CS231154B2 - A process for the preparation of alkyl-7-desoxy-7-RS "-" - thiolinkosaminides - Google Patents

Abstract

A method for producing acyl derivatives of alkyl-7-desoxy-7-RSn-alpha-thiolincosaminides of general formula III consisting in heating alkyl-N-acyl-6,7- -aziridino-6-desamino-7-desoxy-alpha-thiolincosaminides of general formula II with sulfide of general formula K3X-81-Sn-R2-YB4’, wherein the substituents Ac, Acj, Alk, η, R,, R2, RiX and IRa have the meaning given in point 1 of the subject of the invention, at a molar ratio of both substances at a temperature of 70 to 140 °C, preferably at the reflux temperature, if the boiling point of the sulfide is such that the mixture boils below 110 °C, in glacial acetic acid or in other anhydrous lower alkanoic acids or in anhydrous benzoic acid and in other arenic acids containing not more than 12 carbon atoms at atmospheric pressure and in the case where For a low boiling sulfide to provide a reaction mixture that refluxes below 70 °C, it is necessary to carry out the reaction at a pressure higher than atmospheric.

Description

Process for the production of acyl derivatives of alkyl-7-deoxy-7-RSn-alpha-thiolincosaminides of general formula III

consisting in heating an alkyl-N-acyl-6,7-aziridino-6-desamino-7-desoxy-alpha-thiolincosaminide of the general formula II with a sulfide of the general formula ^K 3 ^X - ⁸ 1- ^S n- ^R 2- ^YB 4', wherein the substituents Ac, Acj, Alk, η, R,, R2, RiX and IRa have the meaning given in point 1 of the subject of the invention, at a molar ratio of both substances at a temperature of 70 to 140 °C, preferably at the reflux temperature, if the boiling point of the sulfide is such that the mixture boils below 110 °C, in glacial acetic acid or in other anhydrous lower alkanoic acids or in anhydrous benzoic acid and in other arenic acids containing not more than 12 carbon atoms at atmospheric pressure and, in the case where a sulfide with a low boiling point is used, to provide a reaction mixture that refluxes at a temperature below 70 °C, is necessary to carry out the reaction at a pressure higher than atmospheric.

23H54

The invention relates to a process for the production of acyl derivatives of alkyl-7-deoxy-7-RS _n -alpha-thiolincoseinides of general formula I

where fl represents an integer from 1 to 4, Alk represents an alkyl having up to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl and tert. butyl, or 2-hydroxyethyl; R represents the radical -R,-XRp in which R, is a saturated aliphatic hydrocarbon residue containing up to 18 carbon atoms, an unsaturated aliphatic hydrocarbon residue containing up to 10 carbon atoms, an aromatic hydrocarbon residue containing up to 1 carbon atoms, or an oxacarbocyclic aromatic or thiacarbocyclic aromatic hydrocarbon residue containing up to 8 carbon atoms; XR-j represents hydrogen or 1 or substituent, wherein X is oxygen or sulfur and Rj represents hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxyalkyl, alkylthioalkyl, all having up to 6 carbon atoms, phenyl, benzyl, furyl, furfuryl, thienyl or thenyl; and in the case where R^ and R^ are alkyl, they may be bonded to each other to form an oxacycloalkyl having up to 5 carbon atoms and having up to 6 ring members.

The compounds of general formula I are prepared according to the invention by reacting an alkyl-N-ecyl-6,7-aziridino-6-desamino-7-desoxy-alpha-thiolincosaminide of general formula II

in which Ac and Ac represent carboxyacyl having at most 18 carbon atoms and Alk has the meaning defined above, is heated in the presence of glacial acetic acid or in the presence of other anhydrous lower alkanoic acids, anhydrous benzoic acid or other arenic acids containing at most 12 carbon atoms, with a sulfide of the general formula RjX-Rj-S^-Rg-YR^, in which f1 is 1, 2, 3 or 4; R, and Rg, which may be the same or different, represent saturated aliphatic hydrocarbon residues containing not more than 18 carbon atoms, unsaturated aliphatic hydrocarbon residues containing not more than 10 carbon atoms, cycloaliphatic hydrocarbon residues containing not more than 10 carbon atoms, aromatic hydrocarbon residues containing not more than 11 carbon atoms, or oxacarbocyclic or thiacarbocyclic aromatic hydrocarbon residues containing not more than 8 carbon atoms; R^X and YR^ represent hydrogen or together up to three substituents, wherein X and Y, which may be the same or different, represent oxygen or sulfur and R^ and R^, which may be the same or different, represent hydrogen, carboxyacyl (Ac^), alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxyalkyl, alkylthioalkyl, all having up to 6 carbon atoms, phenyl, benzyl, furyl, furfuryl, thienyl or thenyl; and wherein R^ and Rj, in the case where X is oxygen and Rj is alkyl, may be bonded to each other to form an oxacycloalkyl having up to 5 carbon atoms and having 3 to 6 ring members. If it is desired that in the final product of general formula I fl is greater than 1, -Rg-YR^ must be a radical which readily forms a carbonium ion, for example tertiary butyl or ellil. Opening of the aziridine ring gives an acylated alkyl-7-deoxy-7-RS _n -alpha-thiolincosaminide of general formula III

wherein n, Ze, Ac, X, R, R, and Alk are as defined above.

The acyl groups are then removed by hydrazinolysis in a manner well known per se (see U.S. Patent No. 3,179,565) to yield the alkyl-7-deoxy-7-RS _n -alpha-thiolincosaminide of formula I.

The compounds of the invention (of general formula I) can be used for the same purposes as methyl-alpha-thiolincosaminide (= methyl-6-amino-6,8-dideoxy-1-thio-D-erythro-alpha-D-galacto-octopyranoside, alpha-MTL), as disclosed in U.S. Patent No. 3,380,992, and as methyl-6-amino-7-chloro-6,7,8-trideoxy-1-thio-L-threo- and D-erythro-alpha-D-galacto-octopyranosides (U.S. Patent Nos. 3,496,163 and 3,502,648), and can further be acylated with trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxylic acid as disclosed in said patents, or with N-(2-hydroxyethyl)-L-2-pyrrolidinecarboxylic acid, whereby compounds of general formula IV are formed.

in which R, n and Alk have the meaning defined above and Ac is the acetyl residue of L-2-pyrrolidinecarboxylic acid or N-methyl-, N-ethyl- or N-(2-hydroxyethyl)-L-2-pyrrolidinecarboxylic acid, each of said acids being optionally substituted in position 4 by lower alkyl or lower alkylidene.

It is known that 7-SH analogues can be prepared by heating an aziridine compound of the general formula II, in which Ac and Ac, denote hydrogen atoms, with hydrogen sulfide (U.S. Patent No. 3,544,551). However, it has not yet been possible to replace the hydrogen bonded to sulfur in these compounds, either directly or indirectly. The compounds of the invention are, however, significantly more effective than the corresponding 7-SH compounds. For example, 7-deoxy-7(S)-(methylthio)-lincomycin hydrochloride is several times more effective in vitro against gram-positive bacteria than lincomycin, while 7-deoxy-7(S)-mercaptolincomycin hydrochloride is less effective than lincomycin.

It is also known that 7-OR analogues can be prepared by reacting a compound of formula II with alcohols in the presence of acid. However, attempts to prepare sulfur analogues using mercaptans instead of alcohols have been unsuccessful.

It has now been found that compounds of general formula II undergo sulfidolysis on heating with sulfides (mono, di, tri or tetra) in glacial acetic acid or in other anhydrous lower alkanoic acids or in anhydrous benzoic acid or in other arenic acids containing not more than 12 carbon atoms. The reaction probably proceeds in the following manner*.

AcNH

AcNH

When mixed sulfides are used,

^e OAc _r (S _N 2) ch ₃

SR + ROAc assume the following reaction sequence:

AcNH

CH ₃

S-isoPr + MeOAc

-SMe

AcNHCH, + CHf

AcO°.

soPrOAc

CH,

With polysulfides, the reaction proceeds as follows:

CH,

AcN ^Et 2 ^s n

-HOAc AcNH

CH,

-SET

Using mixed polysulfides, another compound can be obtained, namely a disulfide; for example

23H54 ch ₃

H

AcN ©

ch ₃

-SnR'

AcNH

RS _n R'

AcNH

CH,

With _n -1'

--S— R ch ₃

AcNH thiophilic attack and AcO®

SR + AcOSR'

Polysulfide formation occurs when R e/or R' is a radical that readily forms a carbonium ion, for example tert. butyl or allyl. In the case of tert. butyl, the carbonium ion can cleave a proton to form isobutylene.

With any of the above sulfides, the desired result is achieved simply by heating the alkyl-N-acetyl-6,7-aziridino-6-desamino-7-desoxy-alpha-thiolincosaminide with the corresponding sulfide in glacial acetic acid or in another anhydrous lower alkanoic acid or in anhydrous benzoic acid or in other arenic acids containing up to 12 carbon atoms, for example in propionic acid or in butyric acid.

The reaction is preferably carried out in a solvent boiling in the range of 70 to 1.0°C, and usually an excess of sulfide is used. If necessary, for example, dioxane, carbon tetrachloride, benzene or toluene can be used as solvents, particularly preferably with sulfides boiling above 1.0°C.

The ratio of reactants is not critical to the course of the reaction, but is critical to the yields. Optimum yields are obtained by using about 3 to 7 equivalents of acid, together with a substantial excess, at least twofold, of sulfide. If a sulfide with a low boiling point is used, for example dimethyl sulfide, which has such a low boiling point that it gives a reaction mixture that refluxes at a temperature below 70 °C, it is necessary to carry out the reaction at a pressure higher than atmospheric; if the boiling point of the sulfide is such that the reaction mixture boils above 100 °C, it is necessary to control the temperature. In other cases, it is expedient to heat the reaction mixture to the reflux temperature.

The reaction mixture is worked up by methods well known per se, for example by countercurrent partitioning, chromatography, solvent extraction or crystallization.

The starting compounds of general formula 11 exist in two epimeric forms

The reaction occurs in excess. For example, if dimethyl sulfide is reacted with methyl-N-acetyl-2,3,4-tri-O-acetyl-6(R),7(R)-eziridino-6-desamino-7-deoxy-alpha-thiolincosaminide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-alpha-thiolincosaminide is obtained.

The starting compounds of the general formula II are prepared in a manner known per se by acylation of the compound of the general formula VI

with a suitable acylating agent, such as acetic anhydride or other lower alkanoic acid anhydride, or benzoyl chloride or a similar carboxylic acid halide. Since the amino group and the hydroxy groups acylated at different rates, the N-acyl (Ac) and O-acyl (Ac,) may be the same or different.

Since the said acyl groups (Ac and Ac,) do not occur in the final product, since they are removed in the process according to the invention, it is immaterial what kind they are, as long as they are acyls of carboxylic acids. Suitable carboacyls are acyls of carboxylic acids having a maximum of 18 carbon atoms, or acyls of halogen-, nitro-, hydroxy-, amino-, cyano-, thiocyano- or alkoxy-substituted carboxylic acids having a maximum of 18 carbon atoms. Inert carboxylic acid acyls can be used, i.e. those which are not attacked during the reaction. Acetyl or other lower alkanoyl, or benzoyl or other aroyl, having a maximum of .2 carbon atoms is usual. However, any carboxylic acid can be used.

The starting compounds of general formula VI can be prepared by dehydrohalogenation of compounds of general formula VII.

OH (VII), which are described in U.S. Patent No. 3,502,648. Dehydrohalogenation is carried out according to U.S. Patent No. 3,544,551 by heating the compound of the general formula VII in inert solvents in the presence of an acid acceptor. It is expedient to proceed as follows: a mixture of the starting compound, anhydrous sodium carbonate and dimethylformamide is heated for a short time under reflux, the solvent is distilled off from the reaction mixture and the residue is crystallized from a suitable solvent, for example methanol (see Belgian Patent No. 732,352 of October 30, 1969).

The starting sulfides of the general formula R^X-Rj-S^Rg-YR^ are known compounds. The substituent R in the general formula I is the radical R-jX-Rj-, as defined above.

