CS200171B2 - Process for preparing 1,3-oxazino/5,6-c/rifamycines - Google Patents

Abstract

Novel title cpds. of formula:- (where R1 = 1-6c alkyl, 3-6C alkenyl, 5-6C cycloalkyl, phenyl, benzyl or alpha- or beta- phenethyl) are prepd. by reaction of rifamycin S with a N,N-di-(hydroxy or alkoxy-alkyl)amine.

Description

The present invention relates to a process for the preparation of 1,3-oxazino (5,6-c) rifamycins.

Phenols and hydroquinones are known to react with primary amines in the presence of 2 moles of formaldehyde to form 1,3-benzoxazimes or bis-1,3-oxazines (see J. Am. Chem. Soc. 71, 609, 1949; 4691, 1950, 74, 3601, 1952; 76, 1677, 1954 and J. Org. Chem. 26, 4403, 1961).

It is also known (see J. Org. Chem. 27, 2749; 1962) that bis (alkoxymethyl) amines, i.e. compounds obtained by the reaction of primary amines with 2 mol equivalents of formaldehyde and alkanol, are useful agents capable of converting hydroquinones into bis- 1,3-oxazines.

On the basis of the above procedures, attempts have been made to obtain oxazino-rifamycins from rifamycin SV having a structure similar to that of hydroquinone, but it has been found that rifamycin SV does not respond at all.

Surprisingly, however, it has now been found that rifamycin S, which is a compound having a quinone structure, can be converted to a 1,3-oxazine by reaction with bis- (oxymethyl) - or bis- (alkoxymethyl-Jamio). by reacting rifamycin S. corresponding to formula I

with biis- (1-methoxymethyl) - or. bis (N- _(koxymethyl) amine, the new .získají rafamycinové derivatives [l., 3-oxazind (5,6-c) rifamycins) of the general formula II ¹ $ 1

(R ¹ wherein R ¹ is C 1 -C 4 alkyl, allyl, C 5 -C 6 cycloalkyl, or benzyl.

These novel rifamycin compounds have the following physicochemical properties:

three maxima of absorption are present in the UV spectrum measured in a solution piled at pH 7 at 305 nm, 355 nm and 550 nm;

two characteristic singlets _t at δ 14.3 and δ 9.5 are present in the NMR spectrum measured in solution in dimethyl sulphoxide, inter alia;

the molecular ion in mass spectrography corresponds in both cases to the calculated molecular weight of the compound;

The IR spectrum measured in the nujol suspension contains, inter alia, an absorption maximum at 3400 Gin ¹ (in NH amido group).

It has also been found that the aforementioned 1,3-oxazino (5,6-craframycins of formula II) are antitoiotically active and are useful intermediates for the preparation of 3-iminomethyl derivatives of rifamycin SV, in particular rifampicin.

The term "C 1 -C 4 alkyl" as used hereinbefore and hereinafter includes straight and branched saturated aliphatic hydrocarbon radicals such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

The process according to the invention is characterized in that rifamycin S is reacted with a compound of formula III in an inert solvent at a temperature in the range of from 0 ° C to the boiling point of the solvent.

CH2OR ²

OF

R ¹ —N \

CH ² OR ² (III),

R ¹ has the abovementioned meaning and

R ² represents a hydrogen atom or an alkyl group -S 1 to 4 carbon atoms.

The reaction is preferably carried out in a dipolar. aipnoitlickém · solvent, it should be stressed that !, rifamycin S are reacted with compounds of the formula III to give l, 3-oxazine <ol (5 ₃ 6 c) ^R! famycinů above formula II, and in any other conventional organic solvent ^1.

The term "dipolar aprotic solvent" refers to a highly polar solvent, which is only a very weak hydrogen bond donor (A. J. Parker, Ghemical Reviews 69, 1, 1969). Thus, solvents such as dimethylsulfoxide, dimethylaetamide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, N-methylpyrrolidone, acetone and the like are referred to.

