CS236653B2 - Manucaturing process of 3-iminomethylderivatives of rimaficine sv - Google Patents

Description

The invention relates to a process for the preparation of 3-iminomethyl derivatives of rifamycin SV, which are useful as antibiotics.

French Patent Specification No. 1,457,435 describes 3-iminomethyl derivatives of rifamycin SV having the general formula I

wherein R is oxygen, a hydrogen atom together with a hydroxyl group, a dialkoxy group, an imino group, a substituted imino group, a hydrazone group and a substituted hydrazone group, which compounds are very effective antibiotics against pathogenic bacteria. A representative compound of this class of compounds is 3- (4-methyl-1-piperazinyl) iminomethyl-rif amycin

SV, a substituted hydrazone derivative of 3-formylrifamycin SV, known under the international designation "rifampicin".

According to the above specification, compounds of formula I are prepared by oxidizing the Mannich base of rifamycin SV and hydrolyzing the Schiff base thus obtained to 3-formylrifamycin SV (a compound of the above formula I wherein R is oxygen).

The latter can be converted to acetals (compounds of formula I where R is a dialkoxy group), reduced to the corresponding alcohol (compounds of formula I where R is a hydrogen atom together with a hydroxyl group), or reacted with primary amines to form compounds of formula I, wherein R is substituted imino, or with hydrazines to form compounds of formula I, wherein R is substituted hydrazone.

French Patent Specification No. 1,585,041 discloses an improved process for the preparation of 3-hydrazonomethylderivatives of rifamycin SV, corresponding to formula I above, which comprises rifamycin S of formula II

6 65 2

WHAT

NH (II)

₃ is reacted with formaldehyde and a suitable primary amine, preferably t-butylamine, or an aldiminoderivative obtained from equimolar amounts of the aforementioned primary amine and formaldehyde in the presence of an oxidizing agent, preferably manganese dioxide; mol equivalents of the desired hydrazine to effect both reduction and trans-imination, and finally isolating the compound of formula (I) above wherein R is hydrazone by separating the final product from its salt with a primary amine, preferably tert-butylamine.

Thus, the preparation of the corresponding hydrazonomethyl derivatives according to French Patent No. 1,585,041 starting from rifamycin S is a five-step process comprising condensation to form Mannich base, oxidation to form Schiff base, reduction to the hydroquinone type compound, trans-imination and hydrolysis.

In particular, the intermediate obtained from rifamycin S must be subjected to ascorbic acid reduction prior to trans-imination to convert the quinone-type compound to the corresponding hydroquinone-type compound. The use of ascorbic acid can be avoided by carrying out a transimination reaction with at least 2 mol equivalents of hydrazine, the second mol equivalent being a reducing agent. In any case, however, a salt of the title compound, with the amine used, is precipitated and from which the desired title product must be isolated by hydrolysis.

SUMMARY OF THE INVENTION The present invention provides a process for preparing the 3-iminomethyl derivative of rifamycin SV in quantitative yield, which process is only two-stage, takes place in a very short reaction time and requires the use of inexpensive reagents.

The process according to the invention consists in reacting rifamycin S of formula II with a compound of formula V

CH2OR ²

R1-N (V)

CH ² OR ² where

R ¹ represents a C ¹ -C 6 -alkyl group, a C 2 -C 6 -alkyenyl group, a C 5 -C 6 -cycloalkyl group or a benzyl group; and

R ² represents a hydrogen atom or a C 1 -C 5 -alkyl group, in an inert organic solvent, at a temperature between room temperature and the boiling point of the solvent, to form an intermediate which is treated with water and a water-immiscible inert organic solvent at pH 4-6 the aqueous phase is then removed and the organic phase is treated at 20 to 80 ° C under basic conditions with a primary amine of formula X

R = NH2 (X) wherein

R is as defined above, then the 3-iminomethyl derivative of rifamycin SV of the general formula I is isolated from the organic phase.

236853 where

X is a group. NR in which R represents a benzyl group, or represents an amino, a pin or a 4-methylpiperazino group.

