GB2206577A - New process for the preparation of therapeutically useful pristinamycin IIB sulphone derivatives - Google Patents

Abstract

Pristinamycin IIB sulphone derivatives are prepared by oxidation of the corresponding sulphides with hydrogen peroxide in the presence of an alkali metal tungstate.

Description

"NEW PROCESS" The --esert' invention relates to a new process for the preparation of therapeutically useful pristinamycin 11B sulphate dbrivatives.

European Patent Publication No. 191652 describes therapeutically useful pristinamycin 11B derivatives, of the general formula (I) hereinafter dep.icted, and their acid addition salts, in which R denotes: either a nitrogen-containing 4 to 7-membered heterocyclic ring radical, which may contain 1 or more other hetero atoms chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl; or alkyl of 2 to 4 carbon atoms substituted by 1 or 2 radicals chosen from phenyl, cycloalkylamino of 3 to 6 ring atoms, N-alkyl-N-cycloalkylamino of 3 to 6 ring atoms, alkylamino, dialkylamino and dialkylcarbamoyloxy, the alkyl parts of these 2 latter radicals being unjoined or joined to form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4 to 7-membered heterocyclic ring which may contain another hetero atom chosen from nitrogen, oxygen and sulphur in the form of sulphide or sulphone, and unsubstituted or substituted by alkyl, or alkyl of 2 to 4 carbon atoms substituted by one or more nitrogen-containing, 4 to 7-membered hetercyclic rings which may contain 1 or 2 other hetero atoms chosen from nitrogen, oxygen and sulphur in che form of sulphide or sulphone, and unsubstituted or substituted by alkyl, these heterocyclic rings being linked to the alkyl by a carbon atom of the ring, at least one of the substitutents carried by the said alkyl chain being a nitrogen-containing substituent capable of forming salts, or [(S)-l-methyl-2-pyrrolidinyl]methyl and n is 1 or 2. The alkyl radicals and moieties referred to above are linear or branched and, unless mentioned otherwise, contain l to 10 carbon atoms.

The compounds of formula (I) have isomeric forms and their isomers and their mixtures are included within the terms of the description herein.

When R denotes a heterocyclic radical, this radical can be, for example: 3-azetidinyl, 3-pyrrolidinyl, 3or 4- piperidyl or 3- or 4-azepinyl.

When R denotes an alkyl radical substituted by a heterocyclic ring radical, the heterocyclic ring radical can be chosen, for example, from the radicals listed above or the 2-azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2-azepinyl, piperazinyl, 4-alkylpiperazinyl, quinolyl, isoquinolyl or imidazolyl radicals.

When R contains a dialkylamino or dialkylcarbamoyloxy radical in which the alkyl moieties form a heterocyclic ring with the nitrogen atom to which they are attached, this ring can be chosen, for example, fro; l-azetidinyl, l-pyrrolidinyl, piperidino, 1-azepinyl, morpholino, thiomorpholino in the form of sulphoxide or sulphone, l-piperazinyl, 4-alkyl-l -piperazinyl, N-alkyl-l- homopiperazinyl, or l-imidazolyl.

According to European Patent Publication No. 191662 the compounds of general formula (I) may be prepared by oxidation of a derivative of pristinamycin IIB, of its salt or of a protected derivative, of general formula (II) in which R is defined as above, it being understood that in the cases where R contains a sulphur-containing hetero cyclic ring, the sulphur atom can be in the form of a sulphide, sulphoxide or sulphone.

The reaction is generally carried out by means of an oxidizing agent, optionally prepared in situ, in an aqueous medium or in an organic solvent, preferably a chlorinated solvent (methylene chloride, 1,2-dichloroethane or chloroform, for example) or an alcohol (methanol or tert- butanol, for example) or a mixture of these solvents. Optionally the operation can be carried out under nitrogen.

