MXPA98009350A - New procedure of isomerization of the radicalmetile in 10 of derivatives of the eritromic - Google Patents

Abstract

The object of the invention is an isomerization process characterized in that a compound of formula (Ia) is subjected, in which either X and Y together form a 3-oxo radical, or X represents a hydrogen atom and X represents is a radical (a) in which R2 represents an OHO-acyl, either an O-alkyloxyNH2 radical, R1 represents a hydrogen atom or a methyl radical, Z represents a hydrogen or an acyl radical, R represents a hydrogen atom, a radical NH2 or a radical (CH2) nAr, NH (CH2) nAronN = CH (CH2) nAr, in the form of isomer 10a or of mixture of isomers 10a and 10a, to the action of a basic agent to obtain the compound of formula (I) corresponding, in which the methyl radical in 10 is in position

Description

EGG PROCESS OF ISOMERISATION OF THE RADICAL METHOD EM IO OF DERIVATIVES OF ERYTHROMYCIN.

The invention concerns a new method of isolating the methyl radical in erythromycin derivatives.

The subject of the invention is an isorization process characterized in that a compound of formula (IA) is subjected to: in which either X and Y together form a 3-oxo radical, or X represents a hydrogen atom and Y represents either a radical: REF. 28735 in which R2 represents a hydroxyl radical or an O-acyl radical containing from 2 to 20 carbon atoms, either an O-alkyl radical, containing from 2 to 20 carbon atoms, or an NH2 radical, - Ri , represents a hydrogen atom or a methyl radical, Z, represents a hydrogen or an acyl radical containing from 2 to 20 carbon atoms, - R represents a hydrogen atom, a radical NH2 or a radical (CH2) nAr, NH ( CH2) nAr or N = CH (CH2) nAr in which n represents an integer between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl radical, in the form of isomer 10a or mixture of isomers 10a and lOß, to the action of a basic agent to obtain the corresponding compound of formula (I), in which the methyl radical in 10 is in position β: and in which R, Ri, X and Y, retain their previous meaning and Z ', represents a hydrogen atom or an acyl radical containing from 2 to 20 carbon atoms.

The acyl radical is preferably an acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tervaleryl and pivalyl radical, or a benzyl radical.

By "aryl radical" is meant preferably a phenyl or naphthyl radical, by heteroaryl radical, is meant a radical containing one or more heteroatoms selected preferably from oxygen, sulfur or nitrogen, it may be a thienyl radical, furyl, pyrrolyl, thiazolyl, oxazolyl, i idazolyl, thiadiazolyl, pyrazolyl, or isoxazolyl, of an indolyl, benzofuryl, benzothienyl, quinolinyl or pyridyl imidazoyl radical.

As radical heteroaryl, the radicals can be mentioned, for example: "cO c r -? The invention more particularly has as its object a process characterized in that it is operated in the presence of a basic agent, preferably in catalytic quantity, Z, and Z ', represent a hydrogen atom.

The basic agent is preferably potassium or still a tetra-alkylammonium hydroxide, for example tetrabutylammonium hydroxide or bromide or DBU (1,8-diazabicyclo [5-4-0] undec-7-ene] or an alkaline carbonate, for example sodium or potassium carbonate or soda or tripotassium phosphate or still sodium methylate.

It may be necessary in certain cases to add a phase transfer agent, for example tetrabutyl ammonium bromide.

The object of the invention is very particularly to provide a process characterized in that it is operated in a solvent which may be, for example, tetrahydrofuran, 1-methyl 2-pyrrole idinone in aqueous solution, methylene chloride and more especially an alcohol, in particular methanol and thus the corresponding compound is obtained in which Z 'represents a hydrogen atom, or an acyl radical containing from 2 to 20 carbon atoms.

The object of the invention is more particularly: - an isomerization process of compounds of the formula (IA) in (I) in which R represents an NH2 radical, - a isomerisation process of compounds of formula (IA) in (I) ) in which Ri represents a methyl radical, - a isomerisation process of compounds of formula (IA) in (I) characterized in that X and Y together form a 3-oxo radical, - an isomerisation process of compounds of formula (I) IA) in (I) in which Z and Z 'represent a hydrogen atom.

The invention then concerns a process for converting compounds of formula (IA) in which the methyl radical at 10 is in position to or a mixture of 10a and 10β in compounds of formula (I) in which the methyl radical at 10 is lOß. After the formation of the chain at 11, 12 a mixture of isomers 10a and lOß is obtained, this is how, if the procedure described in EP 676409 is followed, the following reaction is obtained: The product (IA) obtained is a mixture of isomers a and ß, as indicated in example 1 of patent EP 676409. The lOß product is a product endowed with interesting antibiotic properties, it also allows the preparation of other antibiotic products described and claimed in the patent application 676409 according to the procedure: OR II -C- • R R i i 2 The compounds endowed with interesting antibiotic properties are those in which the methyl radical in 10 is in the β position. It is then interesting from a point of industrial view isomerisar product 10 a or mixtures 10a and lOß in products 10 ß. The process of the invention makes it possible mainly to isomerize in lOβ isomers the products of formula (IA) in which R is an NH2 radical, those in which R is a hydrogen atom, or still those in which R is a radical (CH2) n Ar, NH- (CH2.n Ar or N = CH (CH2) n Ar in which n and Ar retain their previous meaning.