Suitable starting sulfides (mono and poly) include, for example, sulfides of saturated aliphatic hydrocarbons, i.e. alkyl sulfides, which may be symmetrical or unsymmetrical and in which alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl, and their isomeric forms, for example dimethyl sulfide, ethylmethyl sulfide, diethyl sulfide, dibutyl sulfide, di-2-butyl sulfide, di-tert. butyl sulfide, methylpropyl sulfide, isopropylmethyl sulfide, ethylpropyl sulfide, ethylisopropyl sulfide, butylmethyl sulfide, 2-butylmethyl sulfide, isobutylmethyl sulfide, tert. butylmethyl sulfide, methylpentyl sulfide, isopropylpropyl sulfide, 1-ethylpropylmethyl sulfide, ethylisobutyl sulfide, tert. of butyl ethyl sulfide, sec. butyl ethyl sulfide, butyl ethyl sulfide, dipropyl sulfide, diisopropyl sulfide, hexyl methyl sulfide, ethyl pentyl sulfide, isobutyl propyl sulfide, sec. butyl propyl sulfide, butyl propyl sulfide, isopropyl isobutyl sulfide, sec. butyl isopropyl sulfide, terc. of butylisopropylsulfide, butylisopropylsulfide, pentylpropylsulfide, heptylmethylsulfide, ethyl-1-methylpentylsulfide, ethylhexylsulfide, ethyl-1-ethylbutylsulfide, ethyl-1,3-dimethylbutylsulfide, butylisobutylsulfide, butyl-sec. butylsulfide, diisobutylsulfide, methyloctylsulfide, hexylpropylsulfide, butylpentylsulfide, butylisopentylsulfide, diisopentylsulfide, dipentylsulfide, isopropyloctylsulfide, isopropyl-1-methylheptylsulfide, decylmethylsulfide, nonylpropylsulfide, butyl-1-propylpentylsulfide, butyloctylsulfide, butyl-1-methylheptylsulfide, bis(1,3-dimethylbutyl)sulfide, di(isohexyl)sulfide, dihexylsulfide, dodeylmethylsulfide, propylundecylsulfide, nonylpentylsulfide, hexyloctylsulfide, hexyl-1-methylheptylsulfide, dodecylethylsulfide, butyldecylsulfide, bis(5-methylhexyl)sulfide, bis(1,4-dimethylpentyl)sulfide, diheptylsulfide, methyltetradecylsulfide, 2-ethylhexyl-1-methylheptyl sulfide, bis(isopropylpentyl)sulfide, bis(2-ethylhexyl)sulfide, dioctylsulfide, hexadecylmethylsulfide, dinonylsulfide, tert.butyl-1-ethyl-1-methylbutylsulfide, butylheptylsulfide, decylmethylsulfide, ethylnonylsulfide, octylpropylsulfide, hexylpentylsulfide, didecylsulfide, didecylsulfide, butylhexadecylsulfide, dodecyloctylsulfide, of ethyl octadecyl sulfide, heptadecylpropyl sulfide, didodecyl sulfide, di(tert. dodecyl) sulfide, ditert. dodecyl) disulfide, di(tert. dodecyl) trisulfide, ditetradecyl disulfide, ditetradecyl tetrasulfide, dodecyl octadecyl sulfide, dihexadecyl sulfide, dihexadecyl disulfide, dihexadecyl trisulfide, dihexadecyl tetrasulfide, di(tert. hexadecyl) tetrasulfide, bls(1,1-dipentylhexyl) disulfide, dioctadecyl disulfide, dioctadecyl trisulfide, and dioctadecyl tetrasulfide; sulfides of unsaturated aliphatic hydrocarbons, for example divinyl sulfide, divinyl disulfide, methyl vinyl sulfide, ethyl vinyl sulfide, propyl vinyl sulfide, isopropyl vinyl sulfide, butyl vinyl sulfide, diallyl sulfide, diallyl disulfide, allyl methyl sulfide, allyl methyl disulfide, allyl ethyl sulfide, allyl ethyl disulfide, allyl propyl sulfide, allyl propyl disulfide, propenyl sulfide, allyl-2-methylallyl sulfide, methyl propenyl sulfide, bis(2-methylallyl) sulfide, ethyl propenyl sulfide, ethyl isopropenyl sulfide, propenyl propyl sulfide, propenyl propyl disulfide, methyl 1-methylallyl sulfide, ethyl methallyl sulfide, 2-butenyl methyl sulfide, 1-butenyl ethyl sulfide,

2-butenyl ethyl sulfide, methyl-1-methyl-2-butenyl sulfide, methyl-2-methyl-2-butenyl sulfide, methyl-3-methyl-3-butenyl sulfide, methyl-2-pentenyl-1-butenyl sulfide, methyl-3-pentenyl-t-butenyl sulfide, methyl-1-methyleneallyl sulfide, ethyl-1-methyleneallyl sulfide, of 1,3-butadienyl ethyl sulfide, 2,3-butadienyl ethyl sulfide, ethynyl methyl sulfide, ethylethynyl sulfide, ethinyl isopropyl sulfide, butylethynyl sulfide, target. butylethynyl sulfide, ethyl-1-propynyl sulfide, ethyl-2-proplnyl sulfide, 1-propynylvinyl sulfide, isopropylpropynyl sulfide, methyl-1-propynyl sulfide, ,-butynylmethylsulfide, 3-butynylmethylsulfide, 1-butynylethylsulfide,

3-butynylethylsulfide, l-buten-3-lnylmethylsulfide, 1-buten-3-ynyl-butylsulfide, 3-butene231154

-1-ynyl-methylsulfide, 3-buten-1-ynyl-ethylsulfide, bis(1-propynyl)sulfide, bis(1-butynyl)sulfide, 1-hexynylvinylsulfide, or ethyl-1-heptynylsulfide; sulfides of cycloaliphatic hydrocarbons, for example cyclopentyl methyl sulfide, cyclopentyl ethyl sulfide, cyclopentyl propyl sulfide, cyclopentyl isopropyl sulfide, cyclopentyl butyl sulfide, cyclopentyl isobutyl sulfide, c,cyclopentyl (sec. butyl) sulfide, cyclopentyl (tert. butyl) sulfide, cyclopentyl pentyl sulfide, dicyclopentyl sulfide, dicyclopentyl disulfide, of cyclohexyl methyl sulfide, cyclohexyl ethyl sulfide, cyclohexyl vinyl sulfide, cyclohexyl butyl sulfide, cyclohexyKsek. butyl)sulfide, cyclohexylpentylsulfide, cyclohexylcyclopentylsulfide, dicyclohexylsulfide, dicyclohexyldisulfide, bis(cyclohexylmethyl)sulfide, 5-ethylthio-2-norbornene, 5-(butylthio)-2-norbornene, bis(4-methylcyclohexyl)sulfide, 3-methyl-1-(4-methylcyclohexylthio)butane, of 1-cyclohexen-1-yl-octylsulfide, 3-cyclohexen-1-yl-3-vinylcyclohexylsulfide, 3-cyclohexen-1-yl-4-vinylcyclohexylsulfide, 1-cyclohexen-1-yl-vinylsulfide, or 2,4,6-cycloheptatrien-1-yl-sulfide and aromatic sulfides, for example methylphenylsulfide, ethylphenylsulfide, propylphenylsulfide, isopropylphenylsulfide, butylphenylsulfide, sec. butylphenylsulfide, isobutylphenylsulfide, target. of butylphenylsulfide, pentylphenylsulfide, isopentylphenylsulfide, hexylphenylsulfide, isohexylrenylsulfide, iso-sec. hexylphenylsulfide, 1-ethyl-1-methylpropyl-phenylsulfide,

of 1,1-dimethylbutyl-phenylsulfide, 1,5-hexadienyl-phenylsulfide, 1-ethyl-1-butenyl-phenylsulfide, 1-tert. butylvinyl-phenylsulfide, phenyl-1-vinyl-3-butenylsulfide, cyclohexylphenylsulfide, cyclohexylphenylsulfide, 1-cyclohexen-1-yl-phenylsulfide, 2-cyclohexen-1-yl-phenylsulfide, 3-cyclohexen-1-yl-phenylsulfide, 1-methylcyclohexyl-phenylsulfide, octylphenylsulfide,

1-ethyl-1-methylpentyl-phenylsulfide, 1-methylheptyl-phenylsulfide, phenyl-1,1,4-trimethyl-3-pentenylsulfide, 3,4-dimethyl-3-cyclohexen-1-yl-phenylsulfide, 3-(cycloocten-1-yl)phenylsulfide, 2-(cycloocten-1-yl)phenylsulfide, 4-(cycloocten-1-yl)phenylsulfide, 2-(3-Cyclohexen-,-yl)ethyl-phenylsulfide, pentyl(p-tolyl)sulfide, hexyl-(o-tolyl)sulfide, 1-ethyl-1-butenyl(p-tolyl)sulfide, di(m-tolyl)sulfide, di(o-tolyl)sulfide, di(p-tolyl)sulfide, di(m-tolyl)sulfide, di(o-tolyl)sulfide, o-tolyl-(p-tolyl)sulfide, butyl-3,4-xylyl sulfide, phenyl-3,4-xylyl sulfide, propyl-(o-propylrenyl) sulfide, o-cymen-3-yl-isopropyl sulfide, p-tert. butylphenyl-isopropylsulfide, isopropylthymylsulfide, terc. butyl-(p-tert. butylphenyl) sulfide, sec. butyl-(o-sec. butylphenyl) sulfide, tert. butyl-o-(2-methylallyl)phenylsulfide, (4-tert.butyl-o-tolyl)methylsulfide, 2-cyclopenten-1-yl-(p-tolyl)sulfide, 2,4,6-cycloheptatrien-1-yl-(p-tolyl)sulfide, 2-cyclopropylferrylsulfide, p-(2,4,6-cycloheptatrien-1-yl)phenylmethylsulfide, butyl-1-naphthylsulfide, butyl-2-naphthylsulfide, 1-methyl-2-(methylthio)acenaphthalene, 2-(methylthioJfluorene, benzylpentylsulfide, benzylhexylsulfide, benzyl-1-ethyl-2-methylpropylsulfide, benzyl-1,1-dimethylbutylsulfide, benzyl-1,3-dimethyl-2-butenylsulfide, benzyl-(2,4,6-cycloheptatrien-1-yl)sulfide, benzylcyclohexylsulfide, methyl-5-phenylpentyl sulfide, benzyl-1,1-dimethyl-2-propynylsulfide, p-methylbenzyl-phenylsulfide, o-methylbenzyl-phenylsulfide, phenethyl-phenylsulfide, benzyl-(p-tolyl)tetrasulfide, benzyl-(p-tolyl)disulfide, benzyl-(m-tolyl)sulfide, benzyl-(p-tolyl)sulfide, dibenyldisulfide, terc. butylstyrylsulfide, butylstyrylsulfide, butyl-1-phenylvinylsulfide, phenylstyrylsulfide, phenyl-1-phenylvinylsulfide, ethyl-1-isopropyl-3-phenylpropadienylsulfide, ethyl-1-methyl-3-phenylpropadienylsulfide, terc. butyl-phenylethynyl sulfide, isobutyl-phenylethynyl sulfide, 2-(methylthio)furan, 3-(methylthio)furan, 2-(ethylthio )furan, 2-[(methylthio)methyl] furan, 2-[\ethylthio Jmethyl] furan, 2-ethylthio-5-methylfuran, 2-ethyl-4-(ethylthio)furan, 2-ethyl-5-(ethylthio)furan,

2-(Butylthio)-5-methylfuran, 2-[(isopropylthio)methyl]furan, 1-[(propylthio)methyl]furan, 2-[(butylthio)methyl]furan, 2-[(tert.butylthioJmethyl]furan, 2-[(isobutylthio)methyl]furan 2-(butylthio)-5-methylfuran, 2-(isobutylthio)-5-methylfuran, 2-[(isopentylthio)methyl]furan

2-[(pentylthio)methyl]furan, 2-[(hexylthio)methyl]furan, 2-[(octylthio)methyl]furan, 2-[(allylthio)methyl]furan, 2-(methylthio)thiophene, 3-(methylthio)thiophene, 2-ethylthiothiophene

3- ethylthiothiophene, 2-(propylthio)thiophene, 2-(isopropylthio)thiophene, 2-(butylthio)thiophene, 2-(sec.butylthio)thiophene, 2-(tert.butylthio)thiophene, 3-£utylthio)thiophene, 3-(butyldithio)thiophene, 2-(pentylthio)thiophene, 2-(isopentylthio)thiophene, 2-(nonylthio)thiophene, 2-(dacylthio)thiophene, 3-(decylthio)thiophene, 2-(undecylthio)thiophene, 2-(dodecylthio)thiophene, 2-(tetradecylthio)thiophene, 2-(vinylthiomethyl)thiophene, 2-(cyclopentylthio)thiophene, 2-(phenyldithio)thiophene, 2-methyl-5-(methylthio)thiophene, 3-methyl-5-(methylthio)thiophene, 2-(ethylthio)-5-methylthiophene, 3-(ethylthio)-2,5-dimethylthiophene, 2-(butylthio)-5-methylthiofpn, 2-(tert. bUtylthio)-5-methylthiophene, 2-(benzylthio)-5-methylthiophene, 2-(benzylthio)-5-methylthiophene,

-ethylthiophene, 2-((ethylthio)methyl] thiophene, 2-[(butylthio)methyl] thiophene, 2-[(isobutylthio)methyl]thiophene, 2-[(butylthio)methyl]-5-methylthiophene, 2-[(isobutylthio)methyl]-5-methylthiophene, 2-[(3-hexylthio)propyl] thiophene, 2-[t>-methyl-alpha-(p-tolylthio)benzyl] furan,

2-[p-methyl-alpha-(p-tolylthio)benzyl]furan, 2-{[2-(butylthio)ethoxy]methyl}furan, 2,5-bis(phenylthio)-3,4-bis(p-tolylthio)thiophene, and similar compounds in which one or both of the groups R and R are substituted as indicated above, for example 3-(ethylthio)-1-propanol,

1-(methylthio)-2-propanol, 2-(ethylthio)ethanol, 3-(ethylthio)-1-propanol, 1-Cethylthio)-2-propanol, 2-(isopropylthio)ethanol, 4-(methylthio)-1-butanol, 4-(methylthio)-2-butanol,

3-(isopropylthio)ethanol, 2-(butylthio)ethanol, 2-(tert.butylthio)ethanol, 3-(methylthio)-1-hexanol, 3-(tert.butylthio)-1-propanol, 2-(hexylthio)ethanol, 8-(methylthio)-1-octanol,

9-(methylthio)-1-nonanol, 2-(octylthio)ethanol, 2-(ethylhexylthio)ethanol, ,-(octylthio)-2-butanol, 2-methyl-1-(octylthio)-2-propanol, 3-methyl-1-(octylthio)-2-butanol, 3-(methylthio)-1,2-propanediol, 2,2'-dithiodiethanol, 1-[(2-hydroxyethyl)thio]-2-propanol, 2-[(2-methoxyethyl)thio]ethanol, 2- [2-(ethylhexyloxy)ethylthio] ethanol, 2-[(1-methylheptyl)thio]-2-propanol, 1-(octylthio)-2-propanol, 2-(decylthio)ethanol, 5-(heptylthio)-1-pentanol, 2-(methylheptyl)thio]-2-propanol, 2-(2-mercaptoethylthio)ethanol,

