DE1920542A1 - Lincomycin derivatives and processes for their preparation - Google Patents

Description

LAWYERS DR. JUR. DIPL-CHEM. WALTER BEIL ALFRED HOEPPENER DR. JUR. DIPL-CHEM. H.-J. WOLFP DR. JUR. HANS CHR. AX

1920 542 Zl April 1969

623 FRANKFURTAM MAIN-UOCUSf

AIKLQNSKASSEtt

Our no.15459

The Upjohn Company
Kalamazoo, Mich., V.St.A.

Lincomycin derivatives and processes for their preparation.

The invention relates to novel compounds of the following general formula

It

-C-FE

in which R is an alkyl radical with no more than 20 carbon atoms, preferably with no more than 8 carbon atoms, a cycloalkyl radical with 3 to at most 8 carbon atoms or one Aralkyl radical with at most 12 carbon atoms, preferably with

808846/1201

-z-

Il

no more than β carbon atoms and R, -C- the acyl radical one L-2-pyrrolidinecarboxylic acid substituted in the 4-position of the general formulas:

OH. V2_j / c OH

"mean, where R, and. R" are alkyl groups with a maximum of 20 carbon atoms (including methylene), preferably with no more than b carbon atoms, cycloalkylidene radicals with 3 to 8 carbon atoms or aralkylidene rep. In with maximum ens 12, preferably with a maximum of 8 carbon atoms and ti .., a hydrogen atom or a rlHp. '/ ert mean. G groups can be merged; ctiered. Examples of lkvlrest-r- with a maximum of 2ü carbon atoms (R, HR-, and HRp) are: methyl-, ethyl-, tropyl-, butyl-, pentyl-, Hexyl, Hept ^ / l-, ethyl, rionyl, Dec.yl-, Un decyl, dodecyl, Tridecyl, letradecyl, pentadecyl, hexadecyl, heptadecyl, OcxaüecyL-, Monaäecyl- and eicosyl- Residues and their isomeric forms.

Examples of CyclotlKvlreste are: eggs Cvelopropyl-, CycloDut \ · L, Cyclop ent yi, cyclohexyl, cycloheptyl, cyclooctyl, 2-i ^v iethyl cyclOOentyl-, 2,3 - Di fflethylcyciobutvl-, 4-i ^v ! ethvlcyclobut ·. '·! - and y-üyc.l ocentvlproOvlrest.

Examples of aralicyl residues are:

9 0 9 8 A 6 / Ί 2 Ü 1

BATH ORIGINAL

the benzyl, phenethyl, u-phenylpropyl and uc-Iüaohthylin ethyl re st.

Examples of the ülKyliden-, Cycloalkyliden- and aralkylidene radicals (R-, and R) include the methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, octylidene, ilonylidene, lexylidene , Undecylidene, Ijodecyliden-, Tridecyliaen-, l'etradecylideri-, Pentaaecyliaen-, Hexaaecyliaen-, Hpptadecyliden-, Octadecyliden-, Nonaaecvliden-, Eicosylidenrest and their isomeric Foimi ^ ii, i ^ r Uyclopropyliden-, Cyclopropyliden- Cyclohexyliden-, Gycloheütyliden-, Cyclooctyliden-, 2-Cyolopropyläthyliden-, 3-Cyc] opentvl-P rop yli α en-, b en zy1i ι e n-, 2-Phenyläthyliden-, 3- Γhenylpropyliaenuna ai \ aphthvlmethvlenrest as well as for their manufacture, ^. It relates in particular to 7-D2SOxylincomycin and its analogues, as well as to experience in the preparation of the compounds mentioned and similar ones and, finally, intercourse in these processes.

The new inventive compounds of the formula I as well as other related connections can be duror. Heating a compound of the general formula

Rü-'J-ΙΓΗ

Io N 5 • ζ Halo 0 Z / sr 5 J HO /

II

Ur.

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BATH ORIGINAL

ti

Il

in which R, -C- means the S-isologue of Ra-G- , with water in dimethylformamide or by heating a new compound of the formula

CH,

III

with hydrogen sulfide in an inert solvent with the formation of a new connection of the general fortfiel

WH,

IV

which, after acylation, give compounds of the formula I, are nergestel.lt. While the first-mentioned method predominantly leads to compounds of the 7 (R) - or L- threo -configuration, the second method predominantly delivers

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Connections of the opposite configuration, viz the 7 (S) or D-erythro configuration.

