction mixture was stirred for 120 to 180 minutes at 20°C to 25°C. The reaction mass was filtered and washed with ethyl acetate and then with ammonium chloride solution followed by brine. The organic layer was evaporated to dryness and 1600 ml isopropyl alcohol was added and the mixture was heated to 70 to 80°C. n-heptane was added, and the reaction FK24015-04-PAT-WO mixture was stirred and filtered. The solid obtained was washed with n-heptane and dried to get 13- [4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl -carbonyl]-baccatinIII (Yield: 98.5%, Purity: 99% by HPLC).

[0254] Step IV: Synthesis of (lS)-4a,10p-Bis(acetoxy)-2a-(benzoyloxy)-5p,20-epoxy-l,7p,13a- trihydroxytaxa-ll-ene-9-one (7-Troc Paclitaxel), Compound of Formula VII 13-[4S,5R]-2-p-methoxyphenyl-4-phenyl-l,3-oxazolidinyl-carbonyl]-baccatin III (250 g) was added in a mixture of ethyl acetate (3000 ml) and Cone, hydrochloric acid (20 g). The reaction mixture was stirred for 6 to 7 hours at 18°C to 22°C. The reaction mixture was washed successively with sodium bicarbonate and brine. The organic layer was evaporated and charged with n-heptane. The reaction mixture was stirred for 60 to 90 minutes 20 to 30°C. The reaction mixture was filtered under vacuum. The obtained material was dried under vacuum at 65°C to 70°C for 8 to 10 hours to yield 7-Troc Paclitaxel (Yield: 98%, Purity: 94% by HPLC)

[0255] Step V: Synthesis of (2a,5p,7p,10p,13a)-4,10-Diacetoxy-13-{[(2R,3S)-3-(benzoylamino)-2- hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (Paclitaxel), compound of Formula I

[0256] Method A: Activated zinc was prepared by heating zinc powder in a solution of ammonium chloride at 85°C to 95°C, followed by cooling to room temperature and filtered. 7-10 Troc-Paclitaxel (100 g) was dissolved in acetone (1500 ml) and activated zinc (300 g) and ammonium chloride solution was added to the solution, followed by addition of acetic acid (8 to 12% of reaction volume). The reaction mixture was stirred for 4 to 6 hours at room temperature. The reaction mixture was filtered and washed with acetone. Water was added to the combined solid and stirred for 1 to 2 hours. The solid was filtered and washed with water and was purified in n-heptane-ethyl acetate mixture (4: 1), filtered and dried to give crude Paclitaxel (Purity: 97.6% by HPLC).

[0257] Method B: Activated zinc was prepared by heating zinc powder in a solution of ammonium chloride at 85°C to 95°C, followed by cooling to room temperature and filtered. 7-Troc-Paclitaxel (100 g) was dissolved in acetone (1500 ml) and water (50 ml) is added followed by addition of acetic acid (120 to 180 ml) and methanol (50 ml) under nitrogen atmosphere. Activated zinc (300 g) and ammonium chloride solution was added to reaction mixture and is stirred for 4-5 hours at room temperature. The reaction mixture was filtered and washed with acetone (1200 ml). 3500 ml water is added to the filtrate and stirred for 1 to 2 hours. The solid was filtered and washed with water and solid obtained was stirred with n-heptane-ethyl acetate mixture (4: 1). The solid after filtration is dried for 10-12 hours under reduced pressure to get Paclitaxel crude (Purity: 97.6% and assay 92% by HPLC). FK24015-04-PAT-WO

[0258] Step VI: Purification of Paclitaxel

[0259] Method A: Crude Paclitaxel (100g) was dissolved in acetone (1000ml) at 40 to 50°C and n-heptane (1000ml) was added to the solution at 40°C to 50°C and stirred for 15 to 20 minutes and cooled to room temperature. The mixture was stirred at room temperature for 1.5 hours and a precipitate was obtained which was filtered. The filtered solid was dissolved in acetone (700ml) and n-heptane (1400ml) was added to the solution at 40 to 50°C, the mixture was stirred and cooled to room temperature and stirred for 1.5 hours. The precipitate was obtained which was filtered and dried to get Paclitaxel Semipure ( 77.6g, Purity: 99.4% by HPLC). Paclitaxel Semipure (65 g ) was dissolved in acetone (1950ml) and n-heptane (4290ml) was added slowly to the mass under stirring. The mass was stirred for 2 hours at 20°-25°C. The precipitated mass was filtered and dried to get Paclitaxel. (59.8g, Purity: 99.6% by HPLC).