1-(2-mercaptoethylthio)-2-propanethiol, 1-(ethylthio)-2-propanethiol, 2-(isopropylthio)ethanethiol, 3-(octylthio)-1-propanethiol, (methylthio)acetaldehyde, dimethyl mercaptal, methyl 2-(methylthio)ethyl ether, ethyl 2-(methylthio)ethyl ether, 1-(methoxymethoxy)-2-(methylthio)-ethane, bis(2-methoxyethyl)sulfide, bis(2-methoxy,ypropyl)sulfide, bis(isopropoxymethyl)sulfide, butyl-2-ethoxyethylsulfide, 2-butoxyethylethylsulfide, 2-butoxyethylbutylsulfide, bis[2-(docenyloxy)ethyl]sulfide, 1,2-bis(methylthio)ethane, 1,2-bis(methylthio)propane, 1-(ethylthio)-2-(methylthio)ethane, 1,2-bis(methylthio)propane, 1,3-bis(methylthio)propane, 1,2-bis(ethylthio)propane, 1,2-bis(butylthio)propane, 1,3-bis(butylthio)propane, 1,3-bis(tert.butylthio)propane, 1,10-bis(methylthio)deca.n, 1,4-bis(butylthio)butane, 1,6-bis(butylthio)hexane, 1,2-bis(butylthio)-3,3-dimethylbutane, 1,2-bis(hexylthio)ethane, 1,3-bis(butylthio)-2,2-bis[(butylthio)methyl]propane, 1,5-bis(decylthio)pentane, 1,4-bis(decylthio)butane, 1,2-bis(decylthio)ethane,

1,5-bis(dodecylthio)pentane, 1,4-bis(dodecylthio)butane, 1,3-bis(dodecylthio)propane, 1,2-bis(dodecylthio)ethane, 1,5-bis(tetradecylthiopentane, 1,4-bis(tetradecylthio)butane, 1,3-»bis(tetradecylthio)propane, 1,2-bis(tetradecylthio)ethane, bis(hexadecylthio)methane, 1,2-bisChexadecylthio)ethane, 1,3-bis(hexadecylthio)propane, 1,4-bis(hexadecylthio)butane, 1,5-bis(hexadecylthio)pentane, 1,2-bis(octadecylthio)ethane, 1-(hexadecylthio)-4-(octadecylthio)butane, 1-(hexadecylthio)-5-(octadecylthio) pentane, t-(octadecylthio)-6-(pentadecylthio)hexane, 2,3-bis(methylthio)propyl methyl ether, 2,3-bis(ethylthio)-1-propanol, 3,4-bis(ethylthio)-2-methyl-2-butanol, 2-(2-ethoxyethyldithio)ethanethiol, 1-(allylthio)-2-propanethiol,

3-(allylthio)-1-propanethiol, 2-(1-propynylthio)ethanol, 2-(2-propynylthio)ethanol, 4-(methylthio)-2-buten-1-ol, 4-(methylthio)-2-butene, 2-ol, 4-(ethylthio)-4-butene _T 1-ol,

-(ethylthio)-3-buten-1-ol, 2-methyl-1-(methylthio)-3-buten,1-ol, 1-(vinylthio)-2-propanol,

1,2-bis(methylthio)ethylene, 1,2-bis(ethylthio)ethylene, bis(ethylthio)acetylene, 2-(cyclohexylthio)ethanol, 3-(cyclohexylthio)-,-propanol, beta-(ethylthio)-4' «^-cyclopentaneethanol, beta-(ethylthio)-^ ¹ '^-cyclohexaneethanol, beta-(ethylthio)-2-cyclohexylethanol, beta-(ethylthio)-3-cyclohexyl-1-propanol, 3-[(4-tert.butylcyclohexyl)thio]-,-propanol, 2-(methylthio)cyclopentanol, 2-(ethylthio>cyclopentanol, 1-[2-(ethylthio)vinyl]-cyclohexanol, 2-(butylthio)cyclohexanol, 2-(ethylthio)cyclohexanol, 2-(4-tert.butylcyclohexyl)thioethyl ether, cyclohexyl-4-(ethylthio)-1,3-butadienyl ether, 1,6-bis(cyclopentylthio)hexane, 1,2-bis(ethylthio)cyclohexane, 1-(ethylthio)-3-methylnonin-3-ol, 2-(hexylthio)ethynyl vinyl sulfide, 1-butenyl-2-(butylthio)ethyl sulfide, butyl-4-(ethylthio)-1,3-butadienyl sulfide, bis[4-(methylthio)butyl] ether, bis 2-(butylthio)ethyl ether, 2-(butylthio)ethyl vinyl ether,

2-(Butylthio)vinyl ethyl ether, 2-(tert.butylthio)vinyl ethyl ether, butyl 2-(vinylthio)ethyl ether, sec.butyl 2-(vinylthio)ethyl ether, 2-(allylthio)ethyl vinyl ether, 2-(methylthio)tetrahydropyran, 3-(methylthio)-3-oxetanemethanol, 2-(ethylthio)ethanol-acetate, 4-(methylthio)-1-butanol-benzoate, 3-(methylthio)-2-propen-1-ol-acetate, 2-(vinylthio)-2-propanol acetate, and 1,2,4-tris(ethylsulfide)benzene, 1,3,5-tris(ethylsulfide)benzene, 2-(butylthio)-1-(p-tolylthio)propane, 1,2-bis(butylthio)benzene, 1-(methylthio)-2-(phenylthio)propane, 2-(Methylthio)-l-(phenylthio)propane, 1,2-bis(phenylthio)ethylene, 1,2-bis(phenylthio)ethane, 1-(benzylthio)-2-(methylthio)benzene, p-(methylthio)-alpha-(phenylthio)toluene, 2-([p-(1-methylpen231154 tyl)phenyl]-thio}ethanol, 2-[(p-butylphenyl)thio]ethanol, 2-[(p-tert.butylphenyl)thio]ethanol, 3-f(p-tert.butylphenyl)thio]-1-propenol, 2-[(3-tert.butyl-5-methylsalicyl)thio]ethanol, 5-(benzylthio)-1-pentanol, o-(benzylthio)benzyl alcohol, p-(benzylthio)benzyl alcohol, 5-(p-tolylthio)-1-pentanol, 1-(phenylthio)-2-hexanol, 2,3-dimethyl-1-(phenylthio)-3-buten-2-ol, 2-methyl-5-(phenylthio)-2-pentenol, 2-methyl-7-(phenylthio)-3,5-heptadiin-2-ol, 2-[(1,2,3,4-tetrahydro-2-naphthyl)thio] ethanol, 3-(phenylthio)-2-norbornene methanol,

2- methylene-5-(phenylthio)-2-norbornane, 2-methylene-6-(phenylthio)-2-norbornane, beta-(phenylthio)phenethylalcohol, m-(hexylthio)phenol, o-hexylthiophenol, o-(heptylthio)phenol, m-(octylthio)phenol, o-(octylthio)phenol, p-(octylthio)phenol, 6-(ethylthio)thymol, 2,6-diisopropyl-4-(methylthio)phenol, 2,3,5,6-tetramethyl-4-[(methylthio)methyl] phenol, 3-methoxy-4-(phenylthio)-o-cresol, 3-(ethylthio)-4-(hexylthio)phenol, 1-(butylthio)-2-naphthol, p-[(phenylthio)methyl]anisole, p-(o-tolylthio)anisole, p-(p-tolyldithio)anisole, p-[(2,2-dimethylpropyl)thio]anisole, 3-(butylthio)phenetol, 1,2-dimethoxy-4-(phenylthio)benzene, 2,4-dimethoxy-1-(phenylthio)benzene, benzyloxy-(phenylthio)methane, 2-[(2-methoxyethyl)thio]-,,2,3,4-tetrahydronaphthalene, benzyl-p-(methylthio)phenyl ether, beta-(ethylthio)-2-isopropyl-4-methyl-phenetol, 3-methyl-4-(propylthio)benzyl-propyl ether, phenyl-2-(phenylthio)vinyl ether, 2-(benzylthio)tetrahydropyran, 3-[(m-tolylthio)methyl]-3-oxetanemethanol,

3-[(o-tolylthio)methyl]-3-oxetanemethanol, 3-[(p-tolylthio)methyl]-3-oxetanemethanol, 1-(epoxyethyl)-4-(phenylthio)benzene, 2,5-bis(ethylthio)furan, 2-{l-[2-(butylthio)ethoxy]propyl]furan, 2-{l-[2-(butylthio)ethoxy]propyl]furan, 2-{l-[2-(butylthio)ethoxy] butyl furan, 2-(l-[2-(butylthio)ethoxy] pentylfuran, 2,3-bis[(ethylthio)methyl]thiophene, 3,4-bis[(ethylthio)methyl] thiophene, 2,5-bis [(propylthio)methylj furan, 2- ] [2-(butylthio)ethoxy]methyl}furan,

2.5-his(butylthio)thiophene, 2,5-bis(tert.butylthio)thiophene, 2-(tert.butylthio)-5-(hexylthio)thiophene, 2-Ctert.butylthio)thiophene butylthio)-5-(isopentylthio)thiophene, 3,4-bis(cyclohexylthio)thiophene,

2.5-bis(phenylthio)thiophene, 2,5-bis(1-naphthylthio)thiophene, 2-(methylthio)-3-thiophenethiol,

5-(methylthio)-2-thiophenethiol, 3-(methylthio)-4-thiophenethiol, 3-(methylthio)-5-thiophenethiol, 5-heptylthio-2-thiophenemethanol, 2-tert. butoxy-5-methylthiothiophene, 2-(tert.butylthio)-5-(hexylthio)thiophene, 2-(diethoxymethyl)-5-ethyl-3-(ethylthio)thiophene, 3-(diethoxymethyl)-5-ethyl-2-(ethylthio)thiophene, 2-(benzylthio)-3-(diethoxymethyl)-5-ethylthiophene, 2,5-bis(2-thienylthio)thiophene, 2,5-bis(3-thienylthio)thiophene, 3,4-bis(2-thienylthio)thiophene,

3,4-bis(3-thienylthio)thiophene, 3,4-bis(cyclohexylthio)-2,5-bis(ethylthio)thiophene.

Any of the above sulfides containing one or more hydroxyl or sulfhydryl groups can be esterified. Acetic acid or benzoic acid is usually used for esterification, but for the reasons given above for the Ac and AC| groups, any carboxylic acid can be used for esterification. In other words, any hydrogen of the hydroxyl and sulfhydryl groups can be replaced by an Acp group which may be the same or different from the Ac groups, on the oxygen in the 2, 3 or 4 position.

Acylation of the compounds of the invention (of general formula I) with L-2-pyrrolidinecarboxylic acid gives compounds of general formula IV. In the case where the substituents Alk and R are methyl and the L-2-pyrrolidinecarboxylic acid is trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxylic acid and the configuration at position 7 is (S), this is 7-deoxy-7(S)-(methylthio)lincomycoin, which is antibacterially many times more effective than lincomycin. This compound and its analogues can be used for the same purposes and in the same way as lincomycin.

The compounds of the invention (of general formula I), as well as their acyl derivatives with L-2-pyrrolidinecarboxylic acid, can exist either in the form of the free base or in the form of an acid addition salt. Unless otherwise specified or unless the context indicates otherwise, both forms, both the acid addition salt and the free base, are always intended. The above-mentioned acid addition salts can be prepared by neutralizing the free base with an appropriate acid to a pH lower than 7.0, preferably to about pH 2 to pH 6. Suitable acids for this purpose include, for example, hydrochloric, sulfuric, phosphoric, thiocyanic, fluorosilicic, hexafluoroarsenic, hexafluorophosphoric, acetic, succinic, citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucilaginous, camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, 3-phenylsalicylic, 5-phenylsalicylic, 3-methylglutaric, orthosulfobenzoic, cyclohexanesulfamic, cyclopentanepropionic, 1,2-cyclohexanedicarboxylic, 4-cyclohexanecarboxylic, octadecenylsuccinic, octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic, Reineke's, dimethyldithiocarbamic, hexadecylsulfamic, octadecylsulfamic, sorbic, monochloroacetic, undeylene, 4'-hydroxyazobenzene-4-sulfonic, octyldecylsulfuric, picric, benzoic, cinnamic, and similar acids.

Acid addition salts can be used for the same purposes as the free bases, but in some cases they are preferable to the bases. For example, the free base can be converted to an insoluble salt, such as a picrate, which can be subjected to purification operations, such as extraction and washing with solvents, chromatography, fractional extraction in a liquid-liquid system, or crystallization, and then the free base can be liberated by the action of alkali or the salt thus purified can be converted to another salt by double decomposition. Alternatively, the free base can be converted to a water-soluble salt, such as a hydrochloride or sulfate, and the aqueous solution of the salt can be extracted with various water-immiscible solvents and the free base can be liberated from the thus purified acidic solution or the salt can be converted to another salt by double decomposition.

The free bases can be used as buffers or as acid-binding agents. They react with isocyanates to form urethanes and can be used to modify polyurethane resins. The addition salt with thiocyanic acid can be condensed with formaldehyde to form resins which can be used as corrosion inhibitors in pickling baths according to U.S. Patents Nos. 2,425,320 and 2,606,155. The free bases are also good vehicles for toxic acids. For example, the addition salts with fluorosilicic acid can be used as moth repellents according to U.S. Patents Nos. 1,915,334 and 2,075,359, and the addition salts with hexafluoroarsenic and hexafluorophosphoric acids can be used as parasiticides according to U.S. Patents Nos. 3,122,536 and 3,122,552.

The essence of the invention is further explained in the following examples, in which parts by weight are given, excluding the volumes of solvents, unless otherwise indicated.

Design examples

Example 1

7-Deoxy-7(S)-(methylthio)lincomycin hydrochloride

Part A-1: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-alpha-thiolincosaminide

A mixture of 5 g (1 moleeq.) of methyl-N-acetyl-2,3,4-tri-O-acetyl-6(R),7(R)-aziridino-6-desamino-7-desoxy-alpha-thiolincosaminide, 50 ml of dimethyl sulfide and 5.25 g (7 moleeq.) of glacial acetic acid is heated for 20 hours in a sealed Pyrex tube on a boiling water bath.