As shown in the formulas below, the HR-j-Reöt may be either in cis or in Jtrans position:

bfl

CH,

-WH

SH

and

ice cream

VI

If desired, the cis and trans isomers can be added before or after substitution of the 7-hydroxy group by cross-flow distribution octer chromatography be separated.

If R ^ in formula B means a hydrogen atom, this can be replaced by a corresponding alkylation or a similar procedure. this happens preferably by reacting the compound of the formula IB or Uli, in which Pw is a hydrogen atom, with an oxo compound (an aldehyde or a ketone) and by hydrogenation of the adduct obtained using a catalyst that is an oil-

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able to saturate fihisohe double bond. Either platinum or palladium can be used as the catalyst. Suitable oxo compounds correspond to the formula Ri-RgCO, in which RcRgC = that above for R _? corresponds to the specified meaning. Examples of such oxo compounds are: formaldehyde, acetaldehyde, propionalaldehyde, butyraldehyde, acetone, isobutylmethylketone, benzaldehyde, phenylacetaldehyde, Kvdrozimtalaehyi, acetophenone, propiophenone, butyrophenone, 3- ^ ethyl-A-phenyl-2-methyl-5-butanone, 2-ethyl-A-phenyl-2-methylbutanone -phenyl-3-pentanone, 3-Cvcloperitanpropionalaehya, Cjrclonexanacetaldehyd, Cvcloheiotan carboxaldehyde, 2,2-Dimethylcyclopropylacetaldehyd, 2,2-Uimethylcyclopropyl-niethyltceton, Cyclopent '-' Linethvllobethyl,.

The starting compounds of Foriael II are thereby produced that one is a compound of the general formula

m _o -

GH

Halo

VII

has R as defined above, N-acylated with a substituted in the 4-position L-2-pyrrolidine carboxylic acid of the general formula A or ti, introduces in the 2-, 3- and 4-btellung a üchutzgruppe

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¹ ORIGINAL BATHROOM

and the obtained compound of the general formula

Il

R ₄ -G-KH

OIL

AcO

Halo

-0

OAc

VIII

SR

OAc

such a protecting group in the Ac, ζ.ΰ. Acetyl, represents with phosphorus pentasulphide in an inert solution sungs'-Li ttel heated. This acyl ie η mg as well as similar, K-acylation mentioned here. "s can according to procedures take place as they are for .iie acylation of Amino sugars are known in the art. The protection the 2-, 3- and 4-positions can ·-also through in the Sugar chemistry "known groups can be reached.

• Leave the common connections of the formula VII establish themselves in such a way that the 7-0H- (rgroup of a connection aer Forin-1

KH,

Uri

IX

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BATH ORIGINAL

by to be specified below, not according to the invention Replaced procedures by halogen and then N-acylated with the corresponding acid. Me N acylation but can also be carried out before the halogenation, so that compounds of the general formula

CiH

fl

R ₄ -C-NH-

OH

—0

which then becomes compounds of the general formula

ti

R ₄ -C -NH

QH.

Hal

XI

can be convicted, who in turn now seek protection ier 2-, 5- and 4-positions by treatment with phosphorus pentasulphide to compounds of the general formula II converted to ground.

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BATH ORIGINAL

The starting compounds of those presented above General formula XI can also be prepared from starting compounds according to US Pat. No. 3,380,992

^{0 of} the general formula X, in which R ^ -C- is a pyrrolidinecarboxylic acid of the general formula which is substituted in the 4-position

(I)) or OH,

means in which Z means a protecting group which by. Solvolysis or hydrogenolysis such as in the United States patent 3 30 0 992, removed can be.

Using the methods of the present invention, each of U.S. Patent 3,380 Convert described compounds into the corresponding compound of the formula I, so that all those compounds are to be regarded as disclosed herein without being specifically named here.