The reaction time depends on both the solvent used and the starting material (III) used. In practice, increasing the molecular weight of the amine of formula III and decreasing the polarity of the solvent increases the reaction time and decreases the yield of the product of formula II due to the presence of reaction by-products and / or unreacted starting material to be removed. When using compounds of the formula III wherein R ¹ represents for example methyl, ethyl, butyl or allyl group and the reaction is carried out in a dipolar aprotidkém solvent such as dimethylsulfoxide, dimethylacetamiidu or dimethylformamide at a temperature from 15 to 100 ° C, a practically pure compound of formula (II) is obtained in approximately quantitative yield, and in a very short reaction time ranging from a few minutes to 2 hours. If used as starting material a compound of formula III ·, wherein R ¹ is a cycloalkyl, phenyl or phenylalkyl radical, the reaction time increased.

In general, when the reaction is carried out in an apolar or protic polar solvent such as benzene, dioxane, tetrahydrofuiran or alcohols, the reaction time may be up to 3-4 hours and the desired product must be separated from the by-products by fractional crystallization from suitable solvents or extraction.

The oxazino (5,6-c) rifamycins thus prepared of the above formula (II) are isolated by known methods such as simple filtration or extraction, evaporation and crystallization.

The novel 1,3-oxazino (5,6-c) rifamycins according to the invention are useful antibiotics which are very effective against pathogenic bacteria, in particular against gram-positive and gram-negative microorganisms such as Staphylococcus aureus, Streptococcus pyogenes or Escherichia coli.

Furthermore, the 1,3-oxazino (5,6-c) rifamycins now available in the novel process of the present invention are useful intermediates for the preparation of the 3-iminomethyl derivatives of rifamycin SV described in French Patent No. 1,457,435, and especially a very important antibiotic known as rifampicin. The conversion of the oxazino (5,6-c) rif-emycins of formula II to the 3-iminoimethylderivatives of rifamycin SV is accomplished by reaction with primary amines, hydrazine, monosubstituted hydrazines and asymmetrically disubstituted hydrazines. For example, by reacting a compound of formula II with 1-amino-4-methylpiperazine in the presence of a secondary or tertiary amine, rifampicin is obtained in (practically quantitative yield) in a very short reaction time ranging from 15 minutes to 3 hours.

The starting materials of formula (III) above are prepared by reacting an amine of formula R ¹ -NH 2 with either 2 equivalents of formaldehyde to give the corresponding bis-hydroxymethyl derivative (compound of formula III wherein R ² is hydrogen) or with 2 equivalents of formaldehyde -a 2 m-equivalents of an alcohol of formula R 2 OH, to form a bis [(lower), alkoxymethyl] derivative (a compound of formula III, wherein R ² is a lower alkyl group. This preparation is described in J. Cihem. Soc. 123, 532 (1923) ).

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

Example 1

A compound of formula II wherein R ¹ is tert-butyl

A solution of 6.5 g of N, N-dihyidroxymethyl-t-butylamine, 40 ml of dimethylformamide and 13.9 g of S difamycinu in a four-necked flask of 100 ml stirred for 60 minutes at 33 ^Q C. The reaction mixture was then poured into »300 ml of acidified acid 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 the desired product are obtained.

The IR spectrum of the product, measured in a chloroform solution, contains bands at 3500, 1715, 1680, 1650, 1380, 1325 and 975 cm ^-1 .

Example 2

A compound of formula II wherein R ¹ is allyl

In a 100 ml four-necked flask, 13.9 g of rifamycin S is first dissolved in 40 mJ of dimethylacetamide, then 7 g of N, N-diisopropoxymethyl-alilylamine are added and the resulting solution is heated at 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. Yield 14.3 g.

The IR spectrum of the product, measured in the chloroform solution, contained bands at 3500, 1740, 1720, 16'50, 1605, 1380, 1330- and 975 cm ^-1 .

Example 3

A compound of formula II, wherein R ¹ represents a cyclehexyl group

A mixture of 13.9 g of rifamycin S, 6.5 g of Ν, dim-dimethoxymethyl-cyclohexyl amine and 40 ml of dimethylsulfoxide was heated to 50 ° C in a 100 ml four-necked flask for 45 minutes. The reaction mixture is then 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. Yield: 15.3 g.