The slightly pink reaction mixture was distilled off at 100 °C, the residue was dissolved in methylene chloride and the solution was stirred with excess saturated aqueous sodium bicarbonate solution. The organic phase was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off on a rotary vacuum evaporator at 40 °C and 0.93 kPa.

A slightly pink solid (5.92 g) is obtained, which according to TLC (on silica gel, in the acetone-Skellysolve B system 1:1) does not contain the starting material, but contains a large zone of a new substance with a lower Rj. The abbreviation TLC stands for thin layer chromatography, and Skellysolve B is the name of technical hexane.

Countercurrent shaking of the aforementioned crude material in the ethanol-water-ethyl acetate-cyclohexane system in the ratio 1:1:1:2 yields methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-alpha-tholine cosaminide with a partition coefficient K = 1.21, which, after recrystallization from a mixture of ethyl acetate and Skellysolve B, forms colorless solids with the following properties:

Melting point 225 to 226 °C

Specific rotation [a] + 225 °C (c 0.9876, chloroform)

Analysis for C ₁ gH ₂ gOgNS ₂

Calculated: 47.88% C, 6.47% H, 3.10% N, 14.20% S;

molecular weight 451.55

Found: 47.87% C, 6.49% H, 3.19% N, 14.31% S;

molecular weight (mass spectrometry, M ⁺ ) 451.

Part B-1: Methyl-7-deoxy-7(S)-methylthio-alpha-thiolincosaminide

A mixture of 8.05 g of methyl-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-methylthio-alpha-thiolincosaminide (see Part A-1) and 100 ml of hydrazine hydrate is heated in an oil bath at 160 °C, stirring with a magnetic stirrer, for 22 hours at reflux. The volatile components are distilled off from the colorless solution from the oil bath under reduced pressure (at 110 °C/0.93 kPa), and the solid residue is recrystallized from methanol. Methyl-7-deoxy-7(S)-methylthio-alpha-thiolincosaminide (B-1) is obtained in the form of colorless needle-like crystals with the following properties:

Melting point 174 to 175 °C

Specific rotation: [o] _D + 260 °C (c 0.6790, water)

Analysis for C^Hg^O^NSg:

Calculated: 42.38% C, 7.47% H, 4.94% N, 22.63% S;

molecular weight 283.41

Found: 42.39% C, 7.52% H, 4.65% N, 22.78% S;

molecular weight (mass spectrometry, M ⁺ ) 283.

part C-1: 7-deoxy-7(S)-(methylthio)lincomycin hydrochloride [Methyl-6,7,8-tridesoxy-7-(methylthio)-6-trans-(1-methyl-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-alpha-D-galactooctopyranoside hydrochloride

23H54

XIX

To a suspension of 4.15 g (2 mol. eq.) of trans-propyl-hydrogen acid hydrochlorides in 150 ml of anhydrous acetonitrile is added 4.44 g (4.4 mol. eq.) of triethylamine. After the solid has dissolved, the solution is cooled in a methanol-ice bath to -5 °C, whereby triethyl ammonium chloride precipitates. To the solution is added 2.73 g (2 mol. eq.) of isobutyl chloroformate at such a rate that the temperature does not exceed -3 °C, and the reaction mixture is stirred for 20 min. at -3 °C to -5 °C. To the resulting mixed anhydride is then added a solution of 2.83 g (1 mol. eq.) of methyl-7-deoxy-7(S)-methylthio-alpha-thiline cosaminide (B-1) in a mixture of 20 ml of methanol and 20 ml of water, whereby the precipitated triethyl ammonium chloride dissolves. After 2 hours, the presence of the starting amino sugar cannot be demonstrated in the reaction mixture by TLC (on silica gel, in the methanol-chloroform system 1:10) and a zone of a new substance with a higher Rp value appears. The volatile components are distilled off on a rotary evaporator at 40 °C/0.93 kPa and the syrupy residue is dissolved in water by adding dilute aqueous hydrochloric acid (1-N) to pH 2. The acidic solution is shaken twice with methylene chloride, the organic extracts are discarded and the pH of the aqueous portion is adjusted to 11 by adding aqueous sodium hydroxide solution (50%). The milky cloudy reaction mixture is shaken three times with methylene chloride, the combined extracts are dried over anhydrous sodium sulfate and the remaining alkaline aqueous portion is discarded.

The solvent is distilled off from the methylene chloride extract on a rotary evaporator at 40 °C/0.93 kPa and the remaining light yellow syrup is chromatographed on a silica gel column (1,200 g column, dimensions 5.8 x 90 cm, loading volume 2,000 ml), using a 1:15 mixture of methanol and chloroform for elution. After a volume of 1,800 ml, 50 ml fractions are collected and the elution process is monitored by TLC on silica gel in the same solvent system.

Fractions 21 to 54 inclusive are combined and the solvents are distilled off. A colorless syrup is obtained which is converted to the hydrochloride by dissolving in water and adding dilute aqueous hydrochloric acid (1-N) to the solution until the pH is about 3. This solution is frozen and lyophilized to give 7-deoxy-7(S)-(methylthio)lincomycin hydrochloride (C-3) as a colorless solid with the following properties:

Specific rotation: [a] _D + 125° (0.8840, water)

Analysis for ^19^36^5^2^2 '

Calculated: 48.23% C, 7.88% H, 5.92% N, 13.56% S, 7.50% Cl;

mol. weight 473.10 (mol. weight free base 436.63)

Found: 48.84% C, 7.71% H, 5.90% N, 12.96% S, 7.25% Cl;

mol. mass (mass spectrometry, M ⁺ free base) 436.

Biological efficacy: in vitro about eight times that of lincomycin, with improved efficacy against gram-negative bacteria.

Example 2

7-Deoxy-7(S)-(ethylthio)lincomycin hydrochloride

Part A-2: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-elfa-thioline coseminite

By the method of Example 1, Part A-1, but using diethyl sulfide instead of dimethyl sulfide and heating to reflux for 7 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-alpha-thiolincosaminide (A-2) is obtained having the following properties:

Partition coefficient K = 1.85 (same solvent system)

Melting point: 236 to 237 °C

Specific rotation: [a] _D + 215° (c 0.95, chloroform)

Analysis for C , OgNSg:

Calculated: 49.01% C, 6.71% H, 3.01% N, 13.77% S;

Not found: 49.18% C, 6.47% H, 3.41% N, 13.17% S.

This compound is also obtained at a partition coefficient K = 6.15 by countercurrent shaking according to Example 12.

Part B-2: Methyl-7-deoxy-7(S)-(ethylthio)-alpha-thiolincosaminide

By the method of Example 1, Part B-1, the above compound (A-2) is converted to methyl-7-deoxy-7(S)-(ethylthio)-alpha-thiolincosaminide (B-2), which crystallizes from methanol in the form of colorless prisms having the following properties:

Melting point: 192 to 194 °C

Specific rotation: [a] ⁺ 253° (c 0.73, water)

Analysis for ^C 1,«23°4 ^N ^2 ^:

Calculated: 44.42% C, 7.79% H, 4.71% N, 21.56% S;

Found: 44.16% C, 7.78% H, 4.72% N, 21.78% S.

Part C-2: 7-Deoxy-7(S)-(ethylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, the above compound (B-2) is converted into 7-deoxy-7(S)-(ethylthio)lincomycin hydrochloride (C-2). After lyophilization, it is obtained in the form of a colorless solid having the following properties:

Specific rotation: [a] _D + 111° (c 0.83, water)

Analysis for ^C 20^38°5 ^N 2^2 *

Calculated: 49.31% C, 8.07% H, 5.75% N, 7.28% Cl, 13.17% S;

molecular weight 450.65 (for free base)

Found: (converted for 9.23% HgO content)

49.52% C, 7.99% H, 5.61% N, 7.55% Cl, 13.46% Sj molecular weight (mass spectrometry for free base) 450.

Biological efficacy: about 8 times that of lincomycin

Example 3

Alternative procedure to example 2

By following the procedure of Example 1, Part A-1, but using diethyl disulfide instead of diethyl sulfide and heating in an oil bath at 110°C for 20 hours, the same 7(S)-(ethylthio) compound is obtained, but in higher yields.

Example 4

7-Deoxy-7(S)-(propylthio)lincomycin hydrochloride Part A-4: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using methylpropyl sulfide instead of dimethyl sulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propylthio)-alpha-thiolincosaminide (A-4) is obtained, which after recrystallization from a mixture of ethyl acetate and Skellysolve B forms colorless needles having the following properties:

Melting point: 259 to 261 °C

Specific rotations: [a] _D ⁺ 203° (c 0.96, chloroform)

Analysis for C ₂₀ H ₃ 3° ₈ NS ₂ :

Calculated: 50.08% C, 6.93% H, 2.92% N, 13.37% S;

Not found: 49.89% C, 6.96% H, 3.02% N, 13.41% S.

Partition coefficient: K = 3.10 (same solvent system)

At the same time, the corresponding 7(S)-(methylthio) compound (A-1) is obtained at a K value of 1.32, in a ratio of 1 part to 3 parts of 7(S)-(propylthio) compound (A-4).

Part B-4: Methyl-7-deoxy-7(S)-(propylthio)-alpha-thiolincosaminide

By the method of Example 1, Part B-1, the above compound (A-4) is converted into methyl-7-deoxy-7(S)-(propylthio)-alpha-thiolincosaminide (B-4). After recrystallization from methanol, it is obtained in the form of colorless plates having the following properties:

Melting point: 189 to 190 °C

Specific rotations: [alpha] _D + 257° (c 0.71, pyridine)

Analysis for C, 2^5^4^2 ^:

Calculated: 46.27% C, 8.09% H, 4.50% N, 20.59% S;

Found: 46.30% C, 8.21% H, 4.38% N, 20.58% S.

Part C-4: 7-Deoxy-7(S)-(propylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, the above compound (B-4) is converted to 7-deoxy-7(S)-(propylthio)lincomycin hydrochloride (C-4), which upon lyophilization forms a colorless amorphous solid having the following properties:

Specific rotation: fajp + '12° (c 0.83, water)

Analysis for ^21^40^5^2^2 * HCl:

Calculated: 50.33% C, 8.25% H, 5.59% N, 7.08% Cl, 12.80% S;

molar mass of the free base 464.68

Found: (converted to water content 5.33 56 H ₂ 0)

50, 12 56 C, 8.03 56 H, 5.74% N, 6.94 56 Cl, 12.57 56 S; mol. mass (mass spectrum of the free base) 464.

Biological activity: about 8 times that of lincomycin

Example 5

Alternative procedure to example 4

By the method of Example 2, Part A-2, but using dipropyl sulfide instead of diethyl sulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propylthio)-alpha-thiolincosaminide (A-4) is obtained.

Example 6

7-Deoxy-7(S)-(isopropylthio)lincomycin hydrochloride

Part A-6: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(isopropylthio)-alpha-thiolincosaminide

By the method of Example 2, Part A-2, but using methyl isopropyl sulfide instead of diethyl sulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(isopropylthio)-alpha-thiolincosaminide is obtained, which upon recrystallization from ethyl acetate forms colorless needles having the following properties (A-6):

Partition coefficient: K = 2.94 in the system ethanol-water-ethyl acetate-cyclohexane in the ratio 1:1:1:2

Melting point: 274.5 to 275.5 °C

Specific rotation: [a] _D + 200° (c 0.87, chloroform)

Analysis for ^C 20 ^H 33°8 ^NS 2 ^:

Calcd: 50.08 56 C, 6.93 » H, 2.92% N, 13.37% S;

Found: 49.79 56 C, 6.95% H, 2.78 56 N, 13.60 56 S.

At the same time, a 7(S)-(methylthio) compound (K = 1.32) is formed in the ratio of 1.5 parts methylthio to 1 part isopropylthio. When diisopropyl disulfide is used instead of methylisopropyl sulfide, only methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(isopropylthio)-alpha-thiolinkosaminid is obtained.

Part B-6: Methyl-7-deoxy-7(S)-(isopropylthio)-alpha-thiolincosaminide

By the method of Example 1, Part B-1, the isopropylthio compound (A-6) obtained in the above manner is converted into methyl-7-deoxy-7(S)-(isopropylthio)-alpha-thiolincosaminide, which crystallizes from methanol in the form of colorless plates having the following properties:

Melting point: 220 to 221 °C

Specific rotation: [o] _D + 269° (c 0.85, pyridine)

Analysis for C]2^25θ4^®2 ^:

Calculated: 46.27% C, 8.09 56 H, 4.50 56 N, 20.59 56 S;

Found: 46.02 56 C, 8.10 56 H, 4.45 56 M, 20.73 56 S.

Part C-6: 7-deoxy-7(S)-(isopropylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, 7-deoxy-7(S)-(isopropylthio)lincomycin hydrochloride is obtained having the following properties:

Specific rotation: [«] _D ⁺ 109° (c 0.97, water)

Analysis for θ21^40θ5^2®2 ’

Calculated: 50.33% C, 8.25% H, 5.59% N, 7.08% Cl, 12.80% S;

molar mass of the free base 464.68

Found: (converted to 5.00% H ₉ 0 content)

50.74% C, 8.50% H, 5.36% < 6.74% Cl, 12.67% Sj mol. mass (mass spectrometry, M ⁺ free base) 464.

Example 7

7(S)-(Cyclohexylthio)-7-deoxylincomycin hydrochloride

Part A-7: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclohexylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using cyclohexylmethyl sulfide instead of dimethyl sulfide and heating the reaction mixture in an oil bath at 115 °C for 24 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclohexylthio)-alpha-thiolincosaminide (K = 5.95 using the solvent system ethanol-water-ethyl acetate-cyclohexane in the ratio 1 : 1 : 1 : 5) is obtained, which crystallizes from ethyl acetate in the form of colorless prisms having the following properties:

Melting point: 248 to 250 °C

Specific rotation: [«] _D ⁺ '84° (c 0.86, chloroform)

Analysis for ¢23^37^8^2^

Calculated: 53.15% C, 7.18% H, 2.70% N, 12.34% Sj

Found: 53.27% C, 7.28% H, 2.79% N, 11.92% S.