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BATH ORIGINAL

- ίο -

The starting compound of the formula VII- and its F-acylate can be obtained by heating a compound of the formula IX or X with Rydon's reagent. The mechanism by which Rydon's reagent is responsible for the substitution of the 7-hyo.roxy group by. Halogen advertises is not fully known. This eschanism leads to a change in configuration, where a 7 (R) - £ Lvaroxy compound with the erythro configuration results in a 7 (b) -iialogen compound with the L- thr eo configuration. Example εν / else the 7 (b) -chloro-7-deoxylincomycin, which entrains the Lin coinycin (which has the D- erytnro -configuration), is in the L-threo configuration.

Rydon reagents are obtained by adding halogen to triphenylphosphine or triphenylphosphn.it or by Addition of an alkyl halide to triphenyl phosphite are una thanks to the angleine formula

XZII

XXIII

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BATH

920542

XXIV

can be represented, in which X means a halogenator, e.g. chlorine, bromine or iodine / ~ Rydori and coworkers, J.Ghem. Soc. , 2224 (1953), 2281 (1954), 3043 (1956) 7. The Rydon reagent can be formed in situ by adding halogen or methyl halide to a solution of the 'i'riphenylphosphine or triphenylphosphite in an inert solvent such as acetonitrile or dimethylformamide, or it can be isolated as a separate entity. In both cases, the reaction with lincomycin or a related compound takes place by contact with the Rydon reagent in an inert solvent such as acetonitrile or dimethylformamide until the 7-hydroxy group has been substituted. The reaction takes place at normal temperature, but it can be warmed slightly if necessary. The temperature is expediently kept between about 20 and about 55 ° G. The product can be obtained from the reaction mixture according to known methods, such as filtration, solution extraction, etc. Preferably the reaction. ^c : Easily treated with methanol to remove any excess.! ^ e Rydoii eyes to destroy, filtered in order to remove existing solids, such as triphenylunosuhinoxide formed during the reaction, and finally lent a Behanalun.-: to obtain the Pi-oauktes uhterzo =; f; n. Itas methanol kaiin before or after filtration

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BATH ORIGINAL

can be added. Preferably the treated and filtered reaction mixture evaporated to dryness and by solvent extraction and / or chromatography cleaned.

In order to substitute chlorine for the 7-hydroxy group by the thionyl chloride process, the starting compound of the formula IX or X, preferably in the form of a. Acid addition salt, for example the hydrochloride, with gentle heating - preferably at reflux temperature - mixed with thionyl chloride, preferably in the presence of an inert solvent, until the desired substitution of the 7-hydroxy group by chlorine has taken place. The reaction is preferably carried out in an inert atmosphere, for example under nitrogen. Carbon tetrachloride can be used as an effective solubilizer, but other inert solvents such as chloroform, methylene chloride, ethylene chloride, ether, benzene and the like can also be used. A satisfactory process consists in stirring the reaction mixture at room temperature for an extended period, for example from about 1 to 18 hours, or as long as is necessary to achieve a relatively clear solution, and then the temperature to about 50 to 100 ⁰ C. , e.g. increased to reflux temperature (for carbon tetrachloride 77 ° C). After completion of the reaction, which is usually the case after about 1 to 5 hours of refluxing, the reaction mixture is allowed to cool down, vertically under nitrogen. Any material that separates out on cooling is combined and dried. The solvent is removed by vacuum distillation at a vessel temperature preferably below about 35 ° C and that

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precipitated material combined, dried and treated with ethanol to remove any remaining sulfite intermediates to be converted into the desired product. The combined material can then be extracted by solvent and / or recrystallization further purify and can either in the form of the free base or as Acid addition salt can be obtained. The proportions of the participants in the reaction can be wide within a range Area fluctuate. However, at least 3 moles of thionyl chloride per mole of starting compound are stoichiometric necessary. Any larger amount can be used, but is normally the use a more than about 10-fold excess is not necessary or not appropriate. Preferably used about a 2 to 3-fold excess. The amount of solvent is not critical; she can accordingly the technical working method can be varied over a wide range. Usually about 15 to about 30 Sufficient volume of solvent per part of solid starting compound. However, the ratio of solvents is important on thionyl chloride with a view to the solubility of the product in thionyl chloride. Becomes a high solvent to thionyl chloride ratio (Vol / Vol) selected, then the desired product is included The reaction mixture cools off and the work-up of the product is simpler. E.g. a product mixture with carbon tetrachloride precipitates directly when the reaction mixture is cooled, if the The vol / vol ratio of carbon tetrachloride to thionyl chloride is maintained above about 10 to 1.