[0260] Method B: Crude Paclitaxel (10g) was added to a mixture of diethyl carbonate (147 ml) and methanol (3ml) and heated at 55 to 60°C to dissolve. The mixture was cooled to 0 to 5°C and stirred for 3 hours. The precipitate obtained was filtered, and dried to get Paclitaxel (7.5g). The filtered solid was dissolved in acetone (45ml) at 40 to 50°C and n-heptane (90ml) was added to the solution. The mixture was cooled to room temperature and stirred for 1.5 hours. The precipitate that was generated, was filtered and dried to get Paclitaxel Semipure (6.4g) (Purity: 99.4% by HPLC). The material obtained was dissolved in acetone (192ml) and n-heptane (422ml) was added slowly to the mass under stirring. The solid was filtered and dried to get Paclitaxel (5.4g) (Purity: 99.6% by HPLC).

[0261] The comparative PMI data for synthesis of Paclitaxel as per the reference examples and as per the present invention is provided in Table 4 as below:

[0262] Table 4

[0263] PMI values may deviate in a range of ±5_

Claims

1. FK24015-04-PAT-WOClaims:

1. A process for the preparation of Paclitaxel of Formula I,comprising the steps of: a) acetylating a compound of Formula II,with an acetylating agent in a solvent to obtain a compound of Formula III,b) protecting the compound of Formula III using a protecting reagent in the presence of a base and a solvent to obtain a compound of Formula IV,FK24015-04-PAT-WO c) condensing the compound of Formula IV with a compound of Formula V,Formula Vin the presence of a coupling agent and a base in a solvent to obtain a compound of Formulawherein PG is a hydroxy protecting group, d) cleaving the oxazolidine ring of the compound of Formula VI with an acid in a solvent to obtain a compound of Formula VII,wherein PG is a hydroxy protecting group, e) deprotecting the compound of Formula VII in a solvent to provide Paclitaxel of Formula I, f) optionally, purifying Paclitaxel of Formula I, wherein in step a), the solvent is selected from acetone and 2-methyl tetrahydrojuran;FK24015-04-PAT-WO in step b), the solvent is selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate; in step c), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and 2-methyl tetrahydrofuran; in step d) the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate; and in step e), the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone.

2. A process for the preparation of Paclitaxel of Formula I, comprising the steps of: a) acetylating a compound of Formula IIwith an acetylating agent in a solvent selected from acetone and 2-methyl tetrahydrofuran, to obtain a compound of Formula III, andb) converting the compound of Formula III to Paclitaxel of Formula I.

3. The process according to claim 1 or 2, wherein the acetylation is performed using an acetylating agent selected from acetic anhydride and acetyl chloride.

4. The process according to claim 3, wherein the acetylation is performed in presence of a Lewis acid catalyst.

5. The process according to claim 4, wherein the Lewis acid is selected from the group consisting of cerous chloride, zinc chloride, titanium chloride, scandium(III) trifluoromethane sulfonate,FK24015-04-PAT-WO aluminum chloride, ytterbium(III) trifluoromethanesulfonate, ytterbium(III) chloride, ytterbium(III)nitrate, lanthanide trifluoromethanesulfonates and lutetium(III) trifluoromethanesulfonate.

6. A process for the preparation of Paclitaxel of Formula I, comprising: a) protecting a compound of Formula IIIusing a protecting reagent in the presence of a base selected from the group consisting of 4- dimethylaminopyridine and imidazole, and a solvent selected from the group consisting of acetone, ethyl acetate, dimethyl carbonate and diethyl carbonate to obtain a compound ofFormula IV, andwherein PG is a hydroxy protecting group, b) converting the compound of Formula IV to Paclitaxel of Formula I.

