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Title:
A NEW IMPROVED PROCESS FOR THE PREPARATION OF STAVUDINE FORM I
Document Type and Number:
WIPO Patent Application WO/2007/099389
Kind Code:
A1
Abstract:
The present invention relates to an improved process for obtaining Stavudine Polymorphic Form I useful in the treatment of retroviral infections.

Inventors:
VENNAPUREDDY RAVINDER REDDY (IN)
SHANKAR RAMA (IN)
DANDALA RAMESH (IN)
MEENAKSHISUNDERAM SIVAKUMARAN (IN)
Application Number:
PCT/IB2006/002082
Publication Date:
September 07, 2007
Filing Date:
July 06, 2006
Export Citation:
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Assignee:
AUROBINDO PHARMA LTD (IN)
VENNAPUREDDY RAVINDER REDDY (IN)
SHANKAR RAMA (IN)
DANDALA RAMESH (IN)
MEENAKSHISUNDERAM SIVAKUMARAN (IN)
International Classes:
C07H19/06; C07H1/06
Foreign References:
US5608048A1997-03-04
US6335753B12002-01-01
US5539099A1996-07-23
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Claims:

WE CLAIM :

I) A new improved process for the preparation of Stavudine polymorphic Form I from comprising a) dissolving the crude stavudine in organic solvents, wherein the said solvent is selected from the group consisting of methylisobutyl ketone, tetrahydrofuran, and mixture of ethanol/cyclohexane, isopropanol/ ethanol, isopropanol/cyclohexane, b) the resultant reaction mixture is first cooled to ambient temperature followed by cooling to 0-5 °C and c) recovering the substantially pure Stavudine Polymorphic Form I by filtration and drying.

2) The process of claim 1, wherein the solvent is methylisobutylketone.

3) The process of claim 1, wherein the solvent is tetrahydrofuran.

4) The process of claim 1, wherein the solvent mixture is isopropanol/ethanol.

5) The process of claim 1, wherein the solvent mixture is ethanol/cyclohexane.

6) The process of claim 1, wherein the solvent mixture is isopropanol/ cyclohexane.

7) The process of claim 5, comprising the step of dissolving stavudine in ethanol and crystallizing it by the addition of cyclohexane.

8) The process according to claim 6, comprising the step of dissolving stavudine in isopropanol and crystallizing it by addition of cyclohexane.

9) A process for the preparation of Stavudine of Formula I in Polymorphic Form I

Formula I

which comprises heating the compound of Formula II

Formula II

in a solvent selected from ketones, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons and nitriles or a mixture thereof and obtaining the Stavudine of Formula I.

10) The process according to claim 9, wherein the ketone is selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone, methyl isoamyl ketone, methyl amyl ketone.

11) The process according to claim 10, wherein the ketones are acetone and methylisobutyl ketone.

12) The process according to claim 9, wherein the ether is selected from tetrahydrofuran, t-butyl propyl ether, isopropyl methyl ether, ethyl methyl ether, methyl tert-butyl ether, isopropyl ether.

13) The process according to claim 12, wherein the ether is tetrahydrofuran.

14) The process according to claim 9, wherein the ester is selected from ethyl acetate, isopropyl acetate.

15) The process according to claim 9, wherein the aromatic hydrocarbon is selected from toluene, xylene.

16) The process according to claim 9, wherein the aromatic hydrocarbon is toluene.

17) The process according to clam 9, wherein the nitrile is acetonitrile.

18) The process according to claim 9, wherein stavudine obtained is either Form I, Form II or Form III.

Description:

Field of the invention

The present invention relates to an improved process for obtaining Stavudine Polymorphic Form I useful in the treatment of retroviral infections, particularly, HIV. The structure of stavudine is as follows :

Background of the Invention

Stavudine, also known as d 4 T, is approved by the U.S. Food and Drug Administration for the therapeutic treatment of patients infected with retroviruses. Stavudine, chemically is I'^'-didehydro-S'-deoxythymidine. The compound, a nucleoside reverse transcriptase inhibitor, and its preparation are disclosed, for example, in US 4,978,655. It is known that Stavudine is effective in the treatment of infections caused by retroviruses such as murine leukemia virus and human immunodeficiency virus, i.e. HIV, HTLV III/LAV virus (the AIDS virus). Stavudine has enjoyed notable commercial success since its introduction. Other processes for making d 4 T have been reported in the literature such as in US 4,904, 770.

There have been several processes reported for synthesizing 2' 5 3'-didehydro-2',3'- dideoxynucleosides such as d 4 T. Most proceed via an anhydronucleoside intermediate which after elimination gives stavudine.