At the same time, the corresponding 7(S)-(methylthio) compound (K = 0.57), already described in Example 1, Part A-1, is obtained in a ratio of approximately 1 part methylthio to 5 parts 7(S)-cyclohexylthio compound.

Part B-7: Methyl-7-deoxy-7(S)-(cyclohexylthio)-alpha-thiolincosaminide

By the method of Example 1, Part B—1, methyl-7-deoxy-7(S)-(cyclohexylthio)-alpha-thiolincosaminide is obtained, which crystallizes from methanol in the form of colorless needles having the following properties:

Melting point: 222 to 223 °C

Specific rotation: [e]jj ⁺ 235° (c 0.62, pyridine)

Analysis for C,^Hg^O^NSg:

Calculated: 51.25% C, 8.32% H, 3.99% N, 18.24% S;

Found: 50.94% C, 8.46% H, 3.69% N, 18.47% S.

Part C-7: 7(S)-(cyclohexylthio)-7-desoxylincomycin hydrochloride

By the method of Example 1, Part C-1, 7(S)-(cyclohexylthio)-7-deoxylincomycin hydrochloride is obtained, having the following properties:

Specific rotation: [a]j, + 95° (c 0.54, water)

Analysis for ^24^44^5^2^2 HCl:

Calculated: 53.26% C, 8.38% H, 5.18% N, 11.85% S, 6.55% Cl;

. mol. mass of the free base 504.74

Found: (converted to 4.42% HgO content)

53.50% C, 8.43% H, 5.16% N, 11.96% S, 6.33% Cl; molecular weight (mass spectrometry, M ⁺ free base) 504.

Example 8

Part A-8: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclopentylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using methylcyclopentyl sulfide instead of dimethyl sulfide and heating the reaction mixture on an oil bath at 100 °C for 16 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclopentylthio)-alpha-thiolincosaminide (A-8) is obtained at a K value of 4.0 in the ethanol-water-ethyl acetate-cyclohexane system in the ratio 1 : 1 : 1 : 3. After recrystallization from ethyl acetate, it is obtained in the form of colorless needles having the following properties:

Melting point: 265 to 265.5 °C

Specific rotations: [«] _D + 187° (c 0.99, chloroform)

Analysis for C ₂₂ H ₃₅ ° ₈ NS ₂ :

Calculated: 52.25% C, 6.98% H, 2.77% N, 12.68% S;

molecular weight 505.64

Found: 52.07% C, 6.88% H, 2.68% N, 12.62% S;

molecular weight (mass spectrometry, M ⁺ ) 505.

If methylcyclopentyl sulfide is replaced by dicyclopentyl disulfide, the same compound is obtained.

Example 9

7(S)-(Butylthio)-7-Deoxylincomycin Hydrochloride Part A-9: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(Butylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 3, but using dibutyl disulfide instead of diethyl disulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(butylthio)-7-deoxy-alpha-'thiolincosaminide (K = 3.35 in the ethanol-water-ethyl acetate-cyclohexane system 1:1:1:3) is obtained, which crystallizes from ethyl acetate in the form of colorless needles having the following properties:

Melting point: 234 to 235 °C

Specific rotation: [α] _D + 197° (c 0.51, chloroform)

Analysis for ^C 2| ^H 35°8 ^NS 2 ^:

Calculated: 51.09% C, 7.15% H, 2.84% N, 12.99% S;

Found: 51.05% C, 7.21% H, 2.63% N, 12.76% S.

Part B-9: Methyl-7(S)-(butylthio)-7-deoxy-alpha-thioline coseminite

By the method of Example 1, Part B-1, methyl-7(S)-(butylthio)-7-deoxy-alpha19 is obtained

-thiolincosaminide, which, after recrystallization from methanol, forms colorless plates having the following properties:

Melting point: 188 to 190 °C

Specific rotation: [“] p ⁺ 250° (c 1.00, pyridine)

Analysis for θ]3^27°4 ^ΝΞ 2 ^:

Calculated: 47.97% C, 8.36% H, 4.30% N, 19.70% S;

Found: 47.88% C, 8.33% H, 4.37% N, 19.69% S.

part C-9: 7-deoxy-7(S)-(butylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, 7-deoxy-7(S)-(butylthio)lincomycin hydrochloride is obtained having the following properties:

Specific rotation: [«] _D + 106° (c 0.65, water)

Analysis for ^C 22 ⁸ 44^5 ^N 2 ^S 2 '

Calculated: 51.29% C, 8.41% H, 5.44% N, 12.45% S, 6.88% Cl;

molecular weight of the free base 478.70;

Found: (converted to 3.82% HjO content)

51.05% C, 8.70% H, 5.13% N, 12.28% S, 6.69% Cl; molecular weight (mass spectrometry, M ⁺ free base) 478.

Example

7-Deoxy-7(S)-(2-hydroxyethylthio)lincomycin hydrochloride Part A-10a: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-desoxy-7(S)-(2-hydroxyethylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using 2-hydroxyethyl methyl sulfide instead of dimethyl sulfide and heating the reaction mixture in a water bath at 100 °C for 5 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyethylthio)-alpha-thiolincosaminide (K = 0.97 in the ethanol-water-ethyl acetate-cyclohexane system 1 : 1 : 1 : 0.5) is obtained, which crystallizes from a mixture of ethyl acetate with Skellysolve B in the form of colorless needles having the following properties:

Melting point: 226 to 228 °C

Specific rotation: [a] _D + 185° (c 1.00, chloroform)

Analysis for C,

Calculated: 47.38% C, 6.49% H, 2.91% N, 13.32% S;

Found: 47.18% C, 6.79% H, 2.86% N, 12.73% S.

Part A-10b: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxyethylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using 2-acetoxyethyl methyl sulfide instead of dimethyl sulfide and heating the reaction mixture in a water bath at 100 °C for 5 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-desoxy-7(S)-(2-acetoxyethylthio)-alpha-thioline cosaminide (K = 0.53 in the ethanol-water-ethyl acetate-cyclohexane system 1 : 1 : 1 : 3) is obtained, which after recrystallization from a mixture of ethyl acetate with Skellysolve B forms colorless needles having

23Π54 the following properties:

Melting point: 206 to 207 °C

Specific rotation: [o] _D + 180° (c 0.79, chloroform)

Analysis for ^c 2i ^H 33°io ^NS 2 ^:

Calculated: 48.17% C, 6.35% H, 2.68% N, 12.25% S;

Found: 48.12% C, 6.37% H, 2.58% N, 11.95% S.

Part B-10: Methyl-7(S)-(2-hydroxyethylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 1, Part B-1, 7-deoxy is obtained from compound A-IOa or A-IOb

-7(S)-(2-hydroxyethylthio)-alpha-thiolincosaminide, which, after recrystallization from a mixture of acetonitrile and ethanol, forms colorless plates having the following properties:

Melting point: 175 to 176 °C

Specific rotation: [a]jj + 234° (c 0.52, water)

Analysis for C^Hg^OjNSg!

Calculated: 42.15% C, 7.40% H, 4.47% N, 20.46% S;

Found: 42.05% C, 7.55% H, 4.43% N, 20.36% S.

)

Part C-10: 7-Deoxy-7(S)-(2-hydroxyethylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, 7-deoxy-7(S)-(2-hydroxyethylthio)lincomycin hydrochloride is obtained in the form of a colorless amorphous substance after lyophilization from an aqueous solution, having the following properties:

Specific rotation: [a] _D + 114° (c 0.91, water)

Analysis for ^20^38 ⁰ 6 ^M 2 ^S 2 . HCl:

Calculated: 47.74 « C, 7.81% H, 5.57% N, 7.05% Cl, 12.75% Sj mol. mass of free base 466.65

Found: (converted to 6.75% HgO content)

48.05% C, 7.70% H, 5.10% N, 6.96% Cl, 12.50% S; molecular weight (mass spectrometry, M ⁺ free base) 466.

This compound is about 8 times more potent than lincomycin, is more effective against gram-negative bacteria in vivo, and is less toxic than 7-deoxy-7(S)-chlorolincomycin hydrochloride.

Example 11

7(S)-(tert.butylthio)-7-deoxylincomylene hydrochloride

Part A-11: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert. butylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example I, Part A-1, but using tert-butyl-2-mercaptoethyl sulfide instead of dimethyl sulfide and heating in an oil bath at 100 °C for 16 hours, crude methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert-butylthio)-7-deoxy-alpha-thiolincosaminide is obtained.

Countercurrent shaking in the ethanol-water-ethyl acetate-cyclohexane system in the ratio: 1:1:3 gives methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert. butylthio)-7-deoxy-alpha-thiolincosaminide at a K value of 2.38. After recrystallization from ethyl acetate, it is obtained in the form of small colorless needles, having the following properties:

Melting point: 272 to 273 °C

Specific rotation: [ _a J _D + 187° (c 0.64, chloroform)

Analysis for 0 ₂ , Η3 ₅ ^θ 8Ν3 ₂ :

Calculated: 51.09% C, 7.15% H, 2.84% N, 12.99% S;

molecular weight 493.63

Found: 51.19% C, 7.28% H, 2.95% N, 13.13 « Sj mol. mass (mass spectrometry, M ⁺ ) 493.

The same compound is obtained, but in lower yields, if di(tert-butyl)sulfide is used in place of dimethylsulfide in the procedure of Example 1, Part A-1.

Part B-11: 7(S)-(tert. butylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 1, Part B-1, methyl-7(S)-(tert. butylthio)-7-deoxy-alpha-thiolincosaminide is obtained.

Part C-11: 7(S)-(tert.butylthio)-7-deoxy-lincomycin hydrochloride

By the method of Example 1, Part C-1, 7(S)-(tert. butylthio)-7-deoxylincomycin hydrochloride is obtained, which forms an amorphous solid after lyophilization of the aqueous solution.

Part D-11: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-[2-(tert.butylthio)ethylthio]-7-deoxy-alpha-thiolincosaminide

The above countercurrent shaking of the crude product (see section A-11) also yields methyl-N-;acetyl-2,3,4-tri-O-acetyl-7(S)-[2-(tert. butylthio)ethylthio]-7-deoxy-alpha-thiolincosaminide with a partition coefficient K * of 7.95. After recrystallization from a mixture of ethyl acetate and Skellysolve B, it is obtained in the form of colorless, irregular plates having the following properties:

Melting point: 164 to 165 °C

Specific rotation: Mp + 164° (c 0.58, chloroform)

Analysis for Ο^Μ^ΟθΝβ^:

Calculated: 49.88% C, 7.10% H, 2.53% N, 17.37% S;

molecular weight 553.75

Found: 49.76% C, 7.03% H, 2.63% N, 17.39% S;

molecular weight (mass spectrometry, U) 553.

Tert. butyl-2-mercaptoethyl sulfide is obtained by reacting sodium tert. butyl mercaptide with diethylene sulfide in an ethylic medium.

By the method of Example 1, Parts B-1 and C-1, methyl-7(S)-[2-(tert. butylthio)ethylthio]-7-deoxy-alpha-thiolincosaminide and 7(S)-[2-(tert. butylthio)ethylthio]-7-deoxy-alpha-thiolincosaminide are prepared from the above methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-[2-(tert. butylthio)ethylthio]-7-deoxylincosaminide.

Example 12

Part A-12: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethyldithio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using a target. butyl ethyl disulfide instead of dimethyl sulfide and heating the reaction mixture in an oil bath at 100 °C for 16 hours, a crude product containing methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethyldithio)-alpha-thiolincosaminide is prepared. Countercurrent shaking of this crude product in the ethanol-water-ethyl acetate-cyclohexane system 1 : 1 : 1 : 3 gives a mixture of methyl-4-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-Blfa-thiolincosaminide (A-12) and methyl-4-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert. butylthio)-7-deoxy-alpha-thiolincosaminide (A-11) in a ratio of 30 to 70. Partition coefficient The K value of this mixture is 2.57. The two products can be separated by gas chromatography and can be distinguished by the fact that the first compound (A-12) shows absorption in the UV region of the spectrum at 245 nm (ε 546), while the second compound (A-11) shows no absorption in the UV region. The first compound (A-12) gives a molecular ion m/e 497 by mass spectroscopy (calculated molecular weight 497.65). The second compound (A-11) is identical to the product obtained in Example 11, Part A-11.

Part B-12:

A solution of 600 mg of the mixture of compounds (A-11 and A-12) obtained in the previous part A-12 in 60 ml of benzene and 2.72 g of trisdiethylamidophosphine was heated under reflux at a gentle boil for 10 hours. The solvent was distilled off under reduced pressure and the remaining syrupy residue was chromatographed on silica gel using a mixture of ethyl acetate and Skellysolve B (1:1) as eluent, whereby the excess reagent and the resulting trisdiethylaminophosphine sulfide, which has an Rp of 0.51 to 0.54, were separated from the crude product. Countercurrent shaking of the thus purified product in the system ethanol-water-ethyl acetate-cyclohexane (1:1:3) yields methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-alpha-thiolincosamine (A-2) at K = 1.43 and the corresponding tert. butyl analogue (A-11) at K = 2.57.

By the method according to Example 1, Parts B-1 and C-1, from the above mixture of ethyldithio and tert. butylthio derivatives in the ratio 30:70 (see Part A-12) there is obtained 1. the corresponding mixture of methyl-7-deoxy-7(S)-(ethyldithio)-alpha-thiolincosaminide and methyl-7(S)-(tert. butylthio)-7-deoxy-alpha-thiolincosaminide, b 2. the corresponding mixture of 7-deoxy-7(S)-(ethyldithio)lincomycin hydrochloride and 7(S)-(tsrc. butylthio)lincomycin hydrochloride.

