SU432721A3 - METHOD OF OBTAINING DERIVATIVES OF 3-FORMILRIPHAMICINE SV - Google Patents

Description

one

This invention relates to a process for the preparation of novel 3-formylrifamycin SV derivatives having valuable pharmacological properties.

Based on the known reaction of aldehydes with hydroxylamines, the proposed method allows to obtain new compounds with better properties than the known derivatives of rifamycin with a similar effect.

A method is proposed for the preparation of o-substituted oximes of 3-formylrifamycin SV of formula I or their hexahydro derivatives,

Me me

BUT

HE

Me o

where R is alkyl at least with 2 carbon atoms, alkenyl, alkynyl, cycloalkyl, alkoxyalkyl. cycloalkoxyalkyl, oxyalkyl. carboxyalkyl, carbalkoxyalkyl, carbamylalkyl, cyanalkyl, nitroalkyl, aryloxyalkyl, aralkoxyalkyl, heterocycloxyalkyl, aminoalkyl, mono- or dialkylaminoalkyl, substituted benzyl, mono- or polyaryl, substituted alkyl with 2-8 carbon atoms, lower alkyl, substituted 1-3 monomer nuclear heterocyclic rings,

containing at least one heteroatom selected from a variety of oxygen, nitrogen and sulfur, with the exception of morpholine; RI is hydrogen or acetyl radical. Alkyl, alkenyl and alkynyl groups contain at most 20 carbon atoms. These groups can be linear or branched. Alkenyl groups may contain one or a plurality of double bonds; alkynyl groups may contain one or many

triple bonds.

Aryl and aralkyl groups are aromatic groups that contain 1-3 carbocyclic rings and may be unsubstituted or may contain one or more substituent groups in the ring, including, for example, lower alkyl with 1-4 carbon atoms, halogen, amino, mono - and dialkylamino, halogen (lower) alkyl, sulfo, fluorosulfonyl, sulfamido, cyano,

carboxy, hydroxy, caroalki, nitro and the like. Cycloalkyl groups usually contain from 3 to 18 carbon atoms.

Heterocyclic moieties contain mono- or 1: 0 or a hetero-heterocyclic ring groups having at least one heteroatom selected from a number of oxygen, nitrogen, or sulfur.

A morpholip is excluded if the heterocycle is a substituent of a lower alkyl group.

The method of preparing the compounds consists in treating 3-formylrifamycin SY or its 25-desacetyl and 16, 17, 18, 19, 28, 29 hexahydro-derivatives in an organic solvent with a stoichiometric amount of o-mixed, hydroxylamine of the formula NHo-O-R, where R has the indicated value, followed by separation of the reaction products by conventional methods.

The compounds obtained are colored solids soluble in common organic solvents, for example benzene, ethyl acetate, chloroform, dioxap, tetrahydrofuran.

The general way of getting about it is with about. To a solution of 0.01 mol of 3-formylriphamycin SV or its 25-desacetyl and 16, 17, 18, 19, 28, 29 hexahydro-derivatives in tetrahydrofuran are added with stirring at room temperature 0.01 mol of o-hydroxyl hydroxylamine. After stirring for 20 minutes - 3 hours, the reaction mixture is examined by silica gel thin-layer chromatography.

After complete disappearance of the starting compound, the solution is concentrated to dryness and the crude compound is purified by recrystallization.

The starting compound for the preparation of hexahydro-produced rifamycins of the formula I, i.e., 16, 17, 18, 19, 28, 29 hexahydro-3-formylrifamycin SV is prepared as follows.

20 g of rifamycin S, dissolved in 600 ml of dry ethanol, are hydrogenated in a bomb with 2 g of P- | -02 as a catalyst for 3 hours at room temperature under a hydrogen pressure of about 5 atm. After filtering off the catalyst, the solution is evaporated to dryness and the dry product, dissolved in tetrahydrofuran, is kept under stirring with 18 g of MpO2 at room temperature. The inorganic precipitate is filtered off and after concentrating the filtrate to a small volume, the mixture is dissolved in ethyl acetate (300 ml) and washed with water. The organic layer is dried over Na9SO4 and after evaporation 8 g of hexatidroformycin are obtained.

SV (t, pl. 158-60 ° C, from methanol). This product is converted to the corresponding 3-formyl derivative in the manner described in Example 5 of British Patent No. 1.219.360. 5 The crude product can be purified by chromatography on a column of its chloroform solution through silica gel and elution with chloroform containing 1% of the methanol. By evaporation of the solution treated with chromatography, 16, 17, 18, 19, 28, 29-hexahydro-3-formyl rifamycin SV is obtained with an mp. 126--133 ° C.

