&agr;-D-pentofuranosides, and a process for preparing the same

Details &agr;-D-pentofuranosides, and a process for preparing the same &agr;-D-pentofuranosides, and a process for preparing the same

1997-04-18

2001-05-08

Tsang, Cecilia (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S122000, C536S124000

Reexamination Certificate

active

06229008

ABSTRACT:

The anti-viral and anti-carcinogenic action of many nucleosides, which are used as pharmaceutical products, is of extremely great interest in medical circles. In recent years, fluorine-containing nucleosides in particular have become increasingly important. Compared with hydroxyl groups, fluorine atoms bond strongly to carbon atoms; they are for the most part chemically inert and have hydrophobic properties. On the other hand, the size of their atoms is similar to the size of hydroxyl groups. If, therefore, hydroxyl groups of a nucleoside are substituted by fluorine atoms, one can expect to obtain an excellent metabolic-antagonistic effect.
Many fluorine-containing nucleosides have already been studied to determine their anti-viral properties and their cytotoxicity. The unusual properties of pyrimidine nucleosides having the formula (T0) defined later herein, and of purine derivatives having the formula (U0), suggest that these substances can be used as therapeutic agents to treat viral, and in particular retroviral infections, such as AIDS, etc.
It is, however, a difficult matter to prepare these target substances. Conventional methods of preparation on a laboratory scale are technically complex, operate with toxic chemicals, and provide low overall yields, which in particular for reasons of costs cannot be improved upon.
A . . . OH, NH
2
, OR′, NR′
2
R′ in A,
B, C, D denotes the usual substituents
B . . . H, CH
2
, CH═CHBr, halogen
C . . . H, NH
2
, Cl, OR′, S′, NHR′, NR′
2
, OX
+
D . . . H, halogen, NH
2
, NR′
2
, N
3
In principle, two modifications must be carried out on the carbohydrate part of the nucleoside: the deoxygenation of the 3-position, as well as the introduction of fluorine into the 2-position.
To perform these modifications of the functionality on the natural nucleoside is a difficult and protracted procedure. For example, Shiragami et al., J. Carbohydrates, Nucleosides & Nucleotides, 11 (2-4), 391-400 (1982) at first produce cordycepin by regioselective bromination, followed by hydrogenolysis, and the cordycepin is then converted by fluorination with diethylaminosulphur trifluoride (DAST fluorination), with a low yield, into 9-(2,3-dideoxy-2-fluoro-&bgr;-D-threo-pentofuranosyl-adenine (2-Fdda). Therefore, in most of the synthesis strategies used so far, first the fluorinated nucleoside was prepared, starting from 2-deoxy-2-fluoro-arabinofuranose derivatives and then the 3-position was deoxygenated. However, the Barton deoxygenation process used, or modifications thereof, cannot be considered as a sensible production strategy for the reasons just given (Marquez et al., J.Med.Chem., (1990), 33, 978-985; Vemishetti et al., EP 428.109; Barchi et al., J.Med.Chem., (1991), 34, 1647-1655; Machin et al., EP 292.023).
It therefore appeared advisable to carry out both manipulations of the carbohydrate part before the nucleoside synthesis.
In EP 463.470, Okabe et al. accordingly propose a complicated, low-yield, 11-stage synthesis of 2,3-dideoxy-2-fluoro-5-0-trityl-&agr;-D-threopentofuranosyl chloride, see formula (C), as the precursor stage of the nucleoside.
An intermediate stage used in this process is obtained by Siddiqui et al., Tetr. Lett. (1994), 35, 3263-3266 from diacetone mannitol.
The hitherto most interesting method of preparing the modified carbohydrate part appears in WO 92/01700. Here, 2 Fdda is produced in a 9-stage synthesis starting from 1,3,5, tri-O-benzoyl-2-deoxy-2-fluoro-&agr;-D-arabinofuranose. However, for synthesizing the decisive intermediate product, 5-0-benzoyl-2,3-dideoxy-2-fluoro-&agr;-D-threopentofuranosyl bromide (see formula (Z)), it is also necessary to use the Barton deoxygenation method.
A new, efficient way has been found of producing a similar but, when used, superior intermediate product:
In particular, the present invention relates to an astonishingly short and efficient method of synthesizing an &agr;-furanoside having the general formula (D), described in detail later herein, in which the 5-position is protected by an ethereal protective group. This furanoside can easily be converted into a halogenose having the general formula (Z), which is dealt with in detail later herein, in which the 5-position is protected by an ethereal protective group.
Among other things, the subject of the invention is the important compound (D1) according to claim
2
, which is also defined further below. It should be mentioned here that two, at first sight similar, compounds—methyl-5-0-benzoyl-2,3-dideoxy-2-fluoro-&agr;-D-threopentofuranoside and methyl-5-0-(tertbutyl-diphenylsilyl)-2,3-dideoxy-2-fluoro-&bgr;-D-threopentofuranoside—were synthesized according to WO 92/01700 as the starting material for a halogenose having the general formula (Z); the compounds (D0), which will also be defined in more detail below, and in particular the important compounds (D1), are far superior to the aforementioned compounds, not only because of their stability in the course of the subsequent reactions, but also because of their better handling characteristics in the necessary purification operations (through suitable substitution, it is possible in each case to emphasize specifically desired properties). While the first-mentioned compound known from WO 92/01700 differs entirely from the new compounds (D0) and (D1) because of its own protective group, which is not of the ether but of the ester type, the second of the above-mentioned compounds also possesses a serious disadvantage because of its &bgr;-position of the aglycone and because of the protective group, which contains in particular Si; protective groups of the type R
0
1
, R
1
1
, according to claims
1
,
2
of this invention are significantly superior to the silicon protective groups as regards stability in the subsequent reactions.
These new, important compounds having the general formula (D) are obtained in the present invention by fluorination from alkyl-5-0-R
1
-3-deoxy-&agr;-D-xylofuranoside (a compound described later on and having the general formula (E)). According to Su et al. (JOC, (1981), 46, 1790-1792) fluorination of the corresponding &bgr;-material did not appear to be promising.
Methyl-5-0-benzoyl-3-deoxy-&agr;-D-xylofuranoside (Jones et al., Tetr.Lett. (1991), 32, 247-250; Nair et al., JACS (1992), 114, 7951-7953) and methyl-3-deoxy-3-deutero-5-0-(4-methoxytrityl)-&agr;-D-xylofuranoside (Pathak et al., Tetr.Lett. (1986), 42-5427-5441) have already been described as by-products in each case.
The present invention relates to a group of closely related pentofuranoside derivates which can easily be converted into each other, and which are important intermediate stages along the path to synthesizing the key compound referred to above; the invention also describes in detail advantageous methods of producing the said compounds and also the use of these compounds.
The following general diagram 1 provides an overview—by no means complete—of the possible range of conversions, starting from the key compound (D) or (D
0
) or (D
1
) and leading to various valuable pharmaceutical active substances.
Diagram 1:
The following compounds are the subjects of the invention and together they form a unified group.
In detail, these compounds are the compounds (D0) according to claim
1
.
Within the framework of the invention, compound (D1) according to claim
2
is in particular preferred. This is an important, central starting product for the uncomplicated, direct conversion into the protected nucleosides having the formula T and U. The essential advantage of these compounds (D1) is that, as was discovered, following suitable substitution of the ethereal protective group at the 5-position, it is possible to achieve high stability of the protective group, which is advantageous to the process, and much easier cleavage of the protective group; also, because the physical properties are modified by the substitution, by-products can be separated out in a technically advantageous manner in the individual stages of the process.
Compound (F) according to clai

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