Example 13

7(S)-(tert.butyldithio)-7-deoxy-lincomycin hydrochloride

Part A—13: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert. butyldithio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 3, but using di(tert. butyl)disulfide instead of diethyldisulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert. butyldithio)-7-deoxy-alpha-thiolincosaminide is obtained, which after recrystallization from a mixture of ethyl acetate and Skellysolve B forms small colorless rods having the following properties:

Melting point: 24.1 to 242 °C

Specific rotation: Wp ⁺ 220° (c 0.56, chloroform)

Partition coefficient K = 7.35 in the system water-ethanol-ethyl acetate-cyclohexene 1:1:1:3

Analysis for θ21^35θβ' ^ί ®3 ^:

Calculated: 47.98% C, 6.71% H, 2.67% N, 18.30% S;

Found: 48.03% C, 6.65% H, 2.65% N, 18.65% S;

mol. mass: calculated 525.70 found (mass spectrometry, M ⁺ ) 525

This compound was also obtained at a K value of 1.43 by countercurrent shaking of the products of Example 2.

Example 14

Alternative procedure to example 1

By the method of Example 3, but using methyl (tert. butyl) sulfide instead of diethyl disulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-alpha-thiolincosaminide is obtained, which is identical to the compound prepared in Example 1, Part A-1. The advantage of this alternative procedure is higher yields of the desired product.

Example 15

Alternative procedure to example 1

By the method of Example 3, but using 1,2-bis(methylthio)ethane instead of diethyl disulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-alpha-thiolincosaminide is obtained, which is identical to the product prepared according to Example 1, Part A-1. In this procedure, which also gives better yields of the 7(S)-methylthio derivative, no 7(S)-[2-(methylthio)ethylthio]-compound is formed, contrary to expectations.

Example 16

7-Deoxy-7(S)-[2-(methylthio)ethylthio]-lincomycin hydrochloride and alternative procedure to Example I

Part A-,6:

By the method of Example 3, but using 2-(methylthio)ethanethiol instead of diethyl disulfide, methyl-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(methylthio)-alpha-thiolincosaminide is obtained, which is identical to the compound prepared according to Example 1, and methyl-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-[2-(methylthio)ethylthio]-alpha-thiolincosaminide in the ratio of 80 parts of the first compound to 20 parts of the second. When the said mixture is shaken countercurrently in the system ethanol-water-ethyl acetate-cyclohexane 1 : 1 : 1 : 3, the second compound is obtained at a K value of 1.84. After recrystallization from a mixture of ethyl acetate with Skellysolve B, colorless needles are formed having the following properties:

Melting point: 236 to 237 °C

Specific rotation: [“]p ⁺ 183° (c 0.93, chloroform)

Analysis for CjqH^OqNSj:

Calculated: 46.94% C, 6.50% H, 2.74% N, 18.80% S;

molecular weight 511.67

Found: 46.96% C, 6.92% H, 2.49% N, 18.38% S;

molecular weight (mass spectrometry, U) 511.

Part B-,6: Methyl-7-deoxy-7(S)-[2-(methylthio)ethylthio]-alpha-thiolincosaminide

By the method of Example 1, Part B-1, using the compound (A-16) prepared in the above-mentioned method as a starting material, methyl-7-deoxy-7(S)-[2-(methylthio)ethylthio]-alpha-thiolincosaminide is obtained. - ¹

Part C—16: 7-Deoxy-7(S)-[2-(methylthio)ethylthio]lincomycin hydrochloride

By the method of Example 1, Part C-1, using the above compound (B-16) as a starting material, 7-deoxy-7(S)-[2-(methylthio)ethylthio]lincomycin hydrochloride was obtained.

Example 17

Alternative procedure to example 1

By the method of Example 3, but using 4-(methylthio)butanethiol instead of diethyl disulfide, methyl-N-ethyl-2,3,4-tri-Q-acetyl-7-deoxy-7(S)-methylthio-alpha-thiolinkos aminide is obtained, which is identical to the compound prepared according to Example 1, Part A-1.

The starting 4-(methylthio)butanethiol is prepared by mono-S-methylation of 1,4-butanedithiol using an equivalent of sodium hydroxide and methyl iodide in ethyl alcohol.

Example 18

Alternative procedure to example 3

By the method of Example 3, but using diethyl trisulfide instead of diethyl disulfide and heating the reaction mixture in an oil bath at 100°C for 16 hours, the same 7(S)-ethylthio compound is obtained in good yields.

Example 19

7-Deoxy-7(S)-[3-(methylthio)propylthio]lincomycin hydrochloride Part A-19: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-[3-(methylthio)propylthio]-alpha-thiolincosaminide

By the method of Example 15, but using 1,3-bis(methylthio)propane instead of 1,2-bis(methylthio)ethane, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-[3-(methyl->thio)propylthio]-alpha-thiolincosaminide is obtained.

When isolated by countercurrent shaking using the same solvent system as in Example 16, the above compounds are obtained at a K value of 2.24. It crystallizes from ethyl acetate as colorless needles having the following properties:

Melting point: 211 to 212 °C

Specific rotation: + 181° Cc 1.1, chloroform)

Analysis for ^C 21 ^H 35°8 ^NS 3 ^:

Calculated: 47.98% C, 6.71% H, 2.67% N, 18.30% Sj mol. mass 525.70

Found: 47.97% C, 6.78% H, 2.62% N, 17.73% S;

molecular weight (mass spectroscopic, M ⁺ ) 525

By the method of Example 1, Parts B-1 and C-1, using the above compound (A-19) as a starting material, methyl-7-desoxy-7(S)-[3-(methylthio)propylthio]-alpha-thiolincosaminide and 7-desoxy-7(S)-[3-(methylthio)propylthio]lincomycin hydrochloride are obtained. In the above procedure, no methylthio derivative is formed, the reaction product is exclusively the 3-(methylthio)propylthio compound.

Example 20

Part A-20:

By the method of Example 16, but using 2-(methylthio)ethanethiol acetate instead of 2-(methylthio)ethanethiol, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetylthio25

23H54

Found:

ethylthio)-7-deoxy-alpha-thiolincosaminide; by countercurrent shaking of the crude product using the same solvent system as in Example 16, the compound is obtained at a K value of 1.55. After recrystallization from ethyl acetate, it is obtained in the form of small colorless rods having the following properties:

Melting point: .98 to 199 °C

Specific rotation: [e) _D + 168° (c 1.0, chloroform)

Analysis for C ₂₎ H ₃₃ O ₉ NS ₃ :

Calculated: 46.73% C, 6.16% H, 2.60% N, 17.63% Sj mol. mass 539.68

Not found: 46.84% C, 6.05% H, 2.56% N, 17.52% S;

mol. mass (mass spectroscopic, M - HCHS) 493.

By the method of Example 1, Parts B-1 and C-1, using the above compound (A-20) as a starting material, methyl-7-deoxy-7(S)-(2-mercaptoethylthio)-alpha-thiolincosaminide and 7-deoxy-7(S)-(2-mercaptoethylthio)lincomycin hydrochloride are obtained,

Example 2,

Part A-2,:

By the method of Example 1, Part A-1, but using 2-methoxyethylmethyl sulfide instead of dimethyl sulfide and heating the reaction mixture in an oil bath at 100 °C for 16 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-desoxy-7(S)-(2-methoxyethylthio)-alpha-thiolincosaminide is obtained. Countercurrent shaking of the crude product in the solvent system ethanol-water-ethyl acetate-cyclohexane in the ratio 1 : 1 : 1 : 2 gives the pure compound at a K value of 0.88. After recrystallization from ethyl acetate it forms colorless rods having the following properties:

Melting point: 225 to 227 °C

Specific rotation: [e] _D ⁺ 171° (o 0.90, chloroform)

Analysis for θ20^33θ9^2 ^:

Calculated: 48.47% C, 6.71% H, 2.83% N, 12.94% S;

molecular weight 495.60

Found: 48.72% C, 6.82% H, 2.79% N, 12.77% S;

mol. mass (mass spectrometry, M ) 495 part B-21: Uethyl-7-deoxy-7(S)-(2-methoxyethylthio)-alpha-thiolincosaminide

By the method of Example 1, Part B-1, methyl-7-deoxy-7(S)-(2-methoxyethylthio)-alpha-thiolincosaminide is obtained, which crystallizes from acetonitrile in the form of colorless needles having the following properties:

Melting point: 169 to 170 °C

Specific rotation: ⁺ 223° (c 0.93, water)

Analysis for ^C 2 ^H 25°5 ^N 2 ^:

Calcd: 44.01515 C, 7.70% H, 4.28% N, 19.58% S;

molecular weight 327.46

44.31% C, 7.35% H, 4.20% N, 19.42% S; molecular weight (mass spectrometry, M ) 327.

Part C-2: 7-Deoxy-7(S)-(2-methoxyethylthio)lincomycin hydrochloride

The method of Example 1, Part C-1, yields 7-deoxy-7(S)-(2-methoxyethylthio)lincomycin hydrochloride, which upon lyophilization forms a colorless amorphous solid having the following properties:

Specific rotation: [a] _D + 106° (c 0.70, water)

Analysis for θ2,^40θ6^2^2 *

Calculated: 48.77% C, 7.99% H, 5.42% N, 6.86% Cl, 12.40% Sj mol. mass (free base) 480.68

Found: (converted for 4.94% water content)

48.90% C, 7.95 « H, 5.51% N, 6.60% Cl, 12.23% Sj mol. mass (mass spectrometry, M ⁺ free base) 480.

Example 22 Part A-22: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(vinylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using divinyl sulfide instead of dimethyl sulfide and heating the reaction mixture to .00 °C for .6 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(vinylthio)-alpha-thiolincosaminide is obtained. Countercurrent shaking of the crude product in the solvent system ethanol-water-ethyl acetate-cyclohexane 1 : 1 : 1 : 3 gives the pure compound at a K value of 1.57. After recrystallization from a mixture of ethyl acetate and Skellysolve B, it is obtained in the form of colorless needles having the following properties:

Melting point: 215.5 to 216 °C

Specific rotation: [o]p + 168° (c 0.79, chloroform)

Analysis for ^c i9 ^H 29°8 ^NS 2 ^:

Calculated: 49.23% C, 6.31% H, 3.02% N, 13.83% S;

molecular weight 463.56

Found: 49.06% C, 6.39% H, 3.13% N, 13.33% Sj molecular weight (mass spectrometry, M ) 463.

By the method of Example 1, Parts B-1 and C-1, using the above compound (A-22) as a starting material, methyl-7-deoxy-7(S)-(vinylthio)-alpha-thiolincoseminite and 7-deoxy-7(S)-(vinylthio)lincomycin hydrochloride are obtained.

Example 23 Part A-23: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(allylthio)-alpha-thiolincosaminide and methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propenylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using diallyl sulfide instead of dimethyl sulfide and heating the reaction mixture to 100°C for 16 hours, a mixture of methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(allylthio)-7-deoxy-alpha-thiolincosaminide and methyl-N-acetyl-2,3,4-tri-G-acetyl-7-deoxy-7(S)-(propenylthio)-alpha-thiolincosaminide is obtained. Countercurrent shaking of the mixture using the solvent system ethanol-water-ethyl acetate-cyclohexane 1 : 1 : 1 : 2 gives the allyl compound at a K value of 1.76 and the propenyl compound at a K value of 3.30. The allyl compound crystallizes from a mixture of ethyl acetate and Skellysolve B in

2311 in the form of colorless needles having the following properties:

Melting point: 235 to 237 °C

Specific rotation: Wp + 194° (c -0.63, chloroform)

Analysis for C20 ^H 31°8 ^NS 2 ^:

Calculated: 50.29% C, 6.54% H, 2.93% N, 13.43% S;

molecular weight 477.59

Found: 50.10% C, 6.67% H, 2.79% N, 13.00% S;

molar mass (mass spectrometry, M ) 477.

The propenyl compound crystallizes from a mixture of ethyl acetate and Skellysolve B in the form of colorless needles having the following properties:

Melting point: 273 to 275 °C

Specific rotation: M p ⁺ 157° (c 1.05, chloroform)

Analysis for OgNSg:

Calculated: as above

Not found: 50.43% C, 6.45% H, 2.96% N, 13.37% S;

molar mass (mass spectrometry, M ) 477

By the method of Example 1, Parts B-1 and C-1, using the above compounds (A-23 allyl and A-23 propenyl) as starting materials, methyl-7(S)-(allylthio)-7-deoxy-alpha-thiolincosaminide, methyl-7-deoxy-7(S)-(propenylthio)-alpha-thiolincosaminide, 7(S)-(allylthio)-7-deoxy-lincomycin hydrochloride and 7-deoxy-7(S)-(propenylthio) lincomycin hydrochloride are obtained.

Example 24

Part A-24: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(allyldithio)-7-deoxy-alpha-thiolincosaminide

The method of Example 1, Part A-1, but using diallyl disulfide instead of dimethyl sulfide and heating the reaction mixture to 100 °C for 16 hours gives a crude product which is chromatographed on silica gel; using a mixture of ethyl acetate and Skellysolve B (1:1) to elute the excess reagent (of lower polarity) and then using ethyl acetate alone to elute the more polar desired product. Countercurrent shaking of the thus purified product using the solvent system ethanol-ether-ethyl acetate-cyclohexane 1:1:1:3 gives pure methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(allyldithio)-alpha-thiolincosaminide (A-24) at a K value of 5.66. It crystallizes from ethyl acetate in the form of massive colorless prisms having the following properties:

Melting point: 211 to 213 °C

Specific rotation: Μβ ⁺ 251° (c 1.00, chloroform)

Analysis for CjqH-jjΟθΝε^:

Calculated: 47.13% C, 6.13% H, 2.75% N, 18.88% S;

molecular weight 509.66

Found: 47.03% C, 6.16% H, 2.56% N, 18.68% S;

molecular weight (mass spectrometry, M ⁺ ) 509

At the same time, the allylthioanalogue (A-21 allyl) is obtained at a K value of 2.03.

