Process to prepare pyrimidine nucleosides

Details Process to prepare pyrimidine nucleosides Process to prepare pyrimidine nucleosides

2000-07-18

2003-07-22

Richter, Johann (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S055300, C536S027110

Reexamination Certificate

active

06596859

ABSTRACT:

BACKGROUND AND BRIEF SUMMARY OF THE INVENTION
Pyrimidine nucleosides are important antiviral agents, increased attention has recently been focused on these compounds with the FDA approval of 3′-azido-2′,3′-dideoxythymidine (AZT) stavudine (D
4
T) as an effective treatment for Acquired Immunodeficiency Syndrome (AIDS). Since the synthesis of such agents utilizes the pyrimidine nucleoside &bgr;-thymidine as a starting material, new methods for the low-cost production of this and other synthetic intermediates are also becoming important. The present invention involves an expeditious route to the O
2
,2′-anhyro-l-(&bgr;-arabinofuranosyl) 5-hydroxy 5,6 dihydro pyrimidine nucleosides, a class of compounds easily converted to the &bgr;-pyrimidine derivatives. Analogous syntheses of these anhydronucleosides is described in the following publications.
Japanese Kokai No. 81 49 398 laid open on May 2, 1981 refers to the synthesis of acylated arabinofuranosylcyclothymine compounds. The process of the Japanese Kokai requires that the imincarabino(1 2:4.5) oxazoline acid addition salt be acylated.
In an article appearing in J. Mo. Biol., 1970, 47, 537 the authors describe the use of a readily available amino-oxazoline carbohydrate derivative as a useful precursor to a variety of anhydronucleosides.
In the reference Kampe, K. D.; Justus Leibigs AnnChem., 1974, (4), 593-607 (ger), reactions of aminooxazolines with unsaturated esters are disclosed. European patent application 0 351 126 discloses a process for the formation of O
2
,2′-anhydro-l-(&bgr;-D-arabinofuranosyl) thymine by reacting 2-amino-&bgr;-D-atabinofurano-oxazoline(s) with an alkyl 3-halo or alkoxy-methacrylate derivative.
In U.S. Pat. No. 5,077,403 is disclosed a process which starts with acrylates or acrylonitriles and related derivatives; compounds that are at a lower oxidation state than other substrates previously used for similar condensations. This results in the formation of 5,6-dihydro pyrimidine nucleoside derivatives which are then oxidized to the required nucleosides in high to excellent yields.
Since the issuance of the ′403 patent, the following articles have been published.
Pragnacharyulu, Palle V. P.; Vargeese, Chandra; McGregor, Michael; Abushanab, Elie,
Diastereomeric
5,-6
Dihydrothymidines. Preparation, Stereochemical Assignments, and MnO
2
Oxidation Studies to Thymidines
, Journal of Organic Chemistry, pp. 3096-3099, 60, 1995;
Rao, A. V. Rama; Gurjar, Mukund K.; Lalitha, Sista V. S.,
Discovery of a Novel Route to &bgr;
-
Thymidine: a Precursor for anti
-
AIDS Compounds
, J. Chem. Soc., Chem. Commun., pp. 1255-1256, 1994;
Barvian, Mark R.; Greenberg, Marc M.,
Diastereoselective Synthesis of Hydroxylated Dihydrothymidines Resulting from Oxidative Street
, J. Org. Chem., 58, 6151-6154, 1993;
Sawai, Hiroaki; Nakamura, Akiko; Sekiguchi, Sumie; Yomoto, Keisuke; Endoh, Masakazu; Ozaki, Hiroaki;
Efficient Synthesis of New
5 -
Substituted Uracil Nucleosides Useful for Linker Arm Incorporation
, J. Chem. Soc., Chem. Commun., pp. 1997-1998, 1994; and
Sawai, Hiroaki; Hayashi, Hidekazu; Sekiguchi, Sumie,
Facile Synthesis of
5
-Substituted Arabinofuranosluracil Derivatives
, Chemistry Letters, pp. 605-606, 1994.
Broadly, the present invention is directed to a process for the production of pyrimidine nucleoside compounds of the formula:
wherein R
1
is hydrogen, alkyl C
1
-C
16
substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyano, carboxy, carboxy esters, carboxamido, N-mono substituted and N,N-disubstituted carboxamido with alkyl, aralkyl and aryl groups; R
2
is hydrogen, alkyl C
1
-C
16
substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl; R
3
is alkyl C
2
-C
6
, branched alkyl, aryl C
2
-C
6
, substituted aryl and R
4
is halogen or H.
A Michael type condensation reaction is effected on a compound of the formula:
with a compound of the formula:
to form a novel compound of the formula:
Compound (
2
) is acylated with a compound of the formula:
R,COCl
to form novel compounds (
3
) and (
6
) depending upon the duration of the reaction.
In the preferred embodiment, compound (
3
) is mixed with pyridine and is reacted with thionyl chloride to form compound (
4
) where R
4
=Cl.
Compound (
4
) is dihalogenated to form compound (
5
).
Compound (
5
) can be hydrolyzed by any well known process to form thymidine.
In an alternative embodiment of the invention, compound (
6
) is mixed with pyridine and is reacted with alkyl or aryl sulfonyl halide to form a novel compound of the formula (
7
).
Compound (
7
) is then mixed with pyridine and thionyl chloride to form a compound of the formula (
8
).
where R
6
is alkyl C
2
-C
6
, branched alkyl, aryl C
2
-C
6
substituted aryl
Compound (
8
) can be converted to either AZT or d
4
t as described in the chemical literature, B. C. Chen. et al., Tetrahedron letters 36, 7957-7960 (1995); B. C. Chen. et al., Tetrahedron letters 36, 7961-7964 (1995).
The present disclosure embodies several inventive embodiments. One embodiment of the invention is a process for the production of compounds (
4
) and (
5
); another embodiment of the invention comprises the compound (
2
) and the method for the production of compound (
2
); another embodiment comprises compound (
3
) and the method for the production of compound (
3
) and the conversion of compound (
3
) into 5 hydroxy 5,6 dihydro pyrimidines, e.g. AZT, d
4
t; another embodiment comprises novel compounds (
6
) and (
7
) and the processes for the production of compounds (
6
) and (
7
); and lastly, another embodiment of the invention comprises a process for the production of compound (
8
).


REFERENCES:
Pragnacharulu et al. J. Org. Chem., vol. 60, pp. 3096-3099, 1995.*
Barvian et al. J. Org. Chem. vol. 58, pp. 6151-6154, 1993.*
Rao et al. J. Chem. Soc. Commun., pp. 1255,1256, 1994.*
Sawai et al., Chem. Lett. , pp. 605-606, 1994.*
Sawai et al., J. Chem. Soc. Chem. Commun., pp. 1997-1998, 1994.

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