The 7-hydroxy group is substituted by iodine by modifying the Rydon reagent procedure.

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rens. The desired halogen substitution is achieved simply by mixing the starting compound of the formula IX or X causes with triphenylphosphine and Tetrajodkoh lenstoff in an inert solvent. the The reaction takes place at room temperature (25 C), but slight warming to reflux temperature can be used from 50 to 60 G.

Examples of solvents are acetonitrile and ulfitromethane, triphenylphosphine and carbon tetraiodine are optimal in equimolar proportions and preferably in a substantial molar excess of the starting compound used. Thus, per mole of starting compound of the formula IX or X are optimal about 4 moles of triphenylphosphine and 4 moles of carbon tetra iodide used. This procedure is also applicable to the chlorination and bromination, if instead of the Carbon tetrachloride or carbon tetrabromide is used.

Any or all of the 2-, 3- and 4-hydroxy groups as well as the 7-SH-G group can, for example, by means of carboxylic acids with preferably before or after the halogenation no more than 18 carbon atoms or by means of halogen atoms, nitro, hydroxy, amino, cyano, thiocyano or alkoxy-substituted carboxylic acids preferably likewise having no more than 18 carbon atoms be esterified.

Examples of such acyl radicals are derived from the following carboxylic acids:

(a) saturated or unsaturated, straight or vertical

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branched chain aliphatic ^ carboxylic acids such as acetic acid, Propionic acid, butyric acid, iso "butyric acid, tert-butyl acetic acid, Valeric acid, isovaleric acid, caproic acid, Caprylic acid, capric acid, dodecanoic acid, lauric acid, Tridecylic acid, myristic acid, pentadecanoic acid, Palm! Tic acid, margaric acid, stearic acid, acrylic acid, Crotonic acid, undecylenic acid, oleic acid, hexynic acid, Heptic acid, octinic acid and the like *;

(B) saturated or unsaturated, alicyclic carboxylic acids such as cyclobutane carboxylic acid, cyel opentane carboxylic acid, Oyclopentane carboxylic acid, methylcyclopentane carboxylic acid, Cyclohexanecarboxylic acid, dirnethylcyclohexanecarboxylic acid, Dipropylcyclohexane carboxylic acid and the like;

(c) saturated or unsaturated, alicyclic aliphatic carboxylic acids such as cyclopentane-acetic acid »cyclopentane-propionic acid, Cyclopentene acetic acid, cyclohexane butyric acid, Methylcyclohexane-acetic acid and the like;

(d) aromatic carboxylic acids such as benzoic acid, toluic acid, naphthoic acid, ethylbenzoic acid, isobutylbenzoic acid, Methylbutylbenzoic acid and the like

(c) aromatic-aliphatic carboxylic acids such as phenylacetic acid, Phenylpropionic acid, phenylvaleric acid, Cinnamic acid, phenylpropiolic acid and naphthylacetic acid and the ^ l

Suitable halogen, metro, hydroxy, amino, Cyano, thiocyano and lower alkoxy radicals sub-

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Substituted carboxylic acids include the above-mentioned hydrocarbon carboxylic acids, by one or more of the halogen atoms, Mitro-, Hydroxy-, Amino-, Cyano- or thiocyano radicals are substituted and contain no more than 18 carbon atoms in total, "or alkoxy-carboxylic acids with no more than 18 carbon atoms. G-suitable alkoxy groups include methoxy, ethoxy, propoxy, Butoxy, amyloxy, hexyloxy, dodecyloxy, Hexadecyloxy group and isomeric forms derived therefrom. Examples of such substituted carboxylic acids are: Mono-, di- and trichloroacetic acid, α- and ß-chloropro-