By the method of Example 1, Parts B-1 and C-1, methyl-7(S)-(allyldithio)-7-deoxy-alpha-thiolincosaminide and 7(S)-(allyldithio)-7-deoxylincomycin hydrochloride are obtained from the above allyldithio compound (A-24).

Example 25

Part A-25: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2,3-dihydroxypropylthio)-alpha-tholine cosaminide

By the method of Example 1, Part A-1, but using 2,3-dihydroxypropylmethylsulfide instead of dimethylsulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-desoxy-7(S)-(2,3-dihydroxypropylthio)-alpha-thiolincosaminide is obtained. Countercurrent shaking of the crude material in the system ethanol-water-ethyl acetate-cyclohexane 1 : 1 : 1.5 : 0.5 gives the solid substance at a K value of 0.91. After recrystallization from ethyl acetate it forms colorless plates having the following properties:

Melting point: 255 to 257 °C

Specific rotation: [«] _D + 164° (c 0.67, chloroform)

Analysis for θ20^33θ10^ ^Ξ 2 ^:

Calculated: 46.95% C, 6.50% H, 2.74% N, 12.54% S;

molecular weight 511.60

Found: 46.64% C, 6.67% H, 2.73% N, 12.59% S;

molar mass (mass spectroscopic, M ) 511

By the method of Example 1, Parts B-1 and C-1, using the above compound (A-25) as a starting material, methyl-7-deoxy-7(S)-(2,3-dihydroxypropylthio)-alpha-thiolincosaminide and 7-deoxy-7(S)-(2,3-dihydroxypropylthio)lincomycin hydrochloride are obtained.

The starting 2,3-dihydroxypropyl methyl sulfide is obtained by reacting 1-chloro-2,3-dihydroxypropane 8 with a methanolic solution of sodium methyl mercaptide.

Example 26

7-Deoxy-7(S)-(phenylthio)lincomycin hydrochloride

Part A-26a: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(phenylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using methyl phenyl sulfide instead of dimethyl sulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(phenylthio)-alpha-thiolincosaminide is obtained, which crystallizes from ethyl acetate in the form of fine colorless needles having the following properties:

Melting point: 275 to 276 °C

Partition coefficient: K = 3.17 in the system ethanol-water-ethyl acetate-cyclohexane 1:1:1:3 Specific rotation: Md ⁺ 164° (c 0.53, chloroform)

Analysis for OgNS ₂ :

Calculated: 53.78% C, 6.08% H, 2.73% N, 12.49% S;

Found: 53.87% C, 6.07% H, 2.48% N, 12.51% S.

23,154

Part A-26b: Alternative procedure

The same compound as in the previous Part A-26a is obtained by the method of Part A-26a, but using benzylphenyl sulfide instead of methylphenyl sulfide. The advantage of this procedure is that it provides the desired product in higher yields.

Part B-26: Methyl-7-deoxy-7(S)-(phenylthio)-alpha-thiolincosaminide

By the method of Example 1, Part B-1, methyl-7-deoxy-7(S)-(phenylthio)-alpha-thiolincosaminide is obtained, which crystallizes from methanol in the form of colorless flat needles having the following properties:

Melting point: .93 to .94 °C

Specific rotation: [«] p + 201° (c 0.88, pyridine)

Analysis for ^C ,5^23°4 ^NS 2 ^:

Calcd: 52.15 56 C, 6.71% H, 4.06 56 N, 18.56% S;

Found: 52.50% C, 6.78% H, 4.24% N, 18.33% S.

part C -26: 7-deoxy-7(S)-(phenylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, 7-deoxy-7(S)-(phenylthio)lincomycin hydrochloride is obtained in the form of a colorless amorphous solid having the following properties:

Specific rotation: [ ^a ]p ⁺ ®,° C ^c water)

Analysis for ^24^38^^282 · ^1101:

Calculated: 53.86% C, 7.35% H, 5.24% N, 11.9856 S, 6.63% Cl;

molar mass of the free base 498.69

Found: (converted to 4.64% HgO content)

54.08 56 C, 7.71% H, 5.55 56 N, 11.86% S, 6.49% Cl; molecular weight (mass spectrometry, free base) 498.

Example 27

7(S)-(Benzylthio)-7-deoxylincomycin hydrochloride

Part A-27: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(benzylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 18, but using dibenzyl sulfide instead of diethyl trisulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(benzylthio)-7-deoxy-sulfa-thiolincosaminide is obtained.

Countercurrent shaking in the solvent system ethanol-water-ethyl acetate-cyclohexane 1:1:0.5:3 gives this compound at a K value of 1.38. After recrystallization from a mixture of ethyl acetate and Skellysolve B, it is obtained in the form of flattened prisms having the following properties:

Melting point: 2.6 to 218 °C

Specific rotation: + .61° (c 1.07, chloroform)

Analysis for C^H^OgNSg:

Calculated: 54.63 « C, 6.30 « H, 2.66 » M, 12.15 » 8j

Found: 55.02% C, 6.44% H, 2.94'» M, 12.19 « S{ molecular weight: calculated 527.64 found (mass spec., M ⁺ ) 527.

Part B-27:

By the method of Example 1, Part B-1, using the above compound (A-27) as the starting material, methyl-7(S)-(benzylthio)-7-deoxy-alpha-thiolincosaminide is obtained, which after recrystallization from methanol forms colorless plates having the following properties:

Melting point: 215 to 216 °C

Specific rotation: [«] _D + 219° (c 0.97, pyridine)

Analysis for ^c i6 ^H 25°4 ^NS 2 ^:

Calculated: 53.45 « C, 7.01 « H, 3.90% N, 17.84 « S;

molecular weight 359.50

Not found: 53.37 » C, 7.07 « H, 4.12% N, 18.07 « S;

mol. mass (mass spec., ϊΊ 359.

Part C-27:

By the method of Example 1, Part C-1, using the above compound (B-27) as a starting material, 7(S)-(benzylthio)-7-desoxylincomyein hydrochloride is obtained in the form of a colorless amorphous solid having the following properties:

Specific rotation: [«] ^ ⁺ 96.5° (c 0.80, water)

Analysis for ^C 25 ^H 40°5 ^N 2^2 ' ^ί *θ ^1:

Calculated: 54.67 » C, 7.53 % H, 5.10 » N, 6.46 « Cl, 11.68 % Sj mol. weight (free base) 512.72

Not found: (converted to 2.74 » water content)

54.89 « C, 7.72 « H, 4.83 » H, 6.28 « Cl, 11.86« Sj mol. mass (mass spec., M ) 512

Example 28

1'-Demethyl-1'-(2-hydroxyethyl)-4 ^, -depropyl-4'-cis-trans-pentyl-7-deoxy-7ÍS)-(methylthio)lincomycin hydrochloride / hydrochloride metbyl-6,7,8-tri-deoxy-7-(methylthio)-6-cis-trans-1-(2-hydroxyethyl)-4-pentyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-alpha-D-galacto-octopyranoside/ part A-28: Hydrochloride 1'-demethyl-1'-carbobenzoxy-4'-depropyl-4'-cis-trans-pentyl-7-deoxy-7(S)-(methylthio)lincomycin

By the method of Example 1, Part C-1, except that cis-trans-1-carbobenzoxy-4-pentyl-L-2-pyrrolidinecarboxylic acid is used instead of trans-propylhydric acid and 2.2 molar equiv. of triethylamine, 1'-demethyl-1'-carbobenzoxy-4'-depropyl-4'-cis-trans-pentyl-7-desoxy-7(S)-(methylthio)lincomycin hydrochloride is obtained. The substance crystallizes from ethyl acetate in fine needles with a melting point of 158-159 °C, having the following properties: Specific rotation: [«] _D + 118° (c 0.84, chloroform)

Analysis for CggH^O·^^:

Calculated: 57.51% C, 7.58% H, 4.79% N, 10.97% S;

molecular weight 584.78

Found: 57.47% C, 7.51% H, 4.73% N, 11.19% S;

mol, mass (mass spec., M ) 584 part B-28: 1'-Demethyl-4'-depropyl-4'-cis-trans-pentyl-7-desoxy-7(S)-(methylthio)lincomycin hydrochloride

A solution of the above-mentioned carbobenzoxy compound (A-28) in ethanol is hydrogenated in the presence of 10% palladium on activated carbon with hydrogen at a pressure of 0.47 kPa. After the hydrogenation is complete, the catalyst is filtered off, the solvent is evaporated to dryness, the residue is taken up in acetone and a stoichiometric amount of aqueous 6 N hydrochloric acid is added. After the addition of ether, 1 '-demethyl-4 -depropyl-4'-cis-trans-pentyl-7-desoxy-7(S)~ -(methylthio)lincomycin hydrochloride (B-28) crystallizes out in the form of small colorless needles with a melting point of 183 to 184 °C (with decomposition), which have the following properties:

Specific rotation: [“] _D ⁺ 139° (c 0.36, pyridine)

Analysis for C^H^gO^N,^ . HCl:

Calculated: 49.31% C, 8.07% H, 5.75% N, 7.28% Cl, 13.17% S;

molecular weight (free base) 450.65

Found: (converted to 4.31% water content)

48.96% C, 8.15% H, 5.78% N, 7.34% Cl, 12.91% Sj mol. wt. (mass spec.) 450 part C-28: 1 '-demethyl-1'-(2-hydroxyethyl)-4'-depropyl-4'-cis-trans-pentyl-7-deoxy-7(S)-(methylthio)lincomycin hydrochloride

The hydrochloride of the N-demethylated compound (see B-28) prepared in the above manner is dissolved in ethyl alcohol, the solution is cooled to 0 °C, excess ethylene oxide is added and the mixture is heated for 2 hours at 100 °C in a sealed tube. After the reaction is complete, the volatile components are distilled off, the light yellow syrupy residue obtained is dissolved in a mixture of chloroform and water and the pH of the mixture is adjusted to 10 with 50% aqueous sodium hydroxide solution. The organic portion is separated, dried over anhydrous sodium sulfate, the chloroform is distilled off and the residue is chromatographed on silica gel using a mixture of methanol and chloroform in a ratio of 1 : 10 to elute the substances. The fractions containing the substance with Rf 0.31 are combined and evaporated to dryness. The residue is mixed with water and the suspension is acidified with normal hydrochloric acid to pH 4, whereby the solid dissolves. Lyophilization of the solution gives the desired product in the form of an amorphous solid having the following properties:

Specific rotations: [®] p ⁺ 88° (c 0.82, water)

Analysis for ^22^42^6^2^2 ’ HCl:

Calculated: 49.74% C, 8.16% H, 5.28% N, 6.68% Cl, 12.07% S;

molecular weight (free base) 494.70

Found: (after conversion to 4.23% water content)

49.76% C, 7.99% H, 4.95% N, 6.76% Cl, 12.31% S; molecular weight (mass spectrometry, M free base) 494.

Example 29 Part A-29: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyphenylthio)-alpha-thiolincosaminide

By the method of Example 18, Part A-18, but using allyl-2-hydroxyphenyl sulfide instead of diethyl trisulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-desoxy-7(S)-(2-hydroxyphenylthio)-alpha-thiollincosaminide was obtained. Countercurrent shaking of the crude product in the ethanol-water-ethyl acetate-cyclohexane system 1:1:1:2 gave a pure substance with a K value of 1.54. After recrystallization from ethyl acetate it formed colorless rods having the following properties:

Melting point: 240 to 241 °C

Specific rotation: [“] p ⁺ '54° (c 0.83, chloroform)

Analysis for Cg^HjjO^NSj:

Calculated: 52.16% C, 5.90% H, 2.65% N, 12.11% S;

molecular weight 529.62

Found: 52.23% C, 5.92% H, 2.72% N, 11.99% S;

molar mass (mass spectrometry, M ) 529.

By the method of Example 1, Parts B-1 and C-1, methyl-7-deoxy-7(S)-(2-hydroxyphenylthio)-alpha-thiolincosaminide and 7-deoxy-7(S)-(2-hydroxyphenylthio)lincomycin hydrochloride are prepared from the above compound.

Example 30

Methyl N-acetyl-2,3,4-tri-O-acetyl~7-deoxy-7C S)-(2-hydroxy-2-methylethylthio)-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using 2-hydroxy-2-methylethyl-methyl sulfide instead of dimethyl sulfide and heating the reaction mixture in an oil bath at 100 °C for 24 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-desoxy-7(S)-(2-hydroxy-2-methylethylthio)-alpha-thiolincosaminide (K = 1.0 in the system ethanol-water-ethyl acetate-cyclohexane 1:1:1: 0.75) is obtained. After recrystallization from ethyl acetate it forms colorless prisms with the following properties:

Melting point: 246 to 251 °C

Specific rotation: [ ^α ]ρ ⁺ '71° (c 0.88, chloroform)

Analysis:

Calculated: 48.47% C, 6.71% H, 2.83% N, 12.94% S;

molecular weight 495.60

Found: 48.51% C, 6.71% H, 2.77% N, 12.72% S;

molar mass (mass spec., M ) 495.

The starting 2-hydroxy-2-methylethyl methyl sulfide is prepared by heating 2-hydroxy-2-methylethyl bromide or 2-hydroxy-1-methylethyl bromide or a mixture of both with sodium methyl mercaptide in ethanol.

If 2-acetoxy-2-methylethyl-methyl sulfide is used in the reaction instead of 2-hydroxy-2-methylethyl-methyl sulfide, methyl-7(S)-(2-acetoxy-2-methylethylthio)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-alpha-thiolincosaminide with a melting point of 199 to 200 °C is obtained.

By the method of Example 1, Parts B-1 and C-1, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxy-2-methylethylthio)-alpha-thiolincosaminide and methyl-7(S)-(2-acetoxy-2-methylethylthio)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-alpha-thiolincosaminide are converted to methyl-7-deoxy-7(S)-(2-hydroxy-2-methylethylthio)-alpha-thiolincosaminide and to 7-deoxy-7(S)-(2-hydroxy-2-methylethylthio)lincosaminide.