Among the oxidizing agents which are suitable for preparing a compound of general formula (I) in which n = 1, it is possible to mention organic peracids: percarboxylic or persulphonic acids (for example peracetic, pertrifluoroacetic, performic, perbenzoic, m-chloroperbenzoic, p-nitroperbenzoic, permaleic, zonoperphthaiic, percamphoric or p-toluenepersulphonic acids) or inorganic peracids (for example periodic or persulphuric acid).

When the intention is to prepare a compound of general formula (I) in which n = 2, the operation is advantageously carried out in the presence of selenium dioxide and hydrogen peroxide, using the salt of the compound of general formula (II), or in the presence of a peracid such as those referred to above, especially pertrifluoroacetic acid, or m-chloroperbenzoic acid.

When the derivative of pristinamycin 11B of general formula (11) is used in the form of a salt, use is made of the salts formed with organic or inorganic acids, preferably with trifluoroacetic, tartaric, acetic, benzoic or hydrochloric acids.

When the compound of general formula (II) is used in the form of a salt or of a protected derivative, the reaction is advantageously carried out at a temperature between -40 and 50"C.

When it is intended to prepare a compound of general formula (I) in which n = 1, it is also advantageous to operate by starting from the derivative of pristinamycin IIB of general formula (II) in the presence of an alkali metal bicarbonate (for example sodium bicarbonate) at a temperature between -60 and -400C.

When R contains an alkylamino or cycloalkylamino substituent, it is also possible to utilize a protected derivative of the compound of general formula (II).

The latter can be protected by any amine-protective group whose introduction and removal do not affect the remainder of the molecule; use is advantageously made of the trifluoroacetyl group which can be removed after the reaction by treatment with an alkali metal bicarbonate (sodium or potassium bicarbonate) in an aqueous solution.

The compounds of general formula (II) can be prepared by the reaction of a compound of general formula: R-SH (III) in which R is defined as above, with the compound of formula (IV) that is to say pristinamycin 11A The reaction is usually carried out in an organic solvent such as an alcohol such as methanol or ethanol, or a chlorinated solvent such as methylene chloride, 1,2-dichloroethane or chloroform, or in a mixture of these solvents (for example methylene chloride/methanol) at a temperature between -30 and 500C.

Occasionally it may be advantageous to operate in the presence of a tertiary amine, for example triethylamine, or of an ethanolamine (for example dimethylethanolamine).

A person skilled in the art will understand that, when R denotes a radical containing a secondary amine group capable of interfering with the reaction, this group will need to be protected beforehand, before the compound of general formula (III) is reacted with the compound of formula (IV). Any usual means which enables a secondary amine function to be blocked in the form of a labile radical can be used for this purpose. It is especially advantageous to use the trifluoroacetyl radical as a blocking radical which can be removed as described above. In such a case, however, it is not absolutely essential to remove the protective radical, and the protected derivative can be used directly in the oxidation reaction.

The compounds of general formula (I) in which n is equal to 2 can also be prepared by the oxidation of a compound of general formula (I) in which n is equal to 1.

The reaction may be carried out under conditions which are similar to the conditions described above for preparing a compound of general formula (I) in which n = 2 starting from a pristinamycin IIB derivative of general formula (II).

It has now been found as a result of research and experimentation that the oxidation of the compounds of general formula (II) may be achieved using hydrogen peroxide in the presence of sodium tungstate by the application or adaptation of known methods.

Accordingly, the present invention provides a process for the preparation of the compounds of general formula (I) in which n is equal to 2 by the oxidation of a compound of general formula (II) using hydrogen peroxide in the presence of an alkali metal ungstate, for example sodium tungstate.

The reaction may be carried out in an aqueous medium e.g. acetone-water or acetonitrile-water, or an inert organic solvent substantially immiscible with water, for example a chlorinated hydrocarbon e.g.

dichloromethane, at a temperature from -50C to ambient temperature.

The process of the present invention gives a better yield and cleaner product than that exemplified in European Patent Publication No. 191662.

