| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 05.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 23.05.00 |
| PATENT TITLE |
4-ethoxy-pyrimidines |
| PATENT ABSTRACT |
4-Ethoxy-pyrimidines useful as intermediates in preparing antiviral 1,3-oxathiolane nucleosides are described. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 28.06.99 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | Jung, M.E. et al New Approach to the Synthesis of .beta.-deoxyribonucleosides: Intramolecular Vorgruggen Coupling, Journal of Organic Chemistry, vol. 58, pp. 807-808, 1993. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of formula (IV) ##STR11## wherein R (which may be the same or different) is hydrogen, C.sub.1-6 alkyl, or halogen, and Y is hydroxy, amino, C.sub.1-6 alkoxy, or OR.sup.1 where R.sup.1 is a chiral auxiliary, which compound is selected from 2-(2,2-dimethoxyethoxy)-4-ethoxy-5-fluoropyrimidine and 2-(2,2-dimethoxyethoxy)-4-ethoxy-pyrimidine. 2. A compound of formula (III) ##STR12## as defined in claim 1, which compound is selected from 2-[(4-ethoxy-5-fluoro-2-pyrimidinyl)oxy]acetaldehyde and 2-[(4-ethoxy-2-pyrimidinyl)oxy]acetaldehyde. |
| PATENT DESCRIPTION |
The present invention is concerned with a process for the preparation of anti-viral 1,3-oxathiolane nucleosides, which employs an intramolecular glycosylation to produce exclusively the .beta.-diastereomer. The invention also relates to novel intermediates obtained by the process. 1,3-Oxathiolane nucleosides possess two chiral centres (at the C1'- and C4'-positions according to the furanose numbering system) and typically exist as diastereomeric pairs of the .alpha.- and .beta.-forms, each form comprising two enantiomers. The .alpha.- and .beta.-diastereoisomers tend to have different anti-viral activities, the .beta.-form typically being the more potent. Similarly, the enantiomeric pairs of each diastereomer tend to have different properties. .beta.-Diastereomers have traditionally been obtained by preparation of the diastereomeric mixture followed by laborious separation of the .beta.-form by physical means such as differential solubility or chromatography. It follows that the overall yield of .beta.-isomer is typically less than 50%. International Patent Application No. (U.S. Pat. No. 5,204,466) describes a process whereby 1,3-oxathiolane nucleosides may be obtained with high .beta.-diastereoselectivity by condensing a carbohydrate or carbohydrate-like moiety with a heterocyclic base in the presence of a specific Lewis acid, typically stannic chloride. The process is further exemplified in International Patent Application No. (U.S. Pat. No. 5,756,706). Further diastereoselective processes for the preparation of nucleoside analogues involving condensation of a carbohydrate or like moiety with a purine or pyrimidine base are described in W095/29174. We have now developed an efficient new process which provides exclusively the .beta.-diastereomer of a 1,3-oxathiolane pyrimidine nucleoside with no .alpha.-contamination. The critical steps involved in the synthesis are cyclisation of an appropriate heterocyclic acetaldehyde with 1,4-dithiane-2,5-diol to give a "5'-tethered" 1,3-oxathiolane nucleoside analogue which then undergoes an intramolecular glycosylation on the same face of the carbohydrate ring to give exclusively the (1'-tethered) .beta.-diastereomer. The intramolecular glycosylation of 5'-tethered furanose nucleosides is known from, inter alia, Japanese Patent No. 06263792-A, but the prior art comprises no reports of applying such methodology to the preparation of anti-viral 1,3-oxathiolane nucleosides. The resulting .beta.-diastereomer may be hydrolysed to the corresponding cytidine analogue or may be resolved by any suitable technique known to a skilled person, for example, by esterification followed by selective enzymatic hydrolysis, removal of the `unwanted` enantiomer and hydrolysis of the ester of desired enantiomeric configuration. Alternatively, it may be possible, for example, by use of a chiral auxiliary, to obtain intermediates substantially enantiomerically pure which intermediates can be carried forward to yield the desired enantiomerically pure product. According to one aspect of the present invention, there is provided a process for the preparation of compounds of formula (I) ##STR1## wherein R is hydrogen, C.sub.1-6 alkyl, or halogen and Y is hydroxy, amino, C.sub.1-6 alkoxy or OR.sup.1, where R.sup.1 is a chiral auxiliary, which process comprises treating a compound of formula (II) ##STR2## wherein R and Y are as hereinbefore defined and R.sup.2 represents hydrogen, C.sub.1-6 acyl, C.sub.1-6 alkyl or halogen with a suitable Lewis acid or a reagent apt to convert the group OR.sup.2 to a leaving group. Suitable Lewis acids include, for example, stannic chloride or trimethylsilyl triflate. Reaction with a Lewis acid is suitably conducted at reduced temperature (e.g. 0.degree. C. to -20.degree. C.) in a polar aprotic solvent followed by treatment with base. Where R.sup.2 is H, the