CLIAMS:Claims:

1) An improved process for the preparation of paclitaxel of Formula (I)

(I)
comprising the steps of:
a) reacting 7-troc baccatin-III of Formula II

(II)
with (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid of Fomula III

(III)
in presence of coupling agent and a solvent to give a compound of Formula IV

(IV)
b) reacting the compound of Formula IV using an organic acid chloride to give a compound of Formula V

(V)

c) deprotecting the compound of formula V to give Paclitaxel of Formula (I)
d) optionally, purifying Paclitaxel.

2) A process for the preparation of paclitaxel according to claim 1, wherein coupling agent is selected from N,N’-dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), or mixtures thereof

3) A process for the preparation of paclitaxel according to claim 1, wherein solvent in step a) is selected from hydrocarbons such as toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform or mixtures thereof.

4) A process for the preparation of paclitaxel according to claim 1, wherein organic acid chloride selected from C2-C6 acid chlorides, benzoyl chloride or mixtures thereof.

5) A process for the preparation of paclitaxel according to claim 1, wherein solvent in step b) selected from alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; hydrocarbons such as toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform or mixtures thereof.

6) A process for the preparation of Paclitaxel intermediate of Formula V comprises
a) reacting 7-troc baccatin-III of Formula II

(II)
with (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid of Fomula III

(III)
in presence of coupling agent and a solvent to give a compound of Formula IV

(IV)
b) reacting the compound of Formula IV using an organic acid chloride to give a compound of Formula V

(V)
7) A process for the preparation of paclitaxel according to claim 1, wherein coupling agent is selected from N,N’-dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), or mixtures thereof

8) A process for the preparation of paclitaxel according to claim 1, wherein acid chloride selected from C2-C6 acid chlorides, benzoyl chloride or mixtures thereof

Dated this 11th day of July, 2014

Signature:
Dr. A.K.CHATURVEDI
,TagSPECI:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of Paclitaxel of Formula (I).

(I)
The present invention further relates to a process for the preparation of Paclitaxel intermediate.

BACKGROUND OF THE INVENTION

Paclitaxel, formerly known as "taxol", is an important chemotherapeutic agent useful for the treatment of human ovarian, breast and lung tumors. It has shown promise for a number of human cancers and its clinical uses have been reported in several review articles. It was approved by USFDA in 1992 and is marketed under the brand name TAXOL®.

Paclitaxel is chemically known as 5ß,20-Epoxy-1,2a,4,7ß,10ß,13a-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate-13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine (I).

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216–217° C

Paclitaxel is a natural compound and was first isolated by Wani, et al., from the bark of Pacific yew (Taxus brevifolia). J. Am. Chem. Soc. 93:2325 (1971) Since that time, researchers have recognized that paclitaxel exists in all other species of the Taxus genus, including European yew (Taxus baccata), Himalayan yew (Taxus Wallichiana), Chinese yew (Taxus celebita), Japanese yew (Taxus cuspidata), Canadian yew (Taxus canadensis), Mexican yew (Taxus globosa), Florida yew (Taxus floridana) and ornamental yew (Taxus media) and all of their hybrids and cultivars.

U.S. Pat. No. 4,924,011 discloses the semi-synthesis of paclitaxel using l0-deacetyl baccatine III protected at the C-7 hydroxyl with a trialkylsilyl group and subsequently acetylated at C-l0. The resulting intermediate is reacted with (2R,3S)-N-benzoy1-2-0-(1-ethoxyethyl)-3-phenyl-isoserine and the resulting product is deprotected to give paclitaxel.

WO-93/06094 discloses the preparation of paclitaxel by reacting a ß-lactam precursor with 7-O-triethylsilylbaccatine III, followed by mild acid hydrolysis.

According to U.S. Pat No. 5,476,954, paclitaxel is prepared starting from l0-deacetylbaccatine III esterified at C-7 with a 2,2,2-trichloroethoxycarbonyl group (TROC). The resulting intermediate is reacted with N-Boc protected Oxazolidine derivative, followed by acid hydrolysis.