If the first solvent used is water miscible, the above intermediate precipitates and can be isolated. The intermediate can then be dissolved in an inert organic solvent and reacted under basic conditions at a temperature in the range of about 20 ° C to about 80 ° C with the primary amine of formula X, whereupon the corresponding 3-iminomethyl derivative of rifamycin SV is isolated. of formula III.

Compounds of formula V are prepared as described in J. Chem. Soc. 123, 532 (1923).

Preferred alkyl groups are straight and branched saturated aliphatic radicals having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, n -hexyl or 2-methylpentyl.

Preferred alkenyl groups are ethylenically unsaturated aliphatic hydrocarbon radicals having 3 to 6 carbon atoms, such as allyl, crotyl, methacrylic, 3-pentenyl or 3-hexenyl.

The reaction temperatures vary according to the invention, depending on the solvent used. When using a chlorinated solvent or generally a polar solvent, the reaction can be carried out at a relatively low temperature (20 to 50 ° C), while using a substantially apolar solvent such as toluene is preferably carried out at a higher temperature.

The reaction time depends on the nature of the starting materials used and the reaction temperature. Although the reaction time can be prolonged up to 24 hours at 40 ^° C and the reaction mixture can be allowed to stand at 0 ° C for an additional 24 hours without any noticeable degradation of the rifamycin molecule, it takes place within the above temperature range (20 ° C). to 80 ° C) conversion of the above intermediate to the 3-iminomethyl derivatives of formula III practically instantly. Generally, under these reaction conditions, the reaction temperature is between a few minutes and a maximum of 3 hours.

The primary amine is preferably used in an amount ranging preferably between a stoichiometric amount and an excess of 4 to 5 moles of the primary amine per mole of the starting intermediate.

Examples of amines in general and broadly which can be reacted with said intermediate to form the corresponding 2-iminomethyl derivatives of the formula III include benzylamine, N - or N -phenethylamine, aniline, o-toluidine, m-toluidine , p-toluidine, 2,6-lutidine, p-chloroaniline, 2-naphthylamine, 2-aminopyridine, 4-aminopyridine, hydrazine, benzylhydrazine, phenylhydrazine, 1-aminopyrrolidine, 1-aminopiperidine, 4-aminomorpholine and 1-amino-4 methylpiperazine, wherein the reaction according to the invention carried out with the latter compound leads to the formation of rifampicin.

The basic conditions under which the reaction is carried out may be achieved either by using an excess (about 4 to 5 moles) of the primary amine, hydrazine, monosubstituted hydrazine, or asymmetrically disubstituted hydrazine, or by adding a secondary or tertiary amine such as pyrrolidine, trimethylamine, triethylamine or 1-methylpyrrolidine into the reaction medium.

Procedure to isolate at the end of the reaction

The 3-iminomethyldeirivatives of formula (III) preferably comprise adjusting the pH of the reaction mixture to slightly acidic values, washing with water to remove excess organic base converted to salt, concentrating the reaction mixture and extracting the residue with a suitable solvent. they are obtained directly from said intermediate in virtually quantitative yield.

Although any of the derivatives of the intermediate can be converted to the corresponding 3-iminomethyl derivative of formula III, the best yields and shortest reaction times are obtained using an intermediate derived from compound V wherein R ¹ is C ¹ -C 6 -alkyl or C 2 -C 6 -alkenyl . In this case, the reaction is complete after 5 to 20 minutes and the compounds of formula III can be isolated in virtually quantitative yield.

The invention is illustrated by the following non-limiting examples.

Example 1

A mixture of 6.5 g of N, N-dihydroxymethyl-t-butylamine, 13 g of rifamycin S and 40 ml of dimethylformamide is heated to 33 ^DEG C. with stirring for 60 minutes. The resulting blue solution is poured into 300 ml of acidified water. 3 ml of acetic acid and extracted with 200 ml of chloroform. 5.5 g of pyrrolidine and 3 g of 1-amino-4-methylpiperazine were added to the organic phase, and the mixture was stirred at 30 ° C for 40 minutes. The reaction mixture is then washed first with water acidified with acetic acid to pH 5 and then with water alone.