The nucleoside derivative, 2',3'-didehydro-3'-deoxythymidine (d 4 T), has previously been prepared by various synthetic processes. Horwitz et al, in

Synthetic Procedures in Nucleic Acid Chemistry (Vol. I) 3 Zorbach (eds) Interscience, New York, p. 344, describe the process as shown below :

DMSQ Purification KOt-Bu [Crude stavudine]

This process utilizes 3',5'-anhydrothymidine as the starting material, and employs flammable and moisture sensitive potassium tertiary butoxide in dimethyl sulfoxide (DMSO). Besides the material handling difficulties, the process is impractical on a large scale due to decomposition of the product during its isolation from a DMSO solution, which involves distillation of dimethylsulphoxide under reduced pressure causing heating of the product at high temperatures and strongly basic conditions for extended periods. All these conditions lead to cleavage of the glycosidic bond to give thymine as undesired side product.

An improvement in isolation noted by Mansuri et al in J. Med. Chem., 1989, 461 gives the potassium salt of d 4 T as an oily solid by dilution of the DMSO reaction mixture with toluene before further processing.

[Crude Stavudine]

However, on a large scale, the volumes of solvents used in this process are unmanageable, difficult to recover and generate large amounts of waste. Also, the isolated salt is very sensitive to moisture and excessive drying. After redissolution and neutralization, crude d 4 T is isolated and dried and a further reslurry in solvent is necessary to obtain the final product.

Starrett, Jr in US 4,904,770 disclosed a modification to the Mansuri process that comprised room temperature reaction of the 3',5' anhydro intermediate with the strong base in a polar organic solvent, e.g. t-BuOK/DMSO followed by trituration of the resulting potassium salt of the 2',3'-didehydro-2',3'-dideoxynucleoside in an organic solvent, e.g. cold toluene. After redissolution and neutralization, crude d 4 T is obtained mixed with inorganic salts. Product is repeatedly extracted in hot acetone and stavudine is obtained by concentrating the acetone extract to dryness. The stavudine obtained has very less purity.

US 5,539,099 describes process suitable for large-scale production of stavudine, the improvement consisting of novel purification step involving the isolation of a stavudine N-methylpyrrolidinone solvate from stavudine reaction mass. The preparation of the said solvate helps in ease of isolation and purification. The improved synthetic process of stavudine is shown below :

1. Alcohol/Base

2. Acetone, NMPO

However, in this process the desolvation of the N-methyl pyrrolidinone is effected with only one solvent, which makes the process left without any alternative options. The prior art does not show any other solvent or solvent mixtures for the desolvation other than isopropanol.

Moreover, this patent does not talk about Polymorphic form of the stavudine produced, indicating probably that stavudine obtained from desolvation needs to be crystallized to obtain desired Polymorphic form.

Further, US 6,635,753 discloses the preparation of substantially pure stavudine from crude stavudine by preparing and cleaving stavudine solvates, i.e., Stavudine N,N-dimethylacetamide solvate, stavudine N,N-dimethylacrylamide solvate, and stavudine N,N-dimethylpropionamide solvate. The solvates are broken by dissolving them in polar protic or aprotic solvents, e.g water, alcohols, ketones and amides, at elevated temperatures (50-100 0 C).

Surprisingly, this patent is also silent about polymorphism of the stavudine obtained.

The existence of three solid state forms of stavudine designated as Form I, II and III was reported in US 5,608,048. The polymorphs of stavudine have been distinguished by their characteristic X-ray powder diffraction patterns. The single crystal X-ray analyses data for these forms have also been reported in US 5,608,048. The single crystal X-ray analyses data of designated Form I was found in agreement with those reported earlier in Biochemical and Biophysical Research Comm, 175 (1), pp 298-304, 1991. The stavudine crystal for that study was obtained by toluene with slow diffusion into methanol solution of stavudine.

The single crystal X-ray analysis data obtained for designated Form II was in agreement with those reported earlier in Molekulyarnaya Biologiya, 25(2), pp 483-91 (1991). The stavudine crystal was grown in this case from saturated stavudine solution in acetone by slow solvent evaporation.

Forms I and II are anhydrous polymorphs whereas, Form III is hydrated and is pseudopolymorphic with respect to Forms I and II. Of the three forms, Form I is stable and shows no tendency for solid state transformations to other Polymorphic forms, thus demonstrating its greater thermodynamic stability relative to the other Forms. Since Form I has been found to be the most thermodynamically stable form, Form I is used commercially for producing solid dosage forms.