WO 2008/074178 discloses a process for the preparation of paclitaxel by reacting protected bacattin III with (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid to give cyclized condensed product, followed by acid hydrolysis

It is apparent from literature that a crucial aspect of paclitaxel semi-synthesis is to selectively protect the hydroxyls on the l0-deacetylbaccatine II, followed by condensation and hydrolysis. The C-7 position is the most reactive and is therefore functionalized with groups which are easy to remove subsequently. The present invention provides an improved process for the preparation of paclitaxel

The present inventors has repeated the above process and found the following disadvantages:
? In most of the patent literature, toluene is used as solvent in coupling stage of 7-Troc with oxazolidine side chain, which is tedious for the removal.
? Unwanted reactions are observed during the formation of paclitaxel, due to the use of strong acid in the ring opening reactions
? The isolation of Paclitaxel is tedious, wherein it involves pH adjustment, water content adjustment and concentration

In view of the above and to overcome the prior-art problems the present inventors have now developed an improved process for the preparation of Paclitaxel, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up.

OBJECTIVE OF THE INVENTION

The main objective of the invention is to provide an improved process for the preparation of Paclitaxel

Yet another objective of the invention is to provide an improved process for the preparation of Paclitaxel intermediate.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of paclitaxel of Formula (I)

(I)
comprising the steps of:
a) reacting 7-troc baccatin-III of Formula II

(II)
with (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid of Fomula III

(III)
in presence of coupling agent and a solvent to provide a compound of Formula IV

(IV)
b) reacting the compound of Formula IV using an organic acid chloride to provide a compound of Formula V

(V)
c) deprotecting the compound of formula V to give Paclitaxel of Formula (I)
d) optionally, purifying Paclitaxel

In another aspect the present invention relates to the preparation of Paclitaxel intermediate of Formula V comprises reacting the compound of Formula IV using an organic acid chloride

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the synthesis of paclitaxel of Formula (I) comprises reacting 7-troc baccatin-III of Formula II with (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid of Formula III in presence of coupling agent selected from N,N’-dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP) or mixtures there of; and a solvent such as hydrocarbons such as toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform or mixtures thereof; preferably methylene dichloride, at a temperature ranging from 20-30°C, preferably at 20-25°C to give a compound of Formula IV.

The present invnetors found that the use of methylene dichloride as a solvent, completes the reaction within hours and conversion is also in the range of 70-75%. After completetion of the reaction, the removal of methylene dichloride is very easy and does not require any cumbersome workup.

On the other hand, the use of methylene dichloride as a solvent moves the rection at low temperature conditions i.e., 20-30°C, preferable at 20-25°C, which helps in avoiding the unwanted reactions and minimizes the formation of impurity.

The condensed intermediate of Formula IV is reacting with an organic acid chloride selected from C2-C6 acid chlorides, benzoyl chloride or mixtures thereof; in presence of a solvent selected from alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; hydrocarbons such as toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform or mixtures thereof, at a temperature ranging from 20-30°C, preferably at 20-25°C to give a compound of Formula V.

The present inventors found that the ring opening reaction using an organic acid chloride helps to handle the reaction at a temperature range of 20-30°C, preferably at 20-25ºC and the reaction is completed within 12 hours, which is industrially viable and cost effective.

On the otherhand, the prior art processes involves the use of organic and inorganic acids for the generation of H+ ion, which will be helpful to open the oxazolidine ring involves the use of more base to neutralize and is also a time captivating process, which is cumbersome and not industrially effective.

The ring opened intermediate of Formula V, is deprotected using a suitable deprotecting agent and a solvent selected from alcohols, such as methanol, ethanol, isopropanol; acetonitrile and acetic acid or mixtures thereof, to give Paclitaxel. In general the 2,2,2-trichloroethoxy carbonyl chloride (Troc) is traditionally removed via Zn insertion, resulting in elimination and decarboxylation.

The obtained Paclitaxel is optionally purified by column chromatography over silica gel using acetone, hexane and methylene dichloride, which is further optionally purified by using Acetone and heptane.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-60°C for time ranging from 12 to 16 hrs depending upon the physical attributes of the end product obtained i.e.Pure Paclitaxel. The drying step is also one of the critical parameter as the temperature become higher the content of 7-epi Paclitaxel will also increases.