The process of the present invention is especially useful for the preparation of the following: - 26-(2-diethylaminoethyl)sulphonylpristinamycin IIB - 26-(2-dipropylaminoethyl)sulphonylpristinamycin IIB - 26-(2-diisopropylaminoethyl)sulphonylpristinamycin 11B - 26-(2-dibutylaminoethyl)sulphonylpristinamycin 11B - 26- (2-diisobutylaminoethyl) sulphonylpristinamycin 11B - 26- (N-ethyl-N-methyl-2-aminoethyl) sulphonyl- pristinamycin 11B - 26-(N-ethyl-N-isopropyl-2-aminoethyl)sulphonylpristinamycin IIss - 26-[2-(l-pyrrolidinyl)ethyl]sulphonylpristinamycin IIB - 26-(2-morpholinoethyl)sulphonylpristinamycin 11B - 26-(2-dimethylaminoethyl)sulphonylpristinamycin IIB - 26- (N-butyl-N-methyl-2-aminoethyl) sulphonyl- pristinamycin IIB and 26-(2-piperidinoethyl)sulphonylpristinamycin IIB in the form of their isomers A or B.

The following example shows how the invention can be put into practice. The NMR spectra of the compound illustrated in this example shows general characteristics which are common to all the compounds of general formula (I) and individual characteristics which are specific to each of the compounds, depending on the substituents. Only the individual characteristics due to the changeable radicals are mentioned in the example which follows. For the compounds of general formula (I), all the protons are designated according to the numbering indicated in the following formula (V).

Unless stated otherwise, all the spectra' wre recorded at 250 MHz in deuterochloroform; e @@ :al shifts are expressed in ppm relative to the tetramethylsilane signal. The abbreviations used in the following text are as follows: s = singlet d = doublet t = triplet mt = multiplet m = unresolved bands dd = doublet of doublets dt = doublet of triplets ddd = doublet of doublets of doublets dddd = doublet of doublets of doublets of doublets It is to be understood tht the various isomers have been classified arbitrarily according to the chemical shifts observed in NMR.

The names isomer A1 and isomer A2 of the compounds of general formula (I) in which n = 1 are given to the isomers which have the characteristics: approximately 1.7 (s, -CH3 at 33); approximately 3.8 (s, CH2 at 17); < ,5 (d, -H27) isomer A2 or > 5 (d, -H27) isomer A1; approximately 5.50 (broad d, -H13); approximately 6.20 (d, -Hll); approximately 6.6 (),NH at 8); # 8 (s, -H20).

The names isomer B1 and isomer B2 of the compounds of general formula (I) in which n 1 l given to the isomers which have the characteristics: approximately 1.5 (s, -CH3 at 33); approximately 3.7 and 3.9 (2d, CH2 at 17); approximately 4.8 (mt, -H13); < 5 (d, -H27) isomer B2 or,5 (d, -H27) isomer B1; approximately 5.70 (borderline AB, -H11 and -HlG); approximately 7.7 (NH at 8); approximately 7.8 (s, -H20).

The name isomer A of the compound of general formula (II) is given to the isomer which has N characteristics identical to those listed above for the isomers Al and A2 of the compounds of general formula (I), it being understood that the H at 27 is characterized by: 4.7 (d, J# 1 Hz).

The name isomer B of the compound of general formula (II) is given to the isomer which has NMR characteristics identical to those listed above for the isomers B1 and B2 of the compounds of general formula (I), it being understood that the H at 27 is characterized by: 4.6 (d, J#2.5 Hz).

In the following example, the name "flash" chromatography is given to a purification technique in which a short chromatography column is used and operated under an intermediate pressure (50 kPa) with the use of a silica with a particular size distribution of 40-53 gum, according to W.C. Still, M. Kahn and A. Mitra (J.Org.Chem. 43, 2923 (1978).

In the example described below, unless state otherwise, all the compounds can be dissolved at strength of at least 2%, in the form of a hydrochloride.