Example 31 - 7-Deoxy-7(S)-(3-hydroxypropylthio)lincomycin hydrochloride ' Part A-31: Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using 3-acetoxypropyl methyl sulfide instead of dimethyl sulfide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy-alpha-thiolincosaminide (K = 1.0 in the ethanol-water-ethyl acetate-cyclohexane system 1 : 1 : 1 : 2) is obtained, which crystallizes from a mixture of ethyl acetate with Skellysolve B in colorless needles having the following properties:

Melting point: 172.5 to 174 °C

Specific rotation: [«] _D + 178° (c 0.94, chloroform)

Analysis for ^C 22 ^H 35 ^ONS 2 ^:

Calculated: 49.15% C, 6.56% H, 2.61% N, 11.93% Sj

Found: 49.31% C, 6.58% H, 2.68% N, 11.83% S.

Part B-31: Methyl-7-deoxy-7(S)-(3-hydroxypropylthio)-alpha-thioline cosamidate

By the method of Example 1, Part B-1, but using methyl-N-acetyl-2,3,4-tri-O-acetyl 7(S)-(3-acetoxypropylthio)-7-deoxy-alpha-thiolincosaminide instead of methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(methylthio)-alpha-thiolincosaminide, methyl-7-deoxy-7(S)-(3-hydroxypropylthio)-alpha-thiolincosaminide is obtained, which upon recrystallization from water forms colorless needles having the following properties:

Melting point: 194 to 196 °C

Optical rotation: |α] _D ⁺ 234° (c 0.79, pyridine)

Analysis for C, 2 ^Η 25°5 ^Νδ 2 ^:

Calculated

Found:

44.01% C, 43.93% C,

7.70% H, 4.28% N, 19.58% S; 7.81% H, 4.45% N, 19.55% S.

Part C-31

Hydrochloride

7-deoxy-7(S)-(3-hydroxypropylthio)lincomycin

By the method of Example 1, Part C-1, but using methyl-7-deoxy-7(S)-(3-hydroxypropylthio)-alpha-thiolincosaminide instead of methyl-7-deoxy-7(S)-(methylthio)-alpha-thiolincosaminide, 7-deoxy-7(S)-(3-hydroxypropylthio)lincosaminide is obtained as an amorphous solid having the following properties:

Specific rotation: [«] _D + 110° (c 0.82, water)

Analysis for ®21^40θ6^2®2 * ^:

Calculated: 48.77% C, 7.99% H, 5.42% N, 6.86% Cl, 12.40% Sj mol. mass of free base 480.68

Found: (converted to 2.86% water content)

49.11 * C, 8.10% H, 5.88% N, 6.82% Cl, 12.15% Si mol. mass (mass spec., M ⁺ ) 480.

Example 32

7(S)-(4-hydroxybutylthio)-7-deoxy-lincosaminide hydrochloride Part A-32: Nethyl-7(S)-(4-acetoxybutylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using 4-acetoxybutyl methyl sulfide instead of dimethyl sulfide, and heating the reaction mixture to 110°C for 20 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(4-acetoxybutylthio)-7-deoxy-alpha-thiolincosaminide (K = 1.32 in the ethanol-water-ethyl acetate-cyclohexane system 1:1:1:2) is obtained. After recrystallization from a mixture of ethyl acetate with Skellysolve B, it is obtained in the form of rosette-shaped fine needles having the following properties:

Melting point: 149 to 150 °C

Specific rotation: [ ^a ] _D ⁺ '7'° (o 0.88, chloroform)

Analysis for ^23^37θ1Ο^θ2 ^:

Calculated: 50.07% C, 6.76% H, 2.54% N, 11.62% Sj

Found: 49.97% C, 6.86% H, 2.50% N, 11.35% S.

Part B-32: Methyl-7-deoxy-7(S)-(4-hydroxybutyl)-alpha-thioline coseminite

By the method of Example 1, Part B-1, methyl-7-deoxy-7(S)-(4-hydroxybutylthio)-alpha-thioline coseminite is obtained from the above compound, which crystallizes from methanol in the form of microcrystalline needles having the following properties:

Melting point: 164 to 165 °C

Specific rotation: [“J _D + 218° (c 0.41, water)

Analysis for Ci3 ^H 27°5 ^NS 2 ^:

Calculated: 45.72% C, 7.97 16 H, 4.10 16 N, 18.78 16 S;

Found: 45.73 16 C, 8.13 16 H, 4.22 56 N, 18.33% S.

Part C-32: 7-deoxy-7(S)-(4-hydroxybutylthio)lincomycin hydrochloride

By the method of Example 1, Part C-1, 7-deoxy-7(S)-(4-hydroxybutylthio)lincomycin hydrochloride is obtained from the above compound in the form of an amorphous solid having the following properties:

Specific rotation: [«] _D + '05° (c 0.96, water)

231.54

Analysis for ^C 22 ^H 42 ⁰ 6 ^M 2 ^S 2 ^,HClÍ

Calculated: 49.74% C, 8.16% H, 5.28% N, 12.07% S, 6.68% Cl;

molar mass of the free base 494.70

Found: (converted to 3.70% HgO content)

49.58% C, 8.19% H, 5.23% N, 12.10% S, 6.48% Cl; molecular weight (mass spectrometry, M free base) 494.

Example 33

Methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(5-acetoxypentylthio)-7-deoxy-alpha-thiolincosamineld

By the method of Example 1, Part A-1, but using 5-acetoxypentylmethylsulfide instead of dimethylsulfide and heating the reaction mixture to 0°C for 16 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(5-acetoxypentylthio)-7-deoxy-alpha-thiolincosaminide is obtained, having a K value of 1.94 in the system ethanol-water-ethyl acetate-cyclohexane 1:1:1:2. After recrystallization from a mixture of ethyl acetate with Skellysolve B, it has the following properties:

Melting point: 158 to .59 °C (needles)

Specific rotation: f“] p + '69° (c 0.60, chloroform)

Analysis for C24^39°1qNS ₂ :

Calculated: 50.95% C, 6.95% H, 2.48% N, 11.34% S;

Found: 50.88% C, 6.98% H, 2.41% N, 11.22% S.

By the method of Example 1, Part B-, and Example 2, Part C-2, methyl-7-deoxy-7(S)-(5-hydroxypentylthio)-alpha-thiolincosaminide and 7-deoxy-7(S)-(5-hydroxypentylthio)lincomycin hydrochloride are obtained from the above compound.

Example 34

Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetoxycyclohexylthio)-7-deoxy-alpha-thiolincosaminide

By the method of Example 1, Part A-1, but using 2-acetoxycyclohexyl-methyl sulfide instead of dimethyl sulfide and heating the reaction mixture to 0°C for 16 hours, methyl-N-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetoxycyclohexylthio)-7-deoxy-alpha-thiolincosaminide is obtained. Countercurrent shaking of the crude material in the solvent system ethanol-water-ethyl acetate-cyclohexane 1:1:0.5:3 gives the pure compound with a K value of 0.80.

After recrystallization from ethyl acetate, it forms colorless needles having the following properties: Melting point: 205 to 206 °C

Specific rotation: [«] _D + 153° (c 0.64, chloroform)

Analysis for ^C 25 ^H 3<)°10 ^NS 2 ^:

Calculated: 51.97% C, 6.80% H, 2.43% N, 11.10% S;

molecular weight 577.70

Found: 51.82% C, 6.87% H, 2.29% N, 11.12 « Sj mol. mass (mass spec., M ⁺ ) 577.

By the method of Example 1, Parts B-1 and C-1, methyl-7-deoxy-7(S)-[(2-hydroxycyclohexyl)thio]-alpha-thiolincosaminide and 7-deoxy-7(S)-[(2-hydroxycyclohexyl)thio]-lincomycin hydrochloride are obtained from the above compound.

Claims (14)

A process for the preparation of acyl derivatives of alkyl-7-desoxy-7-RS _n -.alpha.-thiolincosamides of the formula III, characterized in that the alkyl-N-aoyl-6,7-aziridino-6-desamino-7-desoxy-alpha- the thiolincosaminide of formula II is heated with a sulfide of formula wherein in the above formulas Ac and Ac is an acyl radical of a carboxylic acid having at most 18 carbon atoms, Alk representing an alkyl having at most 4 carbon atoms, or Ac, COH ₂ CH ₂ -n is 1, 2, 3 or 4; R @ ₁ and R @ ₂ , which may be the same or different, denote saturated aliphatic hydrocarbon residues containing up to 18 carbon atoms, unsaturated aliphatic hydrocarbon residues containing up to 10 carbon atoms, cycloaliphatic hydrocarbon residues containing up to 10 carbon atoms, aromatic hydrocarbon residues up to 11 atoms or a residue of oxacarbocyclic aromatic or thiacarbocyclic aromatic hydrocarbons containing not more than 8 carbon atoms, R ^ X and YR ^ represent hydrogen or together at most three substituents, wherein X and Y, which may be the same or different, denote oxygen or sulfur and Rj denote hydrogen, an acyl radical of a carboxylic acid having at most 18 carbon atoms, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxyalkyl, and alkylthioalkyl all having at most 6 carbon atoms, phenyl, benzyl, furyl, furfuryl, thlenyl or thenyl; pripa wherein X is oxygen and R 1 is alkyl, may be attached to each other to form oxacycloalkyl having no more than 5 carbon atoms and having 3 to 6 ring members, at a molar ratio of the two at 70 to 140 ° C, preferably at reflux temperature if the boiling point of the sulphide is such that the mixture boils below 110 ° C, in glacial acetic acid or in other anhydrous lower alkanoic acids or in anhydrous benzoic acid and in other arenic acids containing not more than 12 carbon atoms at atmospheric pressure, and if a low boiling sulfide is used to provide a reaction mixture that refluxes below 70 ° C, the reaction must be carried out at a higher pressure than atmospheric. 2. Method according to claim 1, characterized in that the reaction is carried out with the sulfide of formula R ^ X n ^-S-R 2 ^{-XH -K} 4 ^'is equal to ^{n in} the first 3. The process of claim 1, wherein the reaction is carried out with a sulfide of the formula R @ 1 -R @ 1 -S @ 1 R @ 8 -YR @ 2, wherein n is 2. 4. A process according to claim 1 wherein the reaction is carried out with a sulphide. of the formula R 1 X-R 1 -S 1 R 8 -X R 4 wherein the -R 8 -X R 6 group is a target. butyl or allyl. 5. A process according to claim 3, wherein the reaction is carried out with a sulfide of the formula R @ 1 -R @ 1 -S @ 1 R @ 1 -X @ R @ 1, wherein the group - R @ 8 --X @ R @ 3 is a target. butyl or allyl. 6. The process of claim 1, wherein the reaction is carried out with a sulfide of the formula R @ 1 -R @ 1, -S @ 1 -R @ 8 -X @ R @ 2, wherein the group -R @ 1 --X @ R @ 2 is 2-hydroxyethyl. 7. Process according to claim 1, characterized in that epimeric forms 6 (R), 7 (R) of the general formula II are used as starting materials. 8. A method according to claim 7, characterized in that the reaction is carried out with the sulphide of formula XR R _g -S _n -R., - YR ^, in which n is equal to 1. 9. A process according to claim 7, wherein the reaction is carried out with a sulfide of the formula R @ 1 -R @ 1 -S @ 1 R @ 1 -YR @ 2, wherein n is 2. 10. The method according to claim 7, characterized in that the reaction is carried out with a sulphide of the general formula R _g X-R-S _n -R ₂ -YR ^ in which -R ₂ -YR is tert. butyl or allyl. 11. A process according to claim 9, wherein the reaction is carried out with a sulfide of the formula R @ 1 -R @ 1 -R @ 6 -R @ 8 -R @ 6 -, wherein the -R @ 8 -Y @ R @ 6 group is a target. butyl or allyl. 12. A process for the preparation of the two forms of the 7 (R) and 7 (S) compounds according to item 1 of formula III i characterized by heating a compound of formula II wherein Ac and Ac _{1 are} acyl residues of a carboxylic acid having up to 18 carbon atoms and Alk is alkyl having up to 4 carbon atoms or a group Αο, ΟΟΗ ,, ΟΗ ,, with a sulfide of the formula where n is I, H 1 and R ₂ which may be the same Hebo different, represent radicals of saturated aliphatic hydrocarbons containing up to 18 carbon atoms, residues of unsaturated aliphatic hydrocarbons containing up to 10 carbon atoms, residues of cycloaliphatic hydrocarbons containing at most 10 carbon atoms, residues of aromatic hydrocarbons containing up to 11 carbon atoms or radicals of oxacarbocyclic aromatic or thiocarbocyclic aromatic hydrocarbons containing not more than 8 carbon atoms, R ^ X and YR představují represent hydrogen or together not more than three substituents, where X and Y, which may be the same or different, denote oxygen or sulfur and R ^ and R ^ denote hydrogen, an acyl radical of a carboxylic acid having at most 8 carbon atoms, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxyalkyl, and alkylthioalkyl all having at most 6 carbon atoms, phenyl, benzyl, furyl, furfuryl, thienyl or thenyl; pripa wherein X is oxygen and R 6 is alkyl, may be attached to each other to form an oxeycloalkyl having no more than 5 carbon atoms and having 3 to 6 ring members, provided that when R, XR 1 contains more than 4 carbon atoms, R 8 YR 6 6 H ^brand target. butyl or benzyl; 13. The method of claim 12, characterized in that ^R 2 ^IR 4 <J ^e · ^Tero butyl or allyl. 14. The method according to claim 12, characterized in that R, XR ₃ is 2-hydroxyethyl and R ₂ YR ₄ is selected from the group consisting of alkyl having 1-6 carbon atoms, alkenyl with 1 EŽ 6 carbon atoms, cycloalkyl having 5 to C 6 alkyl and C 1-10 alkyl having 1 to 6 carbon atoms.