The IR spectrum of the product, measured in a chloroform solution, contains bands at 3500, 1720, 1610, 1380, 1340, and 980 cm ^-1 .

In an analogous manner, reaction of rifamycin S with N, N-dimethoxymethyl-cyclopentylamine yields the corresponding compound of the above-mentioned formula II in which R @ ¹ is cyclopentyl.

Example 4

A compound of formula II wherein R ¹ is a benzyl group

In a 100 ml four-necked flask, 13.9 g of rifamycin S was first dissolved in 40% hexamethyltriaimide phosphoric acid, then 7.5 g of N, N-diethoxymethyl-benzylamine was added and the resulting solution was heated at 60 ° C for 20 minutes. The reaction mixture is then poured into 400 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. Yield 15.8 g.

The IR spectrum of the product, measured in a chloroform solution, contained peaks at 3500, 1740, (inflection), 1710, 1680, 1650, 1605, 1380, 1320, and 980 cm ^-1 .

By analogy, the reaction of rifamycin S with N, N-dimethoxymethyl-N, -phenethylamine and N, N-dimethoxymethyl- / henethylamine yields the corresponding compounds of the above-mentioned general formula II, wherein R 1 is α-phenylethyl, respectively. β-phenethyl group.

Example 1 (d 5

A compound of formula II wherein R ¹ is methyl

In a 100 ml four-necked flask, 14 g of rifamycin S are first dissolved in 40 ml of acetone, then 5 g of N, N-diisibutoxymethylmethylamine 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 at 40 ° C under vacuum. 13.8 g of crude product are obtained.

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

The UV spectra measured in phosphate buffer at pH 7 contain absorption maxima at _λm - 306 µm, 354 nm and 560 nm;

In mass spectrometry, the maximum corresponding to the molecular ion has a mass of 750.

The NMR spectrum of the product, measured in solution in dimethylsulfoxide, contains singlets at δ-1.65, 1.93, 1.99, 2.98, 3.71, 9.49 and 14.2; There are no signals in the negative areas of the DC field.

Example 6

A mixture of 14 g of rifamycin S, 50 ml of n-propyl alcohol and 5.5 g of N, N-diisobutoxymethylmethylaimine is stirred at 60 ^DEG C. in a 100 ml 60 ml four-necked flask. The reaction solution is poured into 500 ml of acidified water. 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 crude product was dissolved in chloroform (100 ml) and toluene (250 ml) and petroleum ether (750 ml) were added to the solution. The precipitate formed is filtered off and dried under vacuum at 40 ° C to give 4.2 g of pure product, identical to the product; prepared in Example 5.

By analogy to the reaction of rifiamycin S with N, N -disobutoxyimethylaniline; to give the corresponding compound of formula (II) above, wherein R ¹ is phenyl.

A compound of formula II wherein R ¹ is methyl

Claims (3)

A process for the preparation of 1,3-oxazino (5,6-c Jrifamycins of formula II) 3Z 3 / where R 1 is C 1 -C 4 alkyl, allyl, C 5 -C 6 cycloalkyl, or benzyl, characterized in that rifamycin S is left in an inert organic solvent at a temperature from 0 ° C to the boiling point of the solvent , react with a compound of formula III CH2OR2 z Ri — N \ CH ² OR ² in which. R ¹ has the abovementioned meaning and R ² represents a hydrogen atom or a C 1 -C 4 alkyl group to form a solution which is treated with water acidified to a pH in the range of 4 to 6, then the water and solvent are evaporated to give a solid residue containing the desired product. 2. A process according to claim 1, wherein the inert organic solvent is a dipolar aprotic solvent and the reaction is carried out at a temperature of 1.5 to 100 [deg.] C. 3. A process according to claim 2 wherein the dipolar aprotic solvent is di-dimethylisulfoxide, dimethylformamide or dimethylacetamide.