* pionic acid, α- and Ύ -bromobutyric acid, α- and ß-iodo valeric acid, mevalonic acid, 2- and 4-chlorocyclohexanecarboxylic acid, shikimic acid, 2-nitro-1-methylcyelo butane-carboxylic acid, 1,2,3 »4,5 »6-hexachlorocyclohexanecarboxylic acid, 3-bromo-2-methylcyclohexanecarboxylic acid, 4- and 5-bromo-2-methylcyclohexanecarboxylic acid, 5- and 6-bromo-2-methylcyclohexanecarboxylic acid, 2,3-dibromo-2-methylcyclohexanecarboxylic acid, 2,5-dibromo-2-methylcyclohexanecarboxylic acid, 4,5-üi-bromo-2-ynethyl cyclohexanecarboxylic acid, 5,6-dibromo-2-methylcyclohexanecarboxylic acid, 3-bromo-3-methylcyclohexanecarboxylic acid, 6-bromine -3-methylcyclo hexane-carboxylic acid, 1 _s 6-l) ibromo-3-methyl cyclohexane-carboxylic acid, 2-bromo-4-methylcyclohexane-carboxylic acid, 1,2-

"Di bromo ^ -methylcyclohexanecarboxylic acid, 3-bromo-2,2,3-trimethylcyelopentanecarboxylic acid, l-bromo-3,5-dimethylcyclohexane-carboxylic acid, üomogentisinsäure, o-, m- and p-Chlorbenzoef.-acid, Anisic acid, salicylic acid, p-hydroxybenzoic acid, ß-resorcylic acid, gallic acid, veratrumsäare, Trimethoxybenzoic acid, trimethoxycinnamic acid, 4,4'-dichi orbenzilic acid, o-, m- and p-nitrobenzoic acid, Vyanessi; acid, 3t4- and 3 »5-dinitrober: zoic acid, 2,4,6-trinitrobenzoic acid, Thiocyanoacetic acid, cyanopropionic acid

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acid and lactic acid.

Examples of such alkoxycarboric acids are ethoxyformic acid (ethyl hydrogen carbonate), butyloxyformic acid, pentyloxyformic acid, hexyloxyformic acid, dodecyloxyformic acid, hexadecyloxyformic acid and the like -G groups can, for example, with alkyl radicals with preferably not more than 20 carbon atoms, cycloalkyl radicals with preferably 3 to at most 12 carbon atoms or with ylidene (e.g. 3,4-0-ylidene) groups such as alkylidene group, preferably with at most 20 C atoms or aramethylidine groups and vinylogues derived therefrom with preferably no more than 12 C atoms can be etherified. Examples of alkylidene groups are listed above. Examples of aralkylidene groups are furfurylidene, 5-methylfurfurylidene, benzylidene, m-tolylidene, o-tolylidene, p-tolylidene, o-chlorobenzylidene, m-chlorobenzylidene, m-bromobenzylidene, p-bromobenzylidene , p-kethoxybenzylidene, m-methoxybenzylidene, o-methoxybenzylidene, 3,4-dimethoxybenzylidene, salicylylidene, p-hydroxybenzylidene, 3,4,5-trimethoxybenzylidene, piperonylidene, o-bitrobenzylidene , p-chlorobenzylidene, m-nitrobenzylidene, p-nitrobenzylidene, ß-fiaphthylidene, o-bromobenzylidene, 2,4-I) chlorobenzylidene7 3-methoxy-4-hydroxy-benzylidene, terephthylidene, 3 Λ - Dihydroxybenzylidene and cinnamylidene group. The starting compounds of formula III are prepared by splitting off hydrogen halide from compounds of formula VII. This is expediently done by heating a compound of formula VII with an acid acceptor in

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a solvent. Suitable acid acceptors are including anhydrous sodium carbonate, potassium carbonate, triethylamine, collidine and potassium hydroxide. As a solvent are suitable dimethylformamide, dimethyl sulfoxide, Ethylene glycol, benzene and alcohol. The temperature can are within a range of about 25 G to about the boiling point of the solvent.

According to one embodiment of the invention, a starting compound of the general formula II is included Water heated in dimethylformamide. Preferred, although not required, are the 2-, 3- and 4-hydroxy groups to protect by protecting groups. Sole protection groups sometimes emerge from the process for the preparation of compounds of the formula II; in this case is inre distance at this stage unnecessary. The amount of water is not critical as long as there is a substantial excess and a practically homogeneous solution is obtained. The ratio of water to dimethylformamide is preferably 1: 9 to 1: 1. The solution will be preferably heated under reflux, but it is possible to work at higher or lower temperatures. . Usually, however, it is not necessary or not desirable temperatures below about 25 C octer above about 16O ° C to be used.

