Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-09-30
2003-10-21
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S028100, C536S028200, C536S028400, C536S028520
Reexamination Certificate
active
06635753
ABSTRACT:
BACKGROUND OF THE INVENTION
The synthesis of Stavudine was first reported by J. P. Horwitz et al (J. Org. Chem. (1996) 31, 205) starting from 3′,5′-dimesylthymidine as shown in Scheme 1.
In this synthesis, dimesylthymidine 1 was first treated with sodium hydroxide (3 equivalents) in refluxing water for 2 hours and after work-up the resultant 3,5-anhydrothymidine was treated with potassium t-butoxide in dimethylsulfoxide (DMSO) at room temperature for 2 hours. The reaction mixture was neutralized, evaporated to dryness and after a series of manipulations which included extraction, decolourization, precipitation and recrystallization, gave Stavudine in 79% yield and an overall yield of 56%.
The above procedure was modified by Mansuri et al (J. Med. Chem. (1989) 32, 461) where the potassium t-butoxide/DMSO mixture was poured into 30 volumes of toluene whereby the Stavudine precipitates as the potassium salt along with excess potassium t-butoxide. This modification avoided the distillation of DMSO which caused decomposition of Stavudine. The salt was neutralized in water and the product precipitated. The precipitate was extracted with acetone and then evaporated to dryness to give an off-white solid in 57% yield.
A similar procedure was disclosed by Starret, Jr. et al (U.S. Pat. No. 4,904,770 to Bristol), Mr. Starret was also an author of the Mansuri publication.
A major problem with the above procedure is that the Stavudine potassium salt is sensitive to both moisture and excessive drying thus, resulting in impurities.
Adachi et al. (Carbohydrate Research (1979) 113) overcame some of the decomposition. problems by employing sodium hydroxide in hexamethylphosphorictriamide (HMPA). The HMPA was removed by forming a chloroform complex in an aqueous mixture and Stavudine was isolated from the aqueous phase.
Stavudine has also been proposed to be produced from 5-methyluridine in U.S. Pat. No. 4,904,770 via three proposed routes and from 3′-phenylsilinyl-5′-tritylthymidine (Cosford et al, J. Org. Chem. (1991) 2161) with the latter process requiring column chromatography for purification.
P. M. Skonezny et al. (U.S. Pat. No. 5,539,099 to Bristol) purports to have developed the route for producing Stavudine as shown in Scheme 2.
However, all of the above discussed processes have one major drawback in common in that the final purity of Stavudine was less than the desired 99.5%, at least. Known and difficult to remove impurities using conventional techniques were still present, some of which were thymine, thymidine, threo-thymidine, 3,5-anhydrothymidine and 5′-O-[stavudin-5′″-yl]-threo-thymidine with the latter (Scheme 3) being particularly difficult to remove.
Further, U.S. Pat. No. 5,539,099 teaches the use of only N-methyl-2-pyrrolidinone as suitable to form a solvate of Stavudine whose recovery requires the use of an aprotic ester, amide or ketone solvent. No consideration is given for their use to form a solvate.
It is therefore an object of this invention to provide an improved process which is more efficient, using less toxic materials (for example, using solvents which are at least 20% less toxic than N-Methyl-2-pyrrolidinone) and providing a cleaner and purer product before recrystallization steps are carried out.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of invention and detailed description thereof.
SUMMARY OF THE INVENTION
The present invention provides an improved process for producing substantially pure Stavudine on a large or commercial scale. The invention further provides a process for manufacturing substantially pure Stavudine where the above mentioned impurities found in the prior art processes and other impurities are present at levels substantially much lower than the prior art processes or are not detected at all.
Therefore, according to one aspect of the invention, we provide process for preparing substantially pure Stavudine by preparing a solvate of Stavudine for example, a Stavudine amide by reacting Stavudine with at least one compound selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylacrylamide and N,N-dimethylpropionamide, (preferably Stavudine with N,N-dimethylacetamide) and thereafter, recovering substantially pure Stavudine by breaking the solvate produced.
According to another aspect of the invention, we provide a process for preparing a solvate of Stavudine by reacting Stavudine (for example, crude Stavudine with at least one compound selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylacrylamide and N,N-dimethylpropionamide, (preferably Stavudine with N,N-dimethylacetamide).
According to another aspect of the invention, we provide a process for producing at least one of the following novel compounds selected from the group consisting of Stavudine .N,N-Dimethylacetamide (DMA) solvate, Stavudine .N,N-Dimethylacrylamide (DMAC) solvate, and Stavudine .N,N-Dimethylpropionamide (DMP) solvate, all of which are new compounds and which precipitate as substantially white crystals from N,N-dimethylacetamide, N,N-dimethylacrylamide and N,N-dimethylpropionamide respectively.
According to another aspect of the invention, we further provide a process for the manufacture of Stavudine which leaves most of the impurities behind in the mother liquors.
According to another aspect of the invention, we further provide a process for the breaking of a Stavudine solvate preferably Stavudine DMA solvate by dissolving said solvate in at least one suitable solvent preferably but, not limited to, water, acetone and isopropanol, or combinations thereof, and then concentrating, preferably so that about 1 to 5 volumes of solvent remains depending on the solvent choice, whereupon substantially pure white Stavudine is precipitated if desired. Thereafter, the substantially pure Stavudine is filtered, washed and dried.
Thus, according to another aspect of the invention, Stavudine has been provided in a purity of at least 99.5%. This Stavudine may be combined with suitable adjuvants, carriers, or diluents to prepare dosage forms of pharmaceutical compositions containing Stavudine (such as tablets, capsules, injectibles) in all manner known to persons skilled in the art.
Embodiments of the present invention will now be illustrated.
DISCUSSION OF EMBODIMENTS OF THE INVENTION
In another embodiment, there is provided a process for production of substantially pure Stavudine comprising:
a) the dissolution of crude Stavudine in preferably 1 to 2 parts of a solvent, preferably N,N-dimethylacetamide (DMA), more preferably 1.5 parts of N,N-dimethylacetamide (DMA) at elevated temperatures. If insoluble solids are present after dissolution the mixture can be filtered. To aid in the filtration, the mixture can be diluted with aprotic or protic solvents such as acetone, ethyl acetate, methanol, ethanol or isopropanol and later removed by distillation;
b) the solution from (a) is cooled to ambient temperature or lower whereupon a precipitate forms. If the solution was diluted with a low boiling solvent then that solvent is first removed by distillation before cooling to give crystalline Stavudine DMA solvate;
c) the precipitate is filtered and washed with an aprotic solvent such as acetone, ethyl acetate, methylisobutyl ketone and the like to give substantially white crystals in substantially high yield which have the composition of Stavudine .N,N-dimethylacetamide solvate as indicated by
1
H NMR spectroscopy (see examples following);
d) the above procedure can be repeated with N,N-dimethylacrylamide and N,N-dimethylpropionamide to give the corresponding Stavudine solvate.
In one embodiment, the invention also provides a compound selected from the group of compounds consisting of:
a) Stavudine N,N-dimethylacetamide solvate;
b) Stavudine N,N-dimethylacrylamide solvate; and
c) Stavudine N,N-dimethylpropionamide solvate.
In another embodiment, the invention further provides a process for making Stavudine comprising breaking the solvate of
Murthy K. S. Keshava
Radatus Bruno K.
Brantford Chemicals Inc.
Hughes Ivor M.
Hughes Neil
Owens, Jr. Howard V
Sarkis Marcelo K.
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