The US 5,608,048 teaches a process, whereby Polymorphic Form I of Stavudine is prepared in substantially pure form from a mixture containing one or more of Stavudine Polymorphic Forms I, II and III. This process involves dissolving the mixture under anhydrous conditions in an organic solvent to form a saturated solution at a temperature of at least about 65 °C and continuously cooling the solution with stirring until precipitation of Stavudine Polymorphic Form I is completed. A requirement of the process however, is that the rate of cooling cannot exceed about 2O 0 C per hour until the temperature falls below 4O 0 C. In a preferred embodiment of US λ 048, the temperature is reduced about 1O 0 C over 15 minutes, then held for an hour and the steps repeated until the solution temperature falls below 4O 0 C. There are disclosed further embodiments in US '048 consisting of gradients in cooling the solution of the mixture of Polymorphic forms.

The solvent utilized in the process described in US 5,608,048 is selected from the group of methanol, ethanol, n-propanol, isopropanol, acetonitrile and ethyl acetate. It is emphasized, as stated previously, that the process must be carried out under anhydrous conditions. This process suffers from a number of disadvantages, among which are strict requirements in time and temperature management and control as well as strict moisture control.

US 2003/0225279 Al also describes a process for the formation of Stavudine Polymorphic Form I from a mixture comprising Polymorphic Form I and at least

one of Polymorphic Forms II and III using the technique of Solution-Enhanced Dispersion by Supercritical Fluids (SEDS). This technique requires special apparatus and uses carbon dioxide as supercritical fluid which is disadvantageous in terms of both cost and operability.

The known processes for the preparation of d 4 T were giving rise to a mixture of Form I, II and Form III. Given the pharmaceutical interest in this compound, it is important to be able to obtain exclusively Stavudine Form I by a cost effective method that can be readily applied on an industrial scale, yielding Stavudine Form I in good yield consistently and, especially, with an excellent degree of purity and most importantly free of other undesired Polymorphic Forms.

In accordance with the present invention, a method has been found whereby Stavudine Polymorphic Form I can be readily produced without such strict process control requirements and using simple crystallization/desolvation techniques with a variety of solvents. This has been accomplished by simple recrystallization from a single or a mixture of solvents.

OBJECTIVES OF INVENTION

The objective of the present invention is to develop a new improved process for the preparation of Stavudine Polymorphic Form I from a solvent or mixture thereof which is further free of other Polymorphic Forms II and III.

Another objective of the present invention is to produce substantially pure stavudine Form I by cleaving down the N-methyl pyrrolidinone solvate in suitable solvent other than Isopropyl alcohol

Still another aspect of the present invention is to develop a process for the preparation of Polymorphic Form I of Stavudine by simple crystallizations/desolvations from suitable organic solvents.

SUMMARY OF INVENTION

The present invention relates to a new improved Crystallizations/desolvation methods for the preparation of Stavudine Polymorphic Form I in a variety of solvents and mixture of solvents.

In an second aspect of the present invention is to prepare Stavudine Form I by crystallizing in solvents like methylisobutyl ketone, tetrahydrofuran, or mixture of ethanol/cyclohexane, isopropanol/ethanol, isopropanol/cyclohexane which involves heating the crude stavudine in a solvent or solvent mixture till dissolution, cooling the solution to ambient temperature and subsequent cooling to 0-5 °C so as to obtain the required Form I or adding a co solvent to the solution and then cooling to crystallize the stavudine Form I.

hi another aspect of the present invention relates to a desolvation process for the preparation of Stavudine Form I of Formula I

Formula I

which comprises heating the compound of Formula II

Formula II

in a solvent selected from ketones, ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbons and nitriles or mixtures there of and obtaining the Stavudine of Formula I

DETAILED DESCRIPTION OF INVENTION

Accordingly, the present invention relates to a new improved process for the preparation Stavudine Polymorphic Form I by crystallizing in a suitable solvent selected from methyl isobutyl ketone, tetrahydrofuran, or mixture of ethanol/cyclohexane, isopropanol/ethanol, isopropanol/cyclohexane.

The process consists of dissolving crude stavudine by heating in a solvent or a mixture of solvents. Cooling the solution to ambient temperature and subsequent cooling to 0-5 0 C to complete the crystallization of stavudine Form I. Alternatively adding a co-solvent to the hot solution and then subsequent cooling to crystallize stavudine Form I. The pure stavudine Form I was isolated by conventional techniques like filtration and drying.

Although acetone was used for crystallization in the prior-art, the inventors have found that stavudine crystallized from acetone is also Form I.