According to a further embodiment, a Starting compound of the general formula III by heating in an inert solvent under hydrogen sulfide pressure converted into a compound of the general formula IV. The connection of the Formula III with 2-propanol or a similar solvent mixed, saturated with hydrogen sulfide and heated in a bomb to about 100 C. Higher or lower

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Higher temperatures, for example from about 25 to about 150 ° C., can be used. The compound of formula IV thus obtained can be linsorüießend fertilize with the formation of Vertan of the general J? 'Or-uel I l ^ -acvliert. This procedure ν? This mainly leads to compounds of the 7 (S) - oaer L- tnreo - configuration, while the preheating 1 benmiri level method of operation predominantly results in compounds with the opposite configuration.

According to an alternative procedure, one starts from a compound of the general UOr ¹ Ji el VII and sets this with an acylating agent to form a compound of the general i'or ;; iel

OH,

^ Halo

AcO,

V.

XII

OAc

uji. The Äciyli '? R'in .: k ^r mn in a well-known v / ei se using £ s? L'.: Säurefe.n-, y iri d oaer λπ · - ··! · Lcr.lorid oaer aer S ¹ Iu ^? '-. N!: V.ii'i'ie bzv ;. building halides voretei.end auf-G - rooiiKHuren take place, ünsonlieiena -'Ird die Kj. ' ler I ') r; el XII in it Phosi, horuenta «uifid, as vorst-nond be.-o: r euen, to a compound of the general formula:

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BATH

CH,

It

AcO,

Halo

OAc

XIII

SR

OAc

Il

in which Ro-C- represents the β-isologue of Ac. The compound of the formula XIII is then, in the manner mentioned above, in contact with water in dimethylformamide to form a compound of the general formula

GH,

Acj> lH

AcO

XIV

, OAc

SR

OAc

warmed up; the latter, after ilyarazinolysis (warming with Hydraziη in an inert solvent) a compound the general formula:

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BATH

The compound of the formula XV can then, as described above, be N-acylated to a compound of the general formula I. This process mainly results in compounds of the 7 (R) or D - erythro configurations.

Depending on the pii-v / ert of the environment, the compounds and intermediates of the general formula IA, IB, III and IV are either in protonated or non-protonated form. If the protonated form is desired, then the acid addition salt comes into play, but if the non-protonated form is desired, then the free base comes into question. The free base can be converted into a stable acid addition salt by neutralization with the corresponding acid to below about pH 7.0, preferably to about pH 2 to 6. S ¹ Acids suitable for this purpose include: hydrochloric acid., Sulfuric acid, phosphoric acid, thiocyanic acid, fluorosilicic acid, hexafluoroarsenic acid, hexafluorophosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, pamoic acid, g'holic acid, sulphuric acid, luucic acid , G-lutaric acid,

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Glycolic acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, 3-phenylsalicylic acid, 5-phenylsalicylic acid, 3-toethylglutaric acid, o-sulfobenzoic acid, Gyclopentanpropionäure, 1,2-Cyclo hexanedicarboxylic acid, 4-cyclohexanecarboxylic acid, octadeeenylsuccinic acid ,. Octenyl succinic acid, methanesulf onic acid, benzenesulfonic acid, helianthinic acid, Reineckes salt, dimethyldithiocarbamic acid, cyclohexylsulfamic acid, Hexadecylsulfamic acids cctadecylsulfamic acid, Sorbic acid, irionochloroacetic acid, undecylenic acid, 4'-hydroxyazobenzene-4-sulfonic acid, Octyldecylic acid, picric acid, benzoic acid, cinnamic acid and similar acids.

The acid addition salts can be used for the same Purposes can be used like the free base, or they can be used for processing. For example, the convert the free base into an insoluble salt like the picrate, this then e.g. by solvent extractions and repeated washing, chromatography, fractionated Liquid-liquid extractions and crystallization cleaned and then for regeneration the free üasenforin used by treatment with alkali or can be used to form another salt by metathesis. The free base can, however also into a water-soluble salt, e.g. the hydrochloride or sulfate and the aqueous solution of the salt with various water-immiscible solvents can be extracted before the free base form by treating the acid solution extracted in this way is regenerated, or converted into another salt by metathesis. The free bases of the general Formulas IA, IB, III and. IV can be used as a buffer .- ■ or used as an acid-deadening substance (antacid) -