The organic phase is dried over sodium sulphate, filtered and concentrated to dryness. 15.4 g of crude product are obtained which, after recrystallization from acetone, yields 13.2 g of chromatographically pure rifampicin.

Example 2

To a solution of 18 g of rifamycin S in 65 ml of dime236653 thylsulfoxide, presented in a four-neck. flask ob '] emu 250 ml, 10 ml of di (iso-jmethylaminu methyl (compound of formula V wherein R ¹ represents a methyl group and R ² an isobutyl group) and the resulting solution was heated for 5 minutes at 50 degrees C. The the blue solution is diluted

375 ml of water acidified with 6 ml of 96% acetic acid and extracted with 250 ml of chloroform.

The organic layer was separated, 5.5 g of pyrrolidine and 4 g of 1-amino-4-methylpiperazine were added thereto, the resulting solution was heated at 40 ° C for 60 minutes, then acidified to pH 5 with dilute acetic acid and washed with water. The organic phases are dried over sodium sulphate, filtered and concentrated to dryness. Recrystallization of the residue from acetone yields pure rifampicin in practically quantitative yield.

Example 3

To a solution of 18 g of rifamycin S in 65 ml of dimethyl sulfoxide was added 10 ml of diisobutoxymethylmethylamine, the mixture was heated at 50 ° C for 5 minutes, poured into 375 ml of distilled water acidified with 6 ml of 96% acetic acid and extracted with 250 ml of chloroform. The organic phase was separated, 11 g of triethylamine and 4 g of 1-amino-4-methylpiperazine were added, and the resulting mixture was heated at 40 ° C for 24 hours. By analogy to Example 17, 19.2 g of rifampicin having an activity of 98.7% is obtained.

Example 4

A solution of 6.5 g of N, N-dihydroxymethyl-t-butylamine, 40 ml of dimethylformamide and 13.9 g of rifamycin S is heated to 33 ° C in a 100 ml four-necked flask for 60 minutes.

The reaction mixture is poured into 300 ml of water acidified with 2 ml of acetic acid, the precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C. 14.5 g of product are obtained.

Example 5

To a solution of 7.9 g of the compound prepared in Example 4 in 30 ml of tetrahydrofuran, presented in a 100 ml four-necked flask, was added a mixture of 2.8 g of pyrrolidine and 1.38 g of 1-amino-4-methylpiperazine. After stirring at room temperature for 20 minutes, the reaction is complete. The reaction mixture was dissolved in 100 ml of chloroform, acidified to pH 5 with dilute acetic acid and washed with water. The chloroform phase was dried over sodium sulfate, filtered and the solvent was evaporated. 8.2 g of crude product are obtained which, after recrystallization from acetone, yields 7.2 g of rifampicin as a uniform product (by thin layer chromatography).

Example 6

To a solution of 7.9 g of the compound prepared in Example 4 in 30 ml of tetrahydrofuran was added 4 g of benzylamine and the reaction was completed by stirring at 30 ° C for 15 minutes. The resulting solution was diluted with 100 ml of chloroform, acidified to pH 5 with dilute acetic acid, washed with water and dried over sodium sulfate. After filtration, the solvent was evaporated and the product collected. 7.8 g of 3-benzyliminomethyl-rifamycin SV (Formula III, wherein X is -N-CH2-C6H5) are obtained. The UV spectrum of the product contains a maximum absorption at 555 nm.

Example 7

To a solution of 6 g of the compound prepared according to Example 4 in 30 ml of tetrahydrofuran was added 1.5 g of hydrazine hydrate and the reaction was completed by stirring at room temperature for 5 minutes. By analogy to Example 5, 5.3 g of 3-formylrifarmycin SV hydrazone (Formula III, wherein X is = N-NH 2) are obtained.

The UV spectrum of the product contains a maximum absorption at 325 and 473 nm.

Example 8

13.9 g of rifamycin S are dissolved in 40 ml of dimethylacetamide in a 100 ml 4-neck flask, 7 g of N, N-diisopropoxymethylallylamine are added and the resulting solution is heated to 70 ° C for 15 minutes. The reaction mixture is poured into 300 ml of water acidified with 2 ml of acetic acid, the precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C.

