Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-03-20
2004-10-05
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S017200, C536S017400, C536S017700, C536S018100, C536S018200, C536S018500
Reexamination Certificate
active
06800742
ABSTRACT:
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims priority to Japanese Patent Application No. 152336/2001, filed May 22, 2001, and which is incorporated herein by reference in its entirely.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for producing certain &bgr;-D-ribofuranose derivatives (one of the structural components of certain nucleic acid compounds) or optical isomers thereof. More specifically, the invention relates to a method for producing &bgr;-D-ribofuranose derivatives represented by the following general formulas (1), (3), and (6) (including the &bgr;-L-ribofuranose derivatives as the optical isomers thereof) from the starting material &bgr;-D-ribofuranose-1,2,3,5-tetraacetate or an optical isomer thereof, and a method for producing a series of these synthetic intermediates.
wherein R
1
represents a hydrogen atom or a substituent and n represents an integer of 1 to 5.
wherein R
1
and n have the same meanings as described above and R
2
represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms.
wherein R
2
has the same meaning as described above, and R
3
represents an alkyl group with 1 to 6 carbon atoms.
2. Discussion of the Background
Compound A, shown below, may be prepared by substituting the hydroxyl group at the 5′ position of the sugar moiety (&bgr;-D-ribofuranose) of a nucleic acid with a carboxylic acid amide as represented by the following formula (A), and has bee n recently reported in the forms of numerous pharmaceutical products of adenosine agonists, as described in U.S. Pat. No. 4,968,697 and the published International Patent Application Nos. WO 9502604, WO 9314102, WO 9518817, WO 9423723, and WO 9417090.
wherein B represents a nucleic acid base such as an adenine derivative; and R
2
represents a hydrogen or an alkyl group with 1 to 6 carbon atoms.
To date, Compound A has been synthetically prepared by the following synthesis scheme: (1) protecting the hydroxyl group at the 2′- and 3′-positions of the &bgr;-D-ribofuranose of a nucleic acid with isopropylidene and the like; (2) oxidizing the hydroxyl group at the 5′-position; (3) amidating the resulting carboxylic acid; and (4) subsequently eliminating the protective groups.
Meanwhile, the present inventors have focused their attention on the possibility that the compound represented by the general formula (A) may be synthetically prepared by coupling the nucleic acid base moiety B with &bgr;-D-ribofuranose derivative represented by the general formula (C), which is a route totally unlike the synthetic process described above. In this synthetic process, the sugar moiety, which is readily eliminated from the nucleic acid under acidic conditions, is introduced at the final stage. Thus, the nucleic acid base moiety can be synthetically prepared, separately, under various reaction conditions and attached to the sugar moiety after it has been prepared. Thus, the process is more convenient for the synthesis of compounds with various modified nucleic acid base moieties than the previous process is.
wherein Ac represents an acetyl group; and B and R
2
individually have the same meanings as described above.
It is suggested that the &bgr;-D-ribofuranose derivative represented by the general formula (C) can be readily prepared synthetically from the carboxylic acid compound with the structure of the general formula (1), by amidating of the carboxylic acid compound into amide compounds (3) and (6) and then triacetylating the amide compounds. Hence, the compounds of the structures of the general formulas (1), (3), and (6) may be important intermediates of pharmaceutical products containing a backbone of the general formula (A). Additionally, the optical isomers of these compounds will also be promising as pharmaceutical intermediates.
The compound of the structure of the general formula (6) has previously been prepared synthetically, as described mainly for compounds with a methoxy group at the 1-position in, for example,
Liebigs Ann. Chem
., 1974, 1856-63, by: (1) methylating the hydroxyl group at the 1-position in the starting material &bgr;-D-ribofuranose; (2) protecting the hydroxyl group at the 2- and 3-positions of the resulting 1-O-methoxy-&bgr;-D-ribofuranose with isopropylidene and the like; and then (3) oxidizing the hydroxyl group at the 5-position. The synthetic route is as follows.
The known process however gives a low total yield from the raw material &bgr;-D-ribofuranose. Because both the &agr; form and &bgr; form are essentially produced in the methylation of the hydroxyl group at the 1-position in &bgr;-D-ribofuranose in the presence of acid catalysts, the reduction of the yield is unavoidable and the purification is difficult. The benzylation of the hydroxyl group at the 1-position in &bgr;-D-ribofuranose also has a yield as low as 38% (see
J. Am. Chem. Soc
., vol. 76, pp. 763-767 (1954)). Accordingly, no reaction has been known for introducing alkoxyl group into the 1-position of the &bgr;-D-ribofuranose backbone at a high yield and in a highly &bgr;-selective manner.
Additionally, the oxidation of a compound prepared by substituting the hydroxyl group at the 2- and 3-positions in 1-O-methoxy-&bgr;-D-ribofuranose with isopropylidene is essential for the synthesis of a carboxylic acid compound of the structure of the general formula (3). For the compound with a methoxy group at 1-position, oxidation using potassium permanganate (
Liebigs Ann. Chem
., 1974, 1856-63) and oxidation using 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) (WO 9828319) have been known. However, in these oxidations, the raw materials are so syrupy that the raw materials are purified with much difficulty. The oxidations have been problematic in terms of high reproducibility, since many examples have been known of the blocking of the progress of the oxidation reactions in the presence of even a trace amount of impurities.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide novel methods for producing the compounds of the general formulas (1), (3), and (6) or optical isomers thereof in high yields.
It is another object of the present invention to provide novel methods for producing a series of intermediates, which are useful for producing the compounds of the general formulas (1), (3), and (6) or optical isomers thereof, in high yields.
These and other objects, which will become apparent during the course of the following detailed description, have been achieved by the inventors' surprising discovery that 1-O-benzyl-&bgr;-D-ribofuranose-2,3,5-triacetate can be produced with high efficiency, by preliminarily acetylating the hydroxyl groups at the 1-, 2-, 3, and 5-positions of &bgr;-D-ribofuranose to afford &bgr;-D-ribofuranose-1,2,3,5-tetracetate, and then allowing the resulting tetraacetate form to react with a benzyl alcohol in the presence of an acid to benzylate the 1-position of the ribofuranose backbone in high yield and in a highly &bgr;-selective manner. Additionally, the inventors have found a method for synthetically preparing 1-O-benzyl-&bgr;-D-ribofuranose in high yield by subsequently hydrolyzing the resulting benzyl compound.
The inventors have also found that, because not only 1-O-benzyl-&bgr;-D-ribofuranose but also a compound prepared by protecting the hydroxyl groups at the 2- and 3-positions in the ribofuranose with isopropylidene group can be recovered as crystals, the purification thereof can be readily achieved, and that the control of the TEMPO oxidation of the raw material 1-O-benzyl-2,3-isopropylidene-&bgr;-D-ribofuranose detectable via ultraviolet absorption by HPLC analysis can be carried out readily and the reaction progresses at a high yield.
Based on these two key reactions, the inventors have successfully synthetically prepared the compounds represented by the general formulas (1), (3), and (6) from the raw material &bgr;-D-ribofuranose-1,2,3,5-tetraacetate in high yields. Thus, the invention has been achieved. The present methods can b
Izawa Kunisuke
Koguchi Yoshihito
Torii Takayoshi
Ajinomoto Co. Inc.
McIntosh III Traviss C.
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