In this present invention it was further found, that although not critical, it is preferred to add seed crystals of Form I to the cooled solution of the reaction mixture to initiate quick crystallization and also to increase the yield of Form I. The benefits of the process of forming Stavudine Polymorphic Form I in accordance with the process of the invention are that the solvents used in the crystallization step can be recovered and recycled making the process viable and cost-effective. Also in this present process of invention the high purity stavudine Form I is obtained by simply cooling the stavudine solution to ambient temperature, whereas prior art crystallizations to get Stavudine Form I are tedious, temperature and time dependent.

Another advantage this process has over that of the prior is that it does not require anhydrous solvents thus making the process easy to handle for large-scale production.

In another aspect of the present invention crude stavudine which is normally obtained in crude form is purified by preparing the NMPO solvate and further cleaving down the NMPO solvate in a variety of solvent and solvent mixtures. This cleaving down the NMPO solvent in the above mentioned solvent systems serves the dual purpose of desolvation and crystallizing the Form I. This has not been reported hitherto in the prior-art.

The present invention relates to a new desolvation process for the preparation stavudine Form I by heating or optionally dissolving in a solvent and crystallizing stavudine Form I.

Normally, the stavudine produced by prior-art processes is purified by a number of purification steps like resin treatment or solvate preparations etc to be able to meet the pharmacoepial standards for quality. However, in all these procedures substantially pure stavudine is obtained, but it requires further crystallization step to prepare the desired Polymorphic Form I. Hence the inventors directed their efforts to develop a process whereby desolvation of the solvate and formation of Form I, occur simultaneously in the same reaction vessel.

The inventors have been able to identify conditions and class of solvents that not only breaks the Stavudine solvate but also gives the desired Stavudine Form I. Final stavudine Form I meeting the pharmacoepial standards, can be isolated by simple filtration.

Accordingly, the invention describes a process for the breaking of Stavudine N- methyl pyrrolidinone solvate by heating the said solvate in a class of solvents preferably in ketones, ethers, esters, aromatic hydrocarbons, and nitriles.

The examples of ketones for the desolvation reaction include acetone, methyl ethyl ketone and methyl isobutyl ketone, methyl isoamyl ketone, methyl amyl ketone.

The examples of ethers include tetrahydrofuran, t-butyl propyl ether, isopropyl methyl ether, ethyl methyl ether and methyl t-butylether.

The example of esters include ethyl acetate, isopropyl acetate etc.

The examples of aromatic hydrocarbons include toluene, xylene, etc The examples of nitriles include acetonitrile etc.

The major advantage of this process is that both desolvation and formation of substantially pure stavudine polymorphic Form I occurs in the same reaction pot, thus reducing the batch cycle time and consumption of solvent.

This process has an additional advantage in that since Polymorphic Form of Stavudine is directly obtained from the reaction vessel, there is minimal loss of the product while handling, leading to substantial increase in the yield of the product and making the process cost-effective.

The stavudine obtained by this method has a HPLC purity of > 99.5 % and it meets all the other pharmacoepial monograph requirements. The X-ray powder diffraction patterns and diffraction angles for the product is found concordant with the literature reported values for stavudine Form I.

The X-ray diffraction pattern of Stavuidne Form I obtained by the process of this invention matches with the known data available for Form I in the literature.

In a way both the above new process of the invention rely on purifying crude stavudine as well as being able to furnish Form I. The crude stavudine could be obtained by any of the prior-art methods detailed above.

The invention is further described by the following examples and is not intended to limit the scope of the invention.

EXPERIMENTAL

Example 1

5 gm of Stavudine was added to 150 ml Methylisobutyl ketone and it was heated to 100-105 °C. Heating was continued for 25-30 min to obtain a clear solution. The clear solution thus obtained was cooled to -90 °C and seeded with Stavudine Form I. The solution was further slowly cooled to 25-30 0 C. Stirring was continued at 25-30 0 C for 2 hrs for complete crystallization. The crystallized product was filtered, washed with 10 ml of Methylisobutyl ketone and dried under reduced pressure to yield 4.5 g of Stavudine Form I.

Example 2

5 gm of Stavudine was added to 250 ml Tetrahydrofuran and heated to reflux (65- 67 °C) for 25-30 min to obtain a clear solution. The clear solution thus obtained was slowly cooled to 55 0 C and added 0.1 gm of Stavudine Form I seed to initiate crystallization. The product slurry was slowly cooled to 25-30 °C. Further cooled the product suspension to 0-5 °C and continued stirring for 1 hr to ensure complete crystallization. Filtered the product and dried under reduced pressure to yield 4.2 gm of Stavudine Form I.

