Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-08
2004-04-20
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06723855
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the anti-proliferative compound leflunomide and to a process for synthesizing leflunomide.
BACKGROUND OF THE INVENTION
Pyrimidine biosynthesis is an essential function of cells. It is the biosynthetic pathway to the DNA base constituents of uracil, cytosine and thymine and produces precursors of molecules used in the synthesis of ATP, several cofactors and other important cell components. Uracil, cytosine and thymine are essential to DNA replication during cell proliferation. [Prescott, L. M.; Harley, J. P.; Klein D. A.
Microbiology
203 (4th ed., McGraw Hill, 1999)]. Many diseases are caused by or are aggravated by the failure of natural mechanisms to regulate cell proliferation, such as cancer and some inflammatory diseases like rheumatoid arthritis. Most cancer therapies attempt to suppress the proliferation of rapidly dividing cells. Disruption of the pyrimidine biosynthesis pathway is one way to suppress proliferation of rapidly dividing cells because the disruption interferes with the cell's ability to replicate DNA.
Pyrimidine biosynthesis is a series of enzymatically catalyzed processes that convert carbamoyl phosphate and aspartic acid into cytidine triphosphate. About midway along the pathway lies the conversion of dihydroorotic acid to orotic acid by the dehydroorotate dehydrogenase enzyme. Leflunomide, N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (I), disrupts pyrimidine biosynthesis by inhibiting this enzyme.
Leflunomide has been shown to be effective for treatment of the inflammatory disease rheumatoid arthritis although the mechanism by which it causes this particular therapeutic effect is not completely understood.
The first report of the anti-rheumatic property of leflunomide appeared in U.S. Pat. No. 4,284,786, which disclosed that leflunomide reduced symptoms of adjuvant arthritis in a rat model. This patent also reported that leflunomide may be prepared by reacting a 4-trifluoromethylaniline (“TFMA”) with a 5-methylisoxazole-4-carboxylic acid (“MIA”) derivative. In U.S. Pat. No. 4,284,786, Example (a1), 5-methylisoxazole-4-carboxylic acid chloride (“MIA-Cl”) is reacted with two molar equivalents of TFMA in acetonitrile. This preparation is uneconomical on a large scale because acetonitrile is an expensive solvent.
TFMA is used as a scavenger of the HCl byproduct in the reaction of Example (a1). TFMA is too expensive to be used in this manner in a commercial process. We found that using triethyl amine (“Et
3
N,” pK
b
=3.25) as an acid scavenger as described in Example (a3) of the '786 patent causes significant decomposition of leflunomide to N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide (“HCA”) of formula (II).
Although HCA is the active metabolite of leflunomide that forms in a patient's body, its presence in a pharmaceutical composition is problematic for accurate dosing and also affects other aspects of pharmaceutical processing. An alternative process for making leflunomide that is described in the '786 patent uses the Schotten-Baumann procedure to produce leflunomide with a minimum of contamination by HCA (Example a2 of the '786 patent). However, careful simultaneous addition of MIA-Cl and KOH is required for pH control. Any failure in the simultaneous delivery can lead to a rapid decomposition of leflunomide to HCA. A batch preparation which would not require the equipment, maintenance or sophisticated mechanical expertise for careful flow control would be preferable for a large scale commercial process for manufacturing leflunomide.
In addition to the problem of HCA formation, the production of substantially pure leflunomide is problematic because of the formation of byproducts derived from impurities in the starting materials. Two such impurities have chemical reactivities similar to MIA and TFMA and are carried through the process of the '786 patent to form byproducts that must be removed before the leflunomide can be used as an active ingredient in pharmaceutical. 3-Methyl-isoxazole-4-carboxylic acid is a common impurity in commercially available MIA. 3-Methyl-isoxazole-4-carboxylic acid originating in MIA is transformed by chlorination and reaction with TFMA to N-(4-trifluoromethylphenyl)-3-methyl-isoxazole-4-carboxamide (III). Another troublesome impurity in leflunomide derives from 4-methyl aniline, which is commonly present in minor amounts in TFMA obtained from commercial sources. 4-Methyl aniline forms 5-methyl-N-(4-methylphenyl)-isoxazole-4-carboxamide (IV) upon reaction with MIA-Cl.
It thus would be highly desirable to have available a process for preparing leflunomide substantially free of impurites (II), (III) and (IV) that could be conducted without careful reagent flow control and without costly solvents and bases.
The manufacture of the intermediate MIA-Cl in sufficient purity is also problematic for reasons other than the presence of impurities in the starting materials and the sensitivity of leflunomide to base-induced decomposition. According to a method disclosed in U.S. Pat. No. 4,892,963, Example 2(vi), MIA-Cl may be prepared by reacting MIA with thionyl chloride in the presence of N,N-dimethylformamide (“DMF”) as a catalyst. It has been found that minor amounts of DMF left in the product after evaporation of excess thionyl chloride causes the MIA-Cl to discolor quickly. Discolored MIA-Cl produces leflunomide that is also discolored and too low in purity to be used as an active pharmaceutical ingredient. Additional purification steps are required to render the leflunomide pharmaceutically acceptable. Therefore, it is highly desirable that the MIA-Cl that is used to prepare leflunomide be as free as possible of DMF. High vacuum distillation is required to substantially remove high boiling DMF (bp=153° C. at 760 torr) from the MIA-Cl. The high vacuum (from 0.1 to 20 torr) required for that separation requires an additional investment in equipment. Further, it has been reported that even trace amounts of DMF remaining in the residue after high vacuum distillation can lead to discoloration of the obtained MIA-Cl and color problems with leflunomide.
MIA-Cl has been prepared without DMF as catalyst. [Doleschall, G.; Seres, P.
J. Chem. Soc. Perkin Trans. I,
1988, 1875-1879]; [Fossa, P.; Menozzi, G.; Schenone, P.
Il Farmaco,
1991, 46, 789-802]. However, high reaction temperatures and distillation of the resulting MIA-Cl were required. High reaction temperatures also can lead to discoloration of the MIA-Cl. Moreover, MIA-Cl can explode during distillation if the temperature is allowed to get to high. [Doleschall, et al., at p. 1877]. It therefore would also be highly desirable in a process for preparing leflunomide in high purity from MIA, via an MIA-Cl intermediate, that the MIA-Cl be formed under conditions that do not require that it be distilled before it is used to make leflunomide.
SUMMARY OF THE INVENTION
The present invention provides a practicable, economic process for preparing leflunomide in high yield, high purity and on a large scale from 5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline. The inventive process comprises the steps of chlorinating 5-methylisoxazole-4-carboxylic acid to form 5-methylisoxazole-4-carboxylic acid chloride, contacting the resulting 5-methylisoxazole-4-carboxylic acid chloride, without intermediate distillation, with 4-trifluoromethylaniline in the presence of an alkali metal or alkaline-earth metal bicarbonate and a solvent and crystalizing the leflunomide from the solvent. Suitable reaction solvents include water, ethyl acetate, toluene and dimethyl acetamide.
The present invention provides leflunomide substantially free of HCA and other impurities. The present invention further provides compositions and dosage forms for treating rheumatoid arthritis and other proliferative diseases that contain leflunomide made according to the present invention as well as methods of treating rheumatoid arthritis and oth
Avrutov Ilya
Gershon Neomi
Liberman Anita
Gerstl Robert
Kenyon & Kenyon
Teva Pharmaceutical Industries Ltd.
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