These products are described, for example, in patent applications EP 676409, EP 638584, EP 680967, EP 0596802, EP 487411.

The following examples illustrate the invention without, however, limiting it.

EXAMPLE 1: It is dissolved in 2 ml. of methanol 0.1 g. of the 10a isomer of 11, 12-dideoxy 3-de - ((2,6-dideoxy-3-C-methyl-3-ethyl-10-L-riboexopyranosyl) oxy) 6-0-methyl-3-oxo 12, 11- (oxy-carbonyl (hydrozone) erythromycin (prepared as indicated in European patent application 0676409, B isomers are produced) and 10 μl of a 10% methanolic potassium hydroxide solution is added, and stirred overnight at 20 ° C. and formation of the lOß isomer is observed.This lOß isomer is characterized by its NMR spectrum.

The yield of isomerisation is of the order of 90%.

Proceeding as in Example 1, the lOß isomer of the product of Example 1 was obtained, starting from 0.5 g. of the 10th product: - methanol, 10 volumes; 0.11 ml. of 10% solution of potash in methanol, - methanol, 10 volumes; 0.26 μl. of 40% solution of tetrabutylammonium hydroxide in water. - methanol, 10 volumes; 0.13 ml. of 40% solution of tetrabutylammonium hydroxide in water, - 20% methanol of water, 10 volumes; 0.11 ml. of 10% KOH solution in methanol, - 20% methanol water, 10 volumes; 26 μl of 40% solution of tetrabutylammonium hydroxide in water, - 20% methanol of water, 10 volumes; 0.13 ml. of 40% solution of tetrabutylammonium hydroxide in water. - 20% methanol water, 10 volumes; DBU 30 μl.

EXAMPLE 2: from the mixture of a + β isomers In a three-neck balloon of 1000 ml. provided with stirring, a thermometric probe and a nitrogen arrival in sweep, the following is introduced: - isomer mixture a + ß, 37.8 g. (isomer a = 15.8 g; isomers ß = 22 g.) of 11, 12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl to L-riboexopyranosyl) oxy) 6 -0-methyl 3-oxo 12, 11- (oxycarbonyl) hydrazone) erythromycin (isomer a = 15.8 g .: isomer ß = 22 g.) - anhydrous pure methanol - 10% methanolic potash It is kept under stirring for 20 hours at 20-22 ° C.

The disappearance of the 10 a isomer (< 2%) is checked by HPLC, then it is introduced, controlling the temperature 20-22 ° C, by a water + ice bath: - demineralized water adjust the pH to 10 with acetic acid qs ( ~ 0.250 ml.), Stir 3 hours at 20/22 ° C, cool to 0 + 2 ° C, stir 1 hour at 0 ° C + 2 ° C, drain by clarification with the help of: - demineralized water at 20 ° C Dry in a stove by ventilation at 30 ° C for 16 hours.

The pure β isomer is recovered: 32.6 g.

Yield: 86.2% in relation to the mixture a + ß, EXAMPLE 3: It is dissolved in 1 ml. of metansl, 0.2 g. of a mixture of the 10a and lOß isomers of 11, 12-dideoxy 3-de - ((2,6-dideoxy-3-C-methyl-3-methyl to L-riboexopyranosyl) oxy) 6-O-ethyl-3-oxo 12, 11- (oxycarbonyl) hydrazone) erythromycin (% ß /% a = 0.24) and 50 μl of a 10% methanolic potassium solution is added. The mixture is stirred 16 hours at 20 ° C and the transformation of the 10a isomer into lOß isomer is observed. (% ß /% a = 21).

EXAMPLE 4: It is dissolved in 0.5 ml. of methanol, 0.1 g. of a mixture of the 10a and lOß isomers of 11,12-dideoxy-3-des- ((2,6-dideoxy-3-C-methyl-3-methyl-L-riboexopyranosyl) oxy) 6-0-methyl-3 -oxo 12, 11- (oxycarbonyl) hydrazone) erythromycin (% ß /% a = 0.24) and 0.25 moles per mole of (1,8-diaza-bicyclo [5-4-0] undec-7-ene, The mixture is stirred for 16 hours at 20 ° C and the transformation of the 10a isomer into lOß isomer is observed (% ß /% a = 16.3).

EXAMPLE 5: It is dissolved in 0.5 ml. of dichloromethane, 0.1 g. of a mixture of the 10a and lOß isomers of 11,12-dideoxy-3-de ((2,6-dideoxy-3-C-methyl-3-methyl-L-riboexopyranosyl-9-oi) -6-methyl-3-oxo) , 11- (oxycarbonyl) hydrazone) erythromycin (% ß /% a = 0.24) and add 1 mol per mol of (1,8-diazabicyclo [5-4-0] undec-7-ene. at 20 ° C and the transformation of the 10a isomer into lOß isomer is observed (% β /% a = 2.6).