Example 3

5 gm of Stavudine was added to 60 ml Isopropyl alcohol and it was heated to reflux (78-82 °C). Reflux was maintained for 20 min to obtain a clear solution. 60 ml of cyclohexane was slowly added over a period of 15 min while maintaining mild reflux. Stavudine precipitated after about 10 min of stirring at

reflux. Cooled the product slurry slowly to 25-30 °C. Further cooled the product suspension to 0-5 °C and stirred for 1 hr. The product was filtered and dried under reduced pressure to yield 4.6 gms of Stavudine Form I.

Example 4

5 gm of Stavudine was added to 35 ml Ethanol and heated to reflux (78-80 °C) for about 30 min to obtain a clear solution. To the clear solution 35 ml of cyclohexane was added slowly over a period of 15 min. Product got precipitated during the addition of cyclohexane. The product suspension was slowly cooled to 25-30 °C. Further cooled the suspension to 0-5 °C in 1 hr and stirred for 1 hr at 0- 5 °C. The product was filtered and dried under reduced pressure to yield 4.7 gm of Stavudine Form I.

Example 5

5 gm of Stavudine was added to a solvent mixture of isopropyl alcohol (30 ml) and ethyl alcohol (20 ml). Heated the suspension to reflux (80-82 °C) and continued the reflux for 30 min to obtain clear solution. The clear solution was cooled to 50-55 °C and 0.1 gm of Stavudine polymorphic Form I was added. Further cooled the product suspension to 0-5 ° and continued stirring for 1 hr at 0- 5 °C. The product was filtered and dried under reduced pressure to yield 4.0 gm of Stavudine Form I.

Preparation of Stavudine Form - 1 from N-methyl-2-pyrrolidinone solvate of Stavudine

Example 6

Stavudine N-methyl-2-pyrrolidinone solvate (10 gms,) was added to methyl isobutyl ketone (100 ml) heated to 90-95 0 C. The slurry was stirred at 90-95 0 C for about 30 min and slowly cooled to 30-35 0 C over a period of about 90 minutes. The product slurry was stirred for 2 hrs at 30-35 °C to complete

precipitation. The product was filtered and washed with 20 ml of methyl isobutyl ketone. Product dried under reduced pressure to constant weight to yield 5.9 gm of Stavudine Form I.

Example 7

Stavudine N-methyl-2-pyrrolidinone solvate (10 gms) was added to toluene (100 ml). The slurry was heated and stirred at 90-95 0 C for about 40 min and slowly cooled to 30-35 0 C over a period of 2 hrs. The product slurry was stirred for 2 hrs at 30-35 0 C for complete precipitation. The product was filtered and washed with 20 ml toluene. Dried the product under reduced pressure to constant weight to yield 6.3 gm of Stavudine Form I.

Example 8

Stavudine N-methyl-2-pyrrolidinone solvate (10 gms) was added to acetone (100 ml) and heated to reflux (50-55 0 C). The suspension was stirred at 50-55 0 C for 1 hr. The product suspension was cooled slowly to 18-22 °C in 2 hrs and continued stirring for 1 hr at this temperature. The product was filtered and washed with 20 ml of precooled acetone at 0-5 °C. Dried the product under reduced pressure to constant weight to yield 5.2 gm of Stavudine Form I.

Example 9

Stavudine N-methyl-2-pyrrolidinone solvate (10 gms) was added to ethyl acetate (100 ml) and heated to reflux (76-78 0 C). The suspension was further stirred at 76-78 0 C for 30 min. The product suspension was cooled slowly to 18-22 0 C and stirring continued for 1 hr. The product was filtered and washed with 20 ml of precooled ethyl acetate at 18-22 0 C. The product was dried under reduced pressure to constant weight to yield 6.0 gm of Stavudine Form I.

Example 10

Stavudine N-methyl-2-pyrrolidinone solvate (10 gms) was added to acetonitrile (100 ml ) and heated to 70 0 C and stirred at 70-72 °C for about 15 minutes whereupon a clear solution resulted. The solution was slowly cooled to 15-20 °C and stirring continued at 15-20 0 C for 1 hr. The crystallized product was filtered and washed with 20 ml of precooled acetonitrile at 15-20 °C. Dried the product under reduced pressure to constant weight to yield 5.8 gm of Stavudine Form I.

Example 11

Stavudine N-methyl-2-pyrrolidinone solvate (10 gms) was added to tetrahydrofuran (60 ml) heated and refluxed for 30 min at 65-67 °C to ' obtain a clear solution. The solution was cooled slowly to 0-5 °C in about 90 minutes and stirring continued for 1 hr at 0-5 0 C to complete crystallization. The product was filtered and washed with 15 ml of precooled tetrahydrofuran at 0-5 0 C. Dried the product under reduced pressure to constant weight to yield 4.0 gms of Stavudine Form I.