According to the invention, oximes 3-formylrifamycin SV, 25-desacetyl15 3-formylriphamycin SV and their derivatives hydrogenated at positions 16, 17, 18, 19, 28, 29 were obtained by condensation with o-substituted hydroxylamine RONH2, where R is the following radicals;

0 4-hydroxybutyl, 6-hydroxyhexyl, 8-hydroxyoctyl, 2-methyl-2-penten-3-yl, 2-octene-4-yl, 2-heptin-1-yl, triphenylmethyl, tricyclohexylmethyl, tricyclopentylmethyl, 3-dibutylaminopropyl, cyclopeptyl , cycloheptyl, 2-propoxyethyl 5 2-isopropoxyethyl, 2-benzyloxyethyl, 3-metoksipronil, 3-ethoxypropyl, 3-propoksipro: yl, 3-butoxypropyl, 3-benzyloxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-propoksibutil, 4-isopropoxybutyl, 4-butoxybutyl, 0 4-isobutoxybutyl, 4-phenoxybutyl, 4-benzyloxybutyl, 6-phenoxyhexyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2-diphylamine ethyl, 2-dipropilamipoetil,

2-dibutilami1yuetil, 3-methylaminopropyl, 5 3-dimethylaminopropyl, 3-ethylaminopropyl, 3-diethylaminopropyl, T-dipronilaminopropil, 3-butylaminopropyl, 4-dimethylaminobutyl, 4-diethylaminobutyl, 4-dipropilaminobutil, 4-dibutylaminobutyl, 2-metilfenilami0 Noetus, 2-ethylphenylaminoethyl, 2- (2-methoxyethoxy) -ethyl. 2- (2-ethoxyethoxy) -til, 2- (2-butoxyethoxy) -ethyl, 3-methoxybutyl, 8-phenoxyoctyl, 10-fepoxydecyl, 3- (4-hydroxyphenyl) -propyl, 2- (4-hydroxyphenoxy) - ethyl, 3-carboxy-3-fe5 ylpronyl, 4-carboxybenzyl, 2-carboxybenzyl, 2, 3, 6-trichlorobenzyl, 4-carboxyphenethyl, 3- (4-carboxyphenyl) -nroy1, 4- (4-carboxyphenoxy) -butyl , 2- (3,4-dichlorophenoxy) -ethyl,

2- (2,6-dichlorophenoxy) -ethyl, 3- (4-carboxypheno0 oxn) -propyl, 3- (4-carboxymethoxyphenyl) propyl, 2- (2,6-dimethoxn-4-carboxyphenyl) propyl, carboisobutoxymethyl, 1 -carboisobutoxyethyl, 3- (3-nitro-4-hydroxyphenyl) -nronyl.

3- (1 -apperidino) -propyl, 3- (2-thienyl) propyl, 4- (2-formyl) -butyl, 2- (3-isoxazolyl) -ethyl,

4-) pyridylmethyl, bis- (4-pyridyl) -methyl, 3- (4-pyridyl) -propyl, 3- (8-quinolinium) -propyl, 3- (4-dimethylaminophenoxy) propyl, 5,6-dibromhexyl and many other residues.

Subject invention

Claims (1)

1. A method for preparing prototype 3-formylrifamycin SV of the general formula Me me Me 0 OH J 1 NH OH Me 0 where R - alknlgrunpa no mennley least 2 carbon atoms, alkenyl, alkynyl, tsnkloalkil-, alkoxyalkyl, tsikloalkoksialkil-, hydroxyalkyl, carboxyalkyl-, karbalkoksialKIL-, karbamnlalkil-, tsianalkil-, nntroalKNL-, arile:; glalhil- , aralkoksialkil-, geterotsikloksialkil- and shnoalkilgruppa, mononli di (lower) alkilaminoalknlgruppa substituted benzyl, mono- or ioliarilom alkilgrupia substituted with 2-8 atoms uglroda, a lower alkyl group, a substituted mono- or 3 1-- Ioli PMN heterocyclic rings, containing at least one heteroatom, The selected from the series oxygen, nitrogen and sulfur; with the exception of morpholia as a substituent; RI is hydrogen or acetyl group, or 6, 17, 18, 19, 28, 29 hydrogenated n |) derivatives, o tl and h ayo; and with the fact that 3-formylrifamycin SV, 25-desacetyl-3-formylrifamycin SV or their hexahydro-derivatives are subjected to interaction and triazine, 1N (1 with 3-substitutions of o-substituents; 1: hydroxyl amine of the formulas RONHj. the specified values, with 1second; qi, the selection of the target product by conventional techniques. 2, the method according to claim 1, characterized in that the reaction is carried out in an organic solvent at room temperature, Priority by featured; 07.06.71-method for producing a 1P penetration: 1x 3-formylrifamination SV, 24.06.71 — method for preparing 16, 17, 18, 0, 28, 29 hydrogenated derivatives of 3-formylrifamination — SV,