EXAMPLE 6: It is dissolved in 2 ml. of methanol, 0.1 g. of a mixture of the 10a and lOß isomers of 11,12-dideoxy-3-de - ((2,6-dideoxy-3-C-methyl-3-methyl-L-riboexopyranosyl) oxy) 6-0-methyl-3 -oxo 12, 11- (oxycarbonyl) hydrazone) erythromycin (% ß /%) = 0.24) and 1 mol per mole of potassium carbonate is added. The mixture is stirred 16 hours at 20 ° C and the transformation of the 10a isomer into lOß isomer is observed. (% ß /% a = 49), EXAMPLE 7: It is dissolved in 2 ml. of methanol, 0.1 g. of a mixture of the 10a and lOß isomers of 11,12-deoxy-3-de - ((2,6-dideoxy-3-C-methyl-3-methyl-L-riboexopyranosyl) -oxy) 6-0-methyl 3-oxo 12, 11- (oxycarbonyl) hydrazone) erythromycin (% ß /% a = 0.24) and 1 mole per mole of potassium phosphate is added. 4 It is stirred for 16 hours at 20 ° C and the transformation of the 10a isomer into lOß isomer is observed. (% ß /% a = 10.2).

EXAMPLE 8 Dissolve in 2 ml. of methanol, 0.1 g. of a mixture of the 10a and lOβ isomers of 11,12-dideoxy-3-des- ((2,6-dideoxy-3-C-methyl-3-0-methyl to L-riboexopyranosyl) oxy) 6-methyl-3 -oxo 12, -11- (oxycarbonyl) hydrazone) erythromycin (% b /% a = 0.24) and 0.2 mol per mole of sodium carbonate and 0.2 mole per mole of tetrabutylammonium bromide is added. Stir 16 hours at 20 °. C and the transformation of the 10a isomer into lOß is observed. (% ß /% a = 80).

EXAMPLE 9: It is dissolved in 0-5 ml. of methanol, 0-1 g- of a mixture of the 10a and -lOß isomers of 11, 12-dideoxy 3-des- ((2,6-dideoxy) 3-C-methyl 3-0-methyl to L-riboexopyranosyl ) oxy) 6-0-methyl 3-oxo 12, 11- (oxycarbonyl) hydrazone) erythromycin (% ß /% a = 0.24) and 33 μl of a solution of sodium methylate in methanol is added to 5 g. per ml. Stir 16 hours at 20 ° C and the transformation of the 10a isomer into lOß isomer is observed. (% ß /% a = 0.7).

It is noted that in relation to this date the best method known by the applicant to carry out the said invention is that which is clear from the present description thereof.

Having described the invention as above, it is claimed as property in the following:

Claims (10)

1) Isomerization process characterized in that a compound of formula (IA) is subjected: in which either X and Y together form a 3-oxo radical, or X, represents a hydrogen atom and Y, represents either a radical: wherein R 2 represents a hydroxyl radical or an O-acyl radical containing 2 to 20 carbon atoms, either an O-alkyl radical, containing 2 to 20 carbon atoms, or an NH 2 radical, - Ri, represents a hydrogen atom or a methyl radical, -Z, represents a hydrogen or an acyl radical containing from 2 to 20 carbon atoms, - R represents a hydrogen atom, a radical NH2 or a radical (CH2) - Ar, NH (CH2) nAr or N = CH (CH2) n Ar in which n represents an integer between 1 and 6, and Ar represents an aryl or heteroaryl radical, optionally substituted in the form of 10a isomer or mixture of isomers 10a and lOß, to the action of a basic agent to obtain the corresponding compound of formula (I), in which the methyl radical at 10 is in position β. and in which R, Ri, X and Y retain their previous meaning and Z represents a hydrogen atom or an acyl radical containing from 2 to 20 carbon atoms.

2) Process according to claim 1, characterized in that it is operated in the presence of a basic agent, Z and Z ', represent a hydrogen atom.

3) Process according to claim 1 or 2, characterized in that the basic agent is potash.

4) Process according to claim 1 or 2, characterized in that the basic agent is tetrabutylammonium hydroxide or bromide or an alkaline carbonate for example a sodium or potassium carbonate or soda or DBU (1,8-diazabicyclo [ 5-4-0] undec 7-ene) or tripotassium phosphate or still sodium methylate.

5) Process according to any one of claims 1 to 4, characterized in that it is operated in a solvent that can be tetrahydrofuran, 1-methyl 2-pyrrolidone in aqueous solution, methylene chloride or an alcohol and obtains the corresponding compound in which Z 'represents a hydrogen atom or an acyl radical containing from 2 to 20 carbon atoms.

6) Method according to claim 5, characterized in that it is operated in a methanolic solution.

7) Method according to any one of claims 1 to 6, characterized in that R. represents a radical NH2.

8) Method according to any one of claims 1 to 7. characterized norpne R? Represents a methyl radical.

9) Process according to any one of claims - ^ to 8 'characterized in that X and Y together form a 3-oxo radical.

10) Method according to any one of claims 1 to 9, characterized in that Z Y z '. they represent a hydrogen atom.