group OR.sup.2 may conveniently be converted to a leaving group by reaction with a halogenating agent such as a thionyl halide or an oxalyl halide, or a tosyl or mesyl halide. Other methods for converting OR.sup.2 to a leaving group (i.e. a group which can be readily displaced by the ring nitrogen atom) will be apparent to those skilled in the art. It is to be understood that where the variable R occurs more than once in a general formula, it may represent the same group at each position, or different groups. As used herein halogen means bromine, chlorine, fluorine or iodine, especially chlorine or fluorine, more especially fluorine. The term "chiral auxiliary" describes an asymmetric molecule that is used to effect the chemical resolution of a racemic mixture. Such chiral auxilliaries may possess one chiral centre such as .alpha.-methylbenzylamine or several chiral centres such as menthol. The purpose of the chiral auxiliary, once built into the starting material, is to allow simple separation of the resulting diastereomeric mixture. See, for example, J Jacques et al., Enantiomers, Racemates and Resolutions, pp. 251-369, John Wiley & Sons, New York (1981). Where R.sup.1 represents a chiral auxiliary it will preferably be selected from (d)-menthyl, (I)-menthyl, (d)-8-phenylmenthyl, (I)-8-phenylmenthyl, (+)-norephedrine and (-)-norephedrine. More preferably R.sup.1 is (I)-menthyl, or (d)-menthyl, most preferably (I)-menthyl. According to a further aspect, the present invention provides a process for the preparation of a compound of formula (Ia) ##STR3## wherein R and Y are as previously defined, which process comprises treating a compound of formula (IIa) ##STR4## wherein R, Y and R.sup.2 are as previously defined with a suitable Lewis acid or a reagent apt to convert the group OR.sup.2 to a leaving group. According to another aspect of the invention, there is provided a process for the preparation of compounds of formula (II) which comprises reacting a compound of formula (III) ##STR5## wherein R and Y are as hereinbefore defined, with 1,4-dithiane-2,5-diol at elevated temperature (e.g. 100.degree. C.) in a non-polar aprotic solvent to give a compound of formula (II) wherein R.sup.2 is H. Compounds of formula (II) wherein R.sup.2 is other than H may be prepared from the corresponding hydroxy compound by derivatisation using any standard procedure, for example, treatment with alkanoyl halide/base or carboxylic anhydride/base. Reaction of a compound of formula (III) with 1,4-dithiane-2,5-diol results in a mixture of isomers of the compounds of formula (II) wherein R.sup.2 is H. Where Y is OR.sup.1, the compounds of formula (IIa) may be selectively crystalized from the diastereomeric mixture. In a further or alternative aspect, the present invention accordingly provides a method for obtaining the compound of formula (IIa) wherein R is H and Y is OR.sup.1 from a mixture of isomers by treatment of the mixture of isomers, at least partially in solution, with an agent capable of effecting interconversion of the isomers without complete suppression of the crystallisation of the desired single enantiomer (IIa) wherein R is H and Y is OR.sup.1. Other compounds of formula (IIa) may be prepared from compounds of formula (IIa) wherein R is H and Y is OR.sup.1 by conventional methods. Agents capable of effecting interconversion of the isomers without complete suppression of the crystallisation of the trans isomers include, for example, alcohols, such as, for example, methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, t-butanol, and organic bases, in particular tertiary amines, for example, pyridine and triethylamine and Hunig's base. A preferred agent is triethylamine. The interconversion of isomers may be effected in any suitable solvent or mixture of solvents which does not otherwise react with the alcohols of formula (II), under conditions of concentration and temperature which permit crystallisation of the desired isomer or isomers and which do not cause significant degradation of the desired isomer or isomers. Suitable solvents may include for example, aliphatic or aromatic hydrocarbons, ethers, esters and chlorinated hydrocarbons. The interconversion will preferably be effected at a temperature of about -20.degree. to 120.degree. C., more preferably in the range of about -10.degree. to 80.degree. C., such as about 0.degree. to 50.degree. C. It will be appreciated by those skilled in the art that selection of solvent, temperature, interconversion agent and, particularly, the quantity of the interconversion agent is best conducted as an integrated exercise dependent on the nature of the groups R, R.sup.1 and R.sup.2 present in the isomers. However, when an organic base is used as the interconversion agent, the preferred quantity is generally less than two mole-equivalents based on the total of all isomers of (II) present. The interconversion of isomers may be conducted separately from the preparation of the isomeric mixture; however, it is conveniently conducted concomitantly with