Example 9

To a solution of 7.8 g of the compound prepared in Example 8 in 40 ml of methylene chloride presented in a 100 ml four-neck flask was added a mixture of 2.9 g of 1-methylpyrrolidine and 1.38 g of 1-amino-4-methylpiperazine. .

After stirring for 20 minutes, the reaction is complete, the reaction mixture is dissolved in 100 ml of chloroform, acidified to pH 5 with dilute acetic acid and washed with water. The chloroform phase is dried over sodium sulphate, filtered and concentrated to dryness and the residue is recrystallized from acetone. 7.2 g of pure rifampicin are obtained, which gives only a single spot in the thin-layer chromatogram.

Example 10

A mixture of 13.9 g of rifamycin S, 6.5 g of N, N-dimethoxymethyl-cyclohexylamine and 40 ml of dimethylsulfoxide was heated to 50 ° C in a 100 ml four-necked flask of 100 ml. The reaction mixture is poured into 300 ml of water acidified with 2 ml of acetic acid, the precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C. 15.3 g of product are obtained.

Example 11

To a mixture of 7.1 g of the compound prepared according to Example 10, 45 ml of toluene and 1.2 g of 1-amino-4-methylpiperazine at a temperature of ^75? C add a solution of 3.1 g of pyrrolidine in 5 ml of toluene over 10 minutes.

After heating for 10 minutes, the reaction mixture is cooled, taken up in 100 ml of chloroform, washed with water acidified with acetic acid and then with pure water, the organic phase is dried and concentrated to dryness. Recrystallization of the residue from acetone gave 5.8 g of pure rifampicin.

Example 12

In a 100 ml four-necked flask, 13.9 g of rifamycin S are dissolved in 40 ml of hexamethylphosphoric triamide, 7.3 g of Ν, Ν-diethoxymethyl-benzylamine are added and the resulting solution is poured into 400 ml of acidified water with 2 ml of acetic acid. The precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C.

15.8 g of product are obtained.

Example 13

To a solution of 8.3 g of the compound prepared in Example 12 in 40 ml of methylene chloride presented in a 100 ml four-necked flask was added a mixture of 2.9 g of 1-methylpyrrolidine and 1.38 g of 1-amino-4-methylpiperazine.

After stirring for 20 minutes, the reaction is complete, the reaction mixture is dissolved in 100 ml of chloroform, acidified to pH 5 with dilute acetic acid and washed with water. The chloroform phase is dried over sodium sulphate and, after filtration, concentrated to dryness. Recrystallization of the residue from acetone gave 7.2 g of pure rifampicin which gave only a single spot in the thin layer chromatogram.

Example 14

14 g of rifamycin S are dissolved in 40 ml of acetone in a 100 ml four-necked flask, 5 g of N, N-diisobutoxymethylmethylamine are added and the resulting solution is stirred at 40 ° C for 3 hours. The reaction mixture is poured into 300 ml of water acidified with 3 ml of acetic acid, the precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C. 13.8 g of crude product are obtained.

This crude product was mixed with 60 ml of toluene, presented in a 100 ml flask, stirred at 60 ° C for 10 minutes, then filtered. 12.5 g of product are obtained.

Example 15

A mixture of 14 g of rifamycin S, 50 ml of n-propyl alcohol and 5.5 g of N, N-diisobutoxymethylmethylamine was stirred at 60 ° C in a 100 ml four-necked flask for 60 minutes.

The reaction solution is poured into 500 ml of water acidified with 5 ml of acetic acid, the precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C. 12.2 g of crude product are obtained.

The above crude product was dissolved in 100 ml of chloroform and a mixture of 250 ml of toluene and 750 ml of petroleum ether was added. The precipitate formed is filtered off and dried under vacuum at 40 ° C.

4.2 g of product are obtained, identical to the product prepared in Example 14.