EXAMPLE 1 To a stirred solution of 26-(2-díethy'avInoethy')- thiopristinamycin IIB (isomer A)(5 g) in acetone (100 cc) and water (100 cc) cooled to 60C was added sodium tungstate (0.5 g) followed by hydrogen-peroxide solution (1 cc, 30c/0 w/v 100 vols). Further additions of hydrogen peroxide (1 cc) were made after time intervals of 10, 20, 60, 120 and 180 minutes. The reaction mixture was allowed to warm to room temperature and stirring continued for 2 hours when the mixture was extracted with dichloromethane (100 cc, then 2 x 50 cc).

The combined organic extracts were washed with water (100 cc), dried over anhydrous magnesium sulphate and concentrated to dryness affording a pale yellow solid (4.7 g), which was dissolved in ethyl acetate (200 cc).

The ethyl acetate solution was washed with dilute hydrochloric acid (0.1 N) (100 cc, then 2 x 50 cc), dried over anhydrous magnesium sulphate and evaporated affording a yellow solid (1.0 g) which was purified by "flash" chromatography [eluent : chloroform - methanol (95 to 5 by volume)] 30 cc fractions being collected.

Fractions 2 and 3 were combined and concentrated to dryness affording, after further purification by rn layer chromatography and crystallisation from eft tri acetate, pristinamycin 11A as off-white microcrystals (10 mg).

The combined dilute hydrochloric acid washings from above were washed with ethyl acetate (20 cc), adjusted to pH 7.5 by addition of solid potassium carbonate and extracted with dichloromethane (100 cc, then 2 x 50 cc).

The combined dichloromethane extracts were dried over anhydrous magnesium sulphate and concentrated to dryness affording a yellow solid (2.8 g) which was purified by "flash" chromatography [eluent : chloroform - methanol (95 to 5 by volume)] 30 cc fractions being collected. Fractions 10-12 were combined and concentrated to dryness affording 26-(2-diethylaminoethyl)sulphonylpristinamycin IIB (isomer A)(0.88 g) as an off-white solid.

NtE data confirmed this is identical to the compound of Example 24 of European Patent Publication No. 191662.

Claims (5)

1. Process for the preparation of a compound of general formula I or an acid addition salt thereof in which R denotes either a nitrogen-containing 4 to 7-membered heterocyclic ring radical, which may contain one or more other hetero atoms chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl; or alkyl of 2 to 4 carbon atoms substituted by 1 or 2 radicals chosen from phenyl, cycloalkylamino of 3 to 6 ring atoms, N-alkyl-N-cycloalkylamino of 3 to 6 ring atoms, alkylamino, dialkylamino and dialkylcarbamoyloxy, the alkyl parts of these two latter radicals being unjoined or joined to form, with the nitrogen atom to which they are attached, a saturated or unsaturated 4 to 7-membered heterocyclic ring which may contain another hetero atom chosen from nitrogen, oxygen and sulphur in the form of sulphide or sulphone, and unsubstituted or substituted by alkyl; or alkyl of 2 to 4 carbon atoms substituted by one or more nitrogencontaining, 4 to 7-membered heterocyclic rings which may contain one or two other hetero atoms chosen from nitrogen, oxygen and sulphur in the form of sulphoxide or sulphone, and unsubstituted or substituted by alkyl, these heterocyclic rings being linked to the alkyl by a carbon atom of the ring, at least one of the substituents carried by the said alkyl chain being a nitrogen-containing substituent capable of forming salts, or [(S)-l-methyl-2pyrrolidinyl]methyl and n is equal to 2 which comprises oxidizing a compound of general formula II in which R is as defined above, it being understood that in the cases where R contains a sulphur-containing heterocyclic ring, the sulphur atom can be in the form of a sulphide, suiphoxide, or sulphone, with hydrogen peroxide in the presence of an alkali metal tungstate.

2. A process according to claim 1 in which the oxidation is carried out in an aqueous medium or in an inert organic solvent substantially immiscible with water.

3. A process according to claim 1 or 2 in which the oxidation is carried out at a temperature from -5 0C to ambient temperature.

4. A process according to claim 1 substantially described in the Example.

5. A compound of general formula I as defined in claim 1 when prepared by the process claimed in any one of claims 1 to 4.