Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-12-08
2001-01-23
Kight, John (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S457000, C514S460000, C549S362000, C549S416000, C549S417000
Reexamination Certificate
active
06177457
ABSTRACT:
The present invention relates to a process for the preparation of an antifungal agent and to novel intermediates for use in the synthesis.
The compound of formula (I), pharmaceutically acceptable salts and metabolically labile esters thereof exhibit a particularly desirable spectrum of antifungal activity.
The present invention provides a process for the preparation of compound (I) which comprises cyclisation of a compound of formula (II) wherein L is a group capable of homolytic cleavage e.g. halogen such as bromine and R is hydrogen or a carboxyl protecting group,
followed where desired or necessary by one or more of the following steps;
(i) removal of the carboxyl protecting group R;
(ii) isolation of the compound of formula (I) in the form of a a physiologically acceptable salt thereof;
(iii) conversion of the resultant compound of formula (I) into a metabolically labile ester thereof.
The cyclisation reaction is conveniently carried out using a radical chain carrier in the presence of a radical initiator. Suitable radical chain carriers for use in the reaction include tin radicals and a convenient source of such radicals are the trialkyltin hydrides for example tributyltin hydride. Suitable radical initiators include azoisobutyronitrile. Desirably the reaction is carried out in an aprotic solvent and with heating e.g. 80°-150°. Suitable aprotic solvents include hydrocarbons (e.g. octane) and aromatic hydrocarbons (e.g. toluene).
Conveniently the cyclisation reaction is carried out using a compound of formula (II) wherein L is a bromine atom.
In a preferred embodiment of the invention the cyclisation reaction is carried out using a compound of formula (II) wherein R is a carboxyl protecting group. Suitable carboxyl protecting groups include acid or base labile ester groups such as substituted methyl esters e.g. pivaloyloxymethyl, or trimethylsilylethyloxymethyl.
The carboxyl protecting groups may be removed by conventional procedures well known to those skilled in the art. For example pivaloyloxymethyl may be cleaved by reaction with a suitable base such as an alkali metal alkoxide e.g. sodium methoxide in a suitable solvent such as an alcohol e.g. methanol.
The trimethylsilylethyloxymethyl ester may be cleaved by reaction with fluoride ions e.g. tetrabutylammonium fluoride in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts. Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
Salts of compounds of formula (I) may be conveniently formed by treating a compound of formula (I) with an appropriate salt or base. Thus, for example, salts may conveniently be prepared by treating a compound of formula (I) with a salt or a base selected from sodium or potassium hydroxide, hydrogen carbonate, carbonate or acetate (e.g. potassium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate or potassium acetate), ammonium acetate, calcium acetate or an organic amine e.g. L-lysine as appropriate. The salt may, for example, be prepared by adding the appropriate salt or base (if necessary as an aqueous solution) to a solution or suspension of the compound of formula (I) in a suitable solvent such as an alcohol (e.g. methanol) or dioxane at temperatures of for example 0° C. to 80° C. and conveniently at about room temperature.
Pharmaceutically acceptable salts may also be prepared from other salts including other pharmaceutically acceptable salts of the compounds of formula (I), using conventional methods.
The compound of formula (II) may be prepared by alkylation of the corresponding alcohol (III);
by reaction with the compound (IV);
L
1
CH
2
C(L)═CH
2
(IV)
wherein L
1
is a leaving group such as a halogen e.g. bromine or iodine or an ester e.g. mesylate or tosylate and L has the meanings defined above.
The reaction is carried out in the presence of a base such as aqueous sodium hydroxide and conveniently in a water immiscible organic solvent such as dichloromethane and in the presence of a phase transfer catalyst e.g. cetyltrimethylammonium bromide.
For this reaction it is desirable that any carboxyl protecting group is not a base labile protecting group. A particularly suitable carboxyl protecting group for use in the reaction is the trimethylsilylethyloxymethyl ester.
In an alternative process the compound of formula (II) may be prepared by carrying out an elimination reaction on the diol ( V) or the stereoisomer (VI) thereof;
wherein L and R have the meanings defined above.
Thus in one embodiment of the process the diol (V) may be converted into compound (II) by reaction with phenyl chlorothionoformate in the presence of a base e.g. a tertiary organic base such as triethylamine and 4-dimethylaminopyridine and then treating the resultant di-phenoxythiocarbonate with a source of hydride radicals such as a trialkyltin hydride e.g. tributyltin hydride.
The reaction with phenyl chlorothionoformate is conveniently carried out in an aprotic solvent such as a halohydrocarbon e.g. dichloromethane. The reaction of the resultant dithionocarbonate with the trialkyltin hydride is conveniently carried out in an aromatic hydrocarbon such as toluene and with heating e.g. at reflux.
It will be appreciated if the reaction with the trialkyltin hydride is carried out in the presence of a radical initiator such as azoisobutyronitrile then the compound of formula (II) thus formed will be converted directly into a compound of formula (I). Thus the invention also provides a process for the preparation of a compound of formula (I) which comprises reacting the dithionocarbonate derivative of the diol(V) with a trialkyltin hydride in the presence of a radical initiator; followed where necessary or desired by removal of the carboxyl protecting group.
The diol (VI) may be converted into the required compound (II) by reaction with phenyl chlorothionoformate in the presence of dibutyltin oxide and in a solvent such as toluene, or by reaction with thiocarbonyl diimidazole and treatment of the resulting cyclic thionocarbonate with a trialkylphosphite for example trimethylphosphite.
Alternatively the diol (Vl) may be treated with iodine or triiodoimidazole or iodoform and imidazole in the presence of triphenylphosphine. The reaction is conveniently carried out in an aprotic solvent such as a hydrocarbon e.g. toluene and with heating e.g. at reflux.
The diol (V) may be prepared by alkylation of the triol (VII) wherein R is as defined in formula (II) by reaction with a compound of formula (IV).
The reaction is carried out in the presence of dibutyltin oxide or dibutyltin dimethoxide and in a solvent such as toluene. Conveniently the reaction is also carried out in the presence of fluoride ions.
The triol of formula (VII) wherein R is a carboxyl protecting group may be prepared by esterifying the corresponding compound of formula (VII) wherein R is hydrogen using conventional procedures for preparing such protected carboxylic acid derivatives. Thus compounds wherein R is a substituted methyl group may be prepared by reaction with the corresponding substituted methyl halide e.g. chloride, or bromide in the presence of a base such as a tertiary organic amine such as trialkylamine, or an alkali metal hydroxide, carbonate or bicarbonate.
The diol of formula (VI) may be prepared by reaction of compound (VIII) wherein R is as defined in formula (II)
with the compound (IV) using the alkylation conditions described above for the preparation of compound (II) from compound (III) followed by treatment with hydrochloric acid to remove the acetonide protecting
Bueno Calderon Jose Maria
Chicharro Gonzalo Jesus
Huss Sophie
Roman Jose Fiandor
Rudd Brian Arthur Michael
Covington Raymond
Glaxo Wellcome S.A.
Kight John
Nixon & Vanderhye
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