Example 16

To a mixture of 6.5 g of the compound prepared according to Examples 14 and 15, 45 ml of toluene and 1.2 g of 1-amino-4-methylpiperazine at 75 ° C was added a solution of 3.1 g of pyrrolidine in 5 ml of toluene over 10 minutes. .

After heating for 10 minutes, the reaction mixture is cooled, taken up in 100 ml of chloroform, washed with water acidified with acetic acid and then with water, the dried organic phase is concentrated to dryness and the residue is recrystallized from acetone. 5.8 g of pure rifampicin are obtained.

Example 17

To a solution of 7.5 g of the compound prepared according to Examples 14 and 15 in 50 ml of chloroform was added 4 g of triethylamine and 1.5 g of 1-amino-4-methylpiperazine, and the resulting mixture was stirred for 24 hours. The pH of the reaction mixture is adjusted to 5 with dilute acetic acid, the resulting solution is washed with water, the organic phase is dried over sodium sulphate, filtered, concentrated to dryness and the residue is taken up in 40 ml of acetone. The solution was allowed to stand overnight at 0 ° C and the precipitate was filtered off. 7.2 g of pure rifampicin are obtained (activity 95.5%).

Claims (7)

OVERTAKE A process for the preparation of rifamycin SV 3-iminomethylderiylates of general formula III wherein X is = NR in which R is benzyl or amino or 4-methylpiperazino, wherein rifamycin S of formula II is reacted with a compound of formula V CH2OR ² / R ¹ —N (V) CH ² OR ² where R ^is C1-Cs-alkyl, C2-Ce-alkenyl, C5 - Cg-cycloalkyl or benzyl, preferably t-butyl, methyl or allyl; R ² represents a hydrogen atom or a C 1 -C 5 -alkyl group, in an inert organic solvent, at a temperature between room temperature and the boiling point of the solvent, to give an intermediate which is treated with water and a water-immiscible inert organic solvent at pH 4-6 the phase is then discarded and the organic phase is treated at a temperature between 20 ° C and 80 ° C under basic conditions with a primary amine of formula X VYNALEZU R = NH2 (X) wherein R is as defined above, whereupon a derivative of formula III is isolated from the organic phase. 2. The process of claim 1 wherein the first inert organic solvent is a dipolar aprotic solvent such as dimethylsulfoxide, dimethylformamide or dimethylacetamide. 3. The process according to claim 1, wherein the second inert organic solvent is a chlorinated or aromatic solvent such as chloroform, methylene chloride and toluene. 4. The process according to claim 1, wherein the basic reaction conditions are achieved by adding to the organic phase a secondary or tertiary amine such as pyrrolidine, trimethylamine, triethylamine or 1-methylpyrrolidine. 5. A process according to any one of claims 1 to 4, wherein the derivatives of formula (III) are isolated from the organic phase by acidification to pH 4-5, washing with water, drying the organic phase and evaporating the solvent. 6. A method according to claim 1 for the manufacture of rifampicin, characterized in that the starting materials used are compounds of formula V wherein R ¹ is t-butyl, methyl or allyl, inert organic solvent such as dimethylsulfoxide, or dimethylacetamide dimeíhylíormamid, temperature, 15 to 100 ° C, the second inert organic solvent being methylene chloride or chloroform, the organic phase is treated with 1-amino-4-methylpiperazine at room temperature, basic conditions are achieved by adding pyrrolidine to the organic phase. 7. The process of item 1, for producing the 3-iminomethyl derivative of rifamycin SV of formula III wherein: X is as defined in item 1, wherein rifamycin S of formula II is reacted with a compound of formula V CH2OR ² / R ¹ —N \ CH ² OR ² (V) wherein R ¹ and R ² are as defined in point 1, in a dipolar solvent at a temperature of from 15 to 100 ° C, to form a solution from which by treatment with water acidified to pH 4 to 6 an intermediate is precipitated and dissolved in an inert solvent; at 20 to 80 ° C, it is treated under basic conditions with a primary amine of formula X R = NH2 (X) wherein R is as defined in point 1, then the desired derivative of formula (III) is isolated from the organic solution.