7. The process according to claim 1 or claim 6, wherein the protecting reagent is selected from the group consisting of benzylchloroformate, isobutylchloroformate, di-tert-butyl dicarbonate, chloro(triethyl)silane, trimethylsilyl chloride, 2-chloroethyl formate and trichloroethyl chloroformate.

8. A process for the preparation of Paclitaxel of Formula I, comprising: a) condensing a compound of Formula IVFK24015-04-PAT-WOwherein PG is a hydroxy protecting group, with a compound of Formula V,Formula Vin the presence of a coupling agent and a base in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate, and 2-methyl tetrahydrofuran to obtain a compound of Formula VI, andwherein PG is a hydroxy protecting group b) converting the compound of Formula VI to Paclitaxel of Formula I.

9. The process according to claim 1 or claim 8, wherein the coupling agent is selected from the group consisting of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N,N- dicyclohexylcarbodiimide, N,N’ -diisopropylcarbodiimide, di-2-pyridyl carbonate, hexafluorophosphate benzotriazole tetramethyl uronium, 2-(lH-benzotriazole-l-yl)- 1 , 1 ,3 ,3tetramethyluronium tetrafluoroborate, 2(1 H-7-azabenzotriazole- 1 -yl)- 1 ,1,3,3- tetramethyluronium tetrafluoroborate and l-[(l-(cyano-2ethoxy-2-FK24015-04-PAT-WO oxothylideneaminooxy)dimethylaminomorpholinomethylene)] methanaminium hexafluorophosphate.

10. The process according to claim 1 or claim 8, wherein the base used in the condensing step is 4- dimethylaminopyridine or 2-dimethylaminopyridine.

11. A process for the preparation of Paclitaxel of Formula I, comprising: a) cleaving the oxazolidine ring of a compound of Formula VIwherein PG is a hydroxy protecting group; with an acid selected from hydrochloric acid or sulphuric acid in a solvent selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate and diethyl carbonate to obtain a compound of Formula VII,wherein PG is a hydroxy protecting group, b) deprotecting the compound of Formula VII to provide Paclitaxel of Formula I.

12. The process according to claim 11, wherein acid is used in an amount of 0.05 to 0.08% w / w based on weight of the compound of Formula VI.

13. The process according to claim 1 or claim 11, wherein the deprotection of Formula VII is performed with activated zinc in the presence of an acid in a solvent.

14. The process according to claim 13, wherein said acid is selected from the group consisting of acetic acid, trifluoroacetic acid and formic acid.FK24015-04-PAT-WO15. The process according to claim 13, wherein said solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dimethyl carbonate, diethyl carbonate and acetone.

16. The process according to any of claims 1, 6, 8 or 11, wherein PG is selected from the group consisting of carbobenzyloxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyltriethylsilyl, trimethylsilyl, 2-chloroethoxy and 2,2,2- trichloroethoxycarbonyl, preferably PG is 2,2,2- trichloroethoxy carbonyl.

17. A process for the purification of compound of Formula VI,wherein PG is a hydroxy protecting group, comprising: a) dissolving a compound of Formula VI in isopropyl alcohol; and b) adding n-heptane to the solution obtained at step a), c) isolating the purified compound of Formula VI.

18. A process for the purification of Paclitaxel of Formula I comprising: a) providing Paclitaxel in diethyl carbonate and a C1-C3 aliphatic alcohol, b) heating the mixture of step a) at a temperature 40- 65 °C, and c) isolating the purified Paclitaxel of Formula I.

19. The process according to claim 18, wherein the C1-C3 aliphatic alcohol is selected from methanol, ethanol, isopropyl alcohol and mixtures thereof.

20. Paclitaxel with a purity of more than 99% by HPLC, preferably more than 99.5% by HPLC, most preferably 99.6% by HPLC, obtainable by the process according to any of the preceding claims.

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