that preparation. The interconversion procedure may also be used to increase the isomeric purity of isolated (IIa). By means of the interconversion process, the isolated yield of the desired isomer (IIa) may be enhanced to greater than 50% of theory (based on formation of all stereoisomers), typically to between about 60% and about 90% of theory; but it is not ruled out that yields approaching 100% of theory may be obtained. Compounds of formula (III) may be prepared by reacting a compound of formula (IV) ##STR6## wherein R (which may be the same or different) and Y are as hereinbefore defined, with aqueous trifluoroacetic acid (90%) at elevated temperature. Compounds of formula (IV) may be prepared by reacting a compound of formula (V) ##STR7## wherein R and Y are as hereinbefore defined and Z is a suitable leaving group, for example, chlorine, with a compound of formula (VI) ##STR8## wherein R (which may be the same or different) are as hereinbefore defined, at reduced temperature in a polar aprotic solvent in the presence of base. Compounds of formula (V) may be prepared by reacting a compound of formula (VII) ##STR9## wherein R and Z (which may be the same or different) are as hereinbefore defined, with a suitable nucleophile, for example, in the case where Y in the compound of formula (V) is to be ethoxy, EtO.sup.- (NaOEt/EtOH). Compounds of formulae (VI) and (VII) may be obtained commercially or prepared from commercially available starting materials by methods known to a skilled person, for example, in the case where R in the compound of formula (VII) is to be fluorine and Z chlorine, by treating 5-fluorouracil with phosphorus oxychloride at elevated temperature in the presence of base. As indicated, compounds of formula (I) wherein Y at the C4-position is C.sub.1-6 alkoxy or OR.sup.1 may be converted to a cytidine analogue (Y.dbd.NH.sub.2) by heating with ammoniacal methanol or, where racemic, may be resolved by any suitable technique known to a skilled person, for example, by one of the enzyme procedures described in International Patent No. WO92/14743. According to such a procedure, the racemic .beta.-diastereomer (I) is esterified at the C5'-position using, for example, butyric anhydride, and the racemic ester (VIII) is treated with a suitable enzyme, typically pig liver esterase, to preferentially hydrolyse the `unwanted` enantiomer back to the 5'-OH compound (IX) which is water-soluble and can be separated from the desired (unhydrolysed) enantiomer (X). The latter is converted to the 4-NH.sub.2, 5'-OH compound of desired enantiomeric configuration by heating with ammoniacal methanol. ##STR10## The process of the invention finds particular application in the preparation of (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, (2R,5S)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, (.+-.)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5yl]-cytosine and (.+-.)-cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine. According to a further aspect of the invention, there are provided novel compounds of formulae (IV), (III), (II) and (I) (which latter includes the racemate, the (2S,5R)-enantiomer (IX), the esterified racemate (VIII) and the esterified (2R,5S)-enantiomer (X)). Specific intermediate compounds arising from the preparation of (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, (2R,5S)-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, (.+-.)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine and (.+-.)-cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine include: 2-(2,2-Dimethoxyethoxy)-4-ethoxy-5-fluoropyrimidine 2-(2,2-Dimethoxyethoxy)-4-ethoxypyrimidine 2-[(4-Ethoxy-5-fluoro-2-pyrimidinyl)oxy]acetaldehyde 2-[(4-Ethoxy-2-pyrimidinyl)oxy]acetaldehyde 2-{[(4-Ethoxy-5-fluoro-2-pyrimidinyl)oxy]methyl}-1,3-oxathiolan-5-ol 2-{[(4-Ethoxy-2-pyrimidinyl)oxy]methyl}-1,3-oxathiolan-5-ol 2-{[(4-Ethoxy-5-fluro-2-pyrimidinyl)oxy]methyl}-1,3-oxathiolan-5-yl acetate 2-{[(4-Ethoxy-2-pyrimidinyl)oxy]methyl}-1,3-oxathiolan-5-yl acetate (2S*,5R*)-4-Ethoxy-5-fluoro 1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one (2S*,5R*)-4-Ethoxy-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one (2S*,5R*)-4-Ethoxy-5-fluoro-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]py rimidin-2-one (2S*,5R*)-4-Ethoxy-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2 -one (2S,5R)-4-Ethoxy-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidi n-2-one (2S,5R)-4-Ethoxy-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one (2R,5S)-4-Ethoxy-5-fluoro-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]pyri midin-2-one (2R,5S)-4-Ethoxy-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-o ne The following examples of the process of the invention are for illustration only and are not intended to limit the scope of the invention in any way. In all cases, .sup.1 H NMR and C,H,N elemental analysis were consistent with the proposed structure. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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