Process for the preparation of trifluorothymidine derivatives

Details Process for the preparation of trifluorothymidine derivatives Process for the preparation of trifluorothymidine derivatives

2001-10-09

2002-07-23

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06423852

ABSTRACT:

TECHNICAL FIELD
This invention relates to a process for preparing a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative exhibiting antitumor and antiviral activities.
BACKGROUND ART
1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluorom ethyluracil derivatives (trifluorothymidine derivatives) have attracted attention for many years in terms of their association with nucleic acid bases, uridine and thymidine. In particular, since they exhibit antitumor and antiviral activities, they have been intensely investigated for production as a medical drug or an important intermediate therefor. It is well known in this art that a preparation process considerably depends on the type of a nucleic acid base and that a superior preparation process must be studied for each base.
For example, as described in Nucleic Acid Research 12 6827 (1984) and Nucleosides & Nucleotides 8 549 (1989), a nucleic acid base such as uracil, fluorouracil, thymine and trifluorothymine drastically changes its properties, depending on a substituent on the 5-position. Thus, in its preparation by glycosylation, a process suitable to each reaction must be investigated. In particular, in 5-trifluorouridine, to which this invention is directed, the trifluoromethyl group significantly influences to give the chemical properties of the compound greatly different from unsubstituted uridine or thymidine and reduces a selectivity between &agr;- and &bgr;-forms in glycosylation. It has been, therefore, difficult to establish an industrial process for preparing the &bgr;-form which is practically needed.
Conventional processes for preparing a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative are;
(1) exchanging a nucleic acid base from thymidine and 5-trifluoromethyluracil by, for example, nucleoside-2′-deoxyribose transferase [M. G. Stout, et al., Methods Carbohydr. Res., 7, 19 (1976)];
(2) reacting a halogen atom on the 5-position in a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-halouracyl derivative with trifluoromethyl copper [Y. Kobayashi, et al., J. C. S. Perkin TransI, 2755 (1980)];
(3) electrolysis of an uridine derivative and trifluoroacetic acid [L. Hein, et al., DE 119423 (1976)];
(4) reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine with a methyl 2-deoxy-D-erythro-pentofuranoside derivative in the presence of an acid catalyst [National Publication of the International Patent Application No. 500239-1987];
(5) increasing a molar ratio of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine in its reaction with 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-&agr;-D-erythro-pentofuran osyl chloride or conducting the reaction in the presence of a zinc chloride catalyst [Japanese Patent Laid-Open No. 2-289595; Heterocycles, 31, 569 (1990)].
However, the process described in (1) has a drawback that it is difficult to isolate and purify the desired product from a reaction system. The process, therefore, cannot be suitably applied to large scale synthesis. The process described in (2) has a drawback that a reaction intermediate is quite sensitive to, for example, air. The process described in (3) has a drawback that both yield and current efficiency are low and electric facilities resistant to trifluoroacetic acid are required. The process described in (4) has a drawback that a product is obtained as a mixture of &agr;- and &bgr;-forms which cannot be readily separated so that an isolation yield for the desired &bgr;-form is extremely low.
For the process described in (5), referring to the reaction analysis values described in the literature, one mole of 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-&agr;-D-erythro-pentofuran osyl chloride is treated dropwise with a solution of two moles of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine in chloroform (on the basis of calculation from the values in the literature, an 11.1-fold amount of chloroform to the total amount of 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-&agr;-D-erythro-pentofuran osyl chloride and 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine) to give a selectivity of &bgr;/&agr; form=56/44 while being treated with 8 moles to give a selectivity of &bgr;/&agr; form=74/26.
Zinc chloride may be added instead of increasing a molar ratio of 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine to 3,5-di-O-(p-chlorobenzoyl)-2-deoxy-&agr;-D-erythro-pentofuran osyl chloride to improve a selectivity of &bgr;/&agr; form=about 75/25. The process has an economically and industrially significant drawback that it uses a largely excessive amount of quite expensive 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine and either procedure cannot give a practical &bgr;-selectivity.
Thus, no conventional preparation processes can be suitably applied to stable and low-cost large scale production of a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative important as a medical drug or an intermediate therefor and an improved and useful process has been needed.
DISCLOSURE OF THE INVENTION
An objective of this invention is to solve the above problems in conventional preparation processes and provide a process for preparing a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative with an improved-selectivity by lower-cost and convenient steps.
We have investigated preparation of a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative by reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine with a 2-deoxy-&agr;-D-erythro-pentofuranosyl chloride derivative and have found that in a solvent free system the reaction may proceed with a very high selectivity of &bgr;/&agr; form=96/4. We have also found that a solvent may be added up to a 4-fold mass to the total mass of the reactants for avoiding a tendency to difficulty in stirring due to increased viscosity of the reactants as the reaction proceeds in the solvent free reaction to ensure smooth stirring and good operability and to provide the &bgr;-form of the desired product, the 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative, with an improved selectivity. This invention has been achieved on the basis of these findings.
One aspect of a process for preparing a trifluorothymidine derivative according to this invention comprises the step of reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine represented by formula (1):
as a first material, with a 2-deoxy-&agr;-D-erythro-pentofuranosyl chloride derivative represented by formula (2):
wherein X represents a halogen atom; X
1
and X
2
independently represent a hydrogen atom, methyl group or halogen atom, as a second material in a solvent free system to give a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative represented by formula (3):
Another aspect of a process for preparing a trifluorothymidine derivative according to this invention comprises the step of reacting 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine represented by formula (1):
as a first material, with a 2-deoxy-&agr;-D-erythro-pentofuranosyl chloride derivative represented by formula (2):
wherein X represents a halogen atom; X
1
and X
2
independently represent a hydrogen atom, methyl group or halogen atom, as a second material in the presence of a solvent to give a 1-(2′-deoxy-&bgr;-D-erythro-pentofuranosyl)-5-trifluoromethyl uracil derivative represented by formula (3):
in which the solvent is used in an amount not exceeding a 4-fold mass to the total mass of the first and the second materials.
In the process of the first aspect of this invention, the reaction may be initiated in a solvent free system and then a solvent may be added to the reaction system to conduct the reaction in the presence of the solvent.
According to this invention, since the reaction stoichiometrically proceeds, materials unstable in the air may be used in a needed amount, result

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