The process related impurities that appear in the impurity profile of the Paclitaxel may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:


The 7-troc baccatin-III of Formula II is prepared by any of the priorart process, which are in public domain. However, the process used by the inventor starts from 10-decacetyl bacattin-III. The process is as summarized below:

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

Example 1
Preparation of Coupled product of Formula IV

7-Troc baccatin-III (123.0gm), (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid(86.1 gm) are charged in to a round bottom flask containing pre-cooled Methylene dichloride (2.46 L) at 20-25°C. To the reaction mass DMAP (39.4 gm) and DCC (86.1 gm) solution (DCC in 246 ml Methylene dichloride) were added, maintain the reaction mass for 1 hour and then cool the reaction mass to 10-15°C. Water (246 ml) was added to the reaction mass and stirred for 1 hour. Filtered the material and washed with Methylene dichloride (315 ml) and Hydochloric acid (3%, 3 x 984 ml). The obtained organic layer was washed with saturated sodium chloride solution (984 ml), followed by Methylene dichloride (315 ml). Filtered the material, washed with Methylene dichloride (2 x 315ml) to yield the title product.

Yield: 246.0 gm
Chromatographic Purity (By HPLC): 73.01%

Exmaple 2
Preparation of 7-Troc Paclitaxel

Product obtained in example 1(122.gm) is charged in to the round bottom flask containing Acetyl chloride solution (185 ml Acetyl chloride in 10.5L Ethanol) at 80-10°C. Raise the temperature of the reaction mass to 20-25°C and maintained for 15 hours. Cooled the reaction mass to 10-15°C and then added Triethyl amine (500 ml). Distilled off the solvent to yield yellow gummy solid. To this reation mass Methylene dichloride (1 L) and Water (500 ml) are added and stirred for 30 min at 20-25°C. Separate the total organic layer and distilled off the organic layer to yield yellow gummy solid. To the residue Methnaol (366 ml) was added at 0-5°C and stirred for 2 to 3 hours. Filtered the material, washed with chilled methanol (122 ml) and then dried to yield the title product.

Yield: 117.0 gm
Chromatographic Purity (By HPLC): 96.93%

Exmaple 3
Preparation of Paclitaxel

7-Troc Paclitaxel (118 gm) was charged into the round bottom flask containing Methanol (944 ml) and Acetic acid (944 ml) at 25-30°C. Raise the temperature of the reaction mass to 40-45°C, Zinc dust (177 gm) was added and maintained the reaction mass at 50-55°C for about 70 to 80 min. Filtered the hot reaction mass and washed with Methanol (200 ml). To the filtrate DM water (3.75 L) was added and stirred for 1 hour at 25-30°C. Filtered the reaction mass, washed with DM water (236 ml) and then Methylene dichloride (3 L) was added. Separate the organic layer and then distilled off the solvent completely under vacuum to yield a white solid. To this obtained white solid Hexane (1 L) was added and stirred for 1 hour. Filtered the material and dried the material to yield the tiltle product.

Yield: 107.0 gm
Chromatographic Purity (By HPLC): 93.23%

Exmaple 4
Purification of Paclitaxel

a) Purification by Column chromatography

Paclitaxel (102 gm) purification is carried oput using Column chromatography over silica gel (230-400) mesh by using Methylene dichloride and Ethyl acetate in the ratio of 70:30. Distilled off the solvent to obtain a solid. To this solid Acetone (840 ml) and Hexane (1680 ml) was added at 10-15°C. Filtered the material, washed with Hexane (100 ml) and dried to yield pure Paclitaxel.

Yield: 72.5 gm
Chromatographic Purity (By HPLC): 99.61%

b) Purification using Acetone/Water /MDC treatment

Paclitaxel (70 gm) was charged in to the round bottom flask containing Acetone (700 ml) at 25-30°C and stirred for 15 min. To the reaction mass Water (2100 ml) was added and stirred for 15 min. Cooled to 10-15°C and stirred for 1 hour. Filtered the solid and washed with Water (140 ml). To the wet cake, Methylene dichloride (2.5 L) was added and stirred for 20 min at 25 -30°C. Separate the organic layer. Filtered the material, washed with Methylene dichloride (140 ml) and dried the material to yield pure Paclitaxel.

Yield: 70 gm
Chromatographic Purity (By HPLC): 99.70%

c) Purification using Acetone/n-Heptane

Paclitaxel (70 gm) was charged in to the round bottom flask containing Acetone (1400 ml) and n-Heptane (3500 ml) at 10-15°C. Cooled to 0-5°C and stirred for 3 hours. Filtered the solid, washed with n-Heptane (210 ml) and dried the material to yield pure Paclitaxel.
Yield: 64 gm
Chromatographic Purity (By HPLC): 99.71%

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.