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are set. The compounds of the general formulas I, II, III and IV react with isocyanates to form of urethanes and can be used to modify polyurethane resins. The long chain links i.e. those in which HRp denotes an alkyl radical with 8 carbon atoms upwards have surface-active substances Properties and can be used as a shredding and emulsifying agent. Kaph condensation with formaldehyde the thiocyanic acid addition salt forms resinous substances which, according to US Pat. No. 2,425,320 and 2,606,155 are useful as pickling inhibitors. the Free bases are also good carriers for toxi see Acids. For example, the fluorosilicic acid addition salts can be used as moth agents according to the USA patents 1,915,334 and 2,075,359 and the hexafluoroarsenoic acid and hexafluorophosphoric acid addition salts as parasiticides according to US Patents 3 122 53b and 3 122 552. The compounds of the general formulas I and IV are free radical scavengers and can be used to terminate free radical reactions can be used.

The T-mercapto-T-desoxylincomycin and its close analogues, ie, where -R-, Η the B'ormel a cis or trans -Alkvlrest having at most 8 carbon atoms, R? a hydrogen atom, a methyl or ethyl radical and R an alkyl group with no more than 8 carbon atoms mean, have antibacterial properties that are slightly less than those of lincomycin; but they can be used for the same purposes as lincomycin. The other analogs and isomers have similar but less pronounced antibacterial properties and can be used for the same purposes as lincomycin

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be used where larger quantities are not unpleasant.

The following examples explain the invention without restricting it. Unless otherwise noted, Parts and percentages are based on weight and solvent ratios are based on volume.

Example 1:

7 (S) -Mercapto-7-deoxylincomycin - ^ "methyl-7-mercapto-6,7,8-trideoxy-6- ( trans -l-methyl-A-propyl-L ^ -pyrrolidincarboxamido) -l-thio- L- threo -q-3> - galacto -octo -

CH,

SH

NS,

OH

XVI

Part A-I

Methyl 6,7-aziridino-7-deoxv-tt-thiolincosaminide.

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OH,

-Cl

CH ₂

OH 7 [ XVII

SMe

HO / -O

(oh Υ

N Υ SMe

OH

A mixture of 1 g of methyl 7 (S) -chloro-7-deoxy- <xthioline cosaminide and 3 g of anhydrous sodium carbonate in 40 ml of dimethylformamide was refluxed for 5 minutes. The solvent was distilled under vacuum a "b and the residue was recrystallized from methanol. 370 mg (yield: 45.2 ^a ß>) of methyl 6,7-aziridino-7-deoxy-a-thiolincosaminide were thereby

^v "ο
Obtained melting point of 192-198. After concentrating the mother liquors, a second crop of crystals of 160 mg (18.5 %) with a melting point of 182 189 ° C. was obtained. Two recrystallizations from methanol-acetone gave crystals with a melting point of 203 220 ⁰ C and / "α _7 _D + 320 ° (dim ethyl sulf oxide).

Analysis:

Calculated for

C = 45.94; H = 7.28; N = 5.95; found:

C = 45.97; H = 7.44; N = 6.19.

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Part B-I

Methyl-TiSj-mercapto-T-deoxy-a-thiolincosaminia.

SMe

XIX

A mixture of 1.5 g of methyl-o ^ -azaridino ^ -deoxyoc-thiolincosaminia in 30 ml of 2-propanol, while cooling in a bath, an ice-methanol mixture was saturated with HpS. The reaction mixture was heated in a bomb on a steam bath for 5 hours. During this time broke up the methyl-ö.T-azaridino-T-deoxy-a-thiolincos aminide gradually and formed a solution from which crystalline methyl-7 (s) -mercapto-7-deox.y-a-thiolin cosaminide began to fail. After filtration of the cooled mixture, 1.6 g of methyl 7 (δ) -mereapto-7-deoxy-α-thiolincosaminide were obtained obtained with a melting point of 190-197. Part of it was made from ethanol recrystallized to obtain an analytical sample. Melting point 195-198 ° C.

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Analysis;

Calculated for CgH ₁₉ NO ₄ S ₂ :

C = 40.13; H = 7.11; B = 5.20; S = 23.80; found: G = 40.36; H = 7.12; N = 5.03; S = 24.21.

Part C-I

7 (s) mercapto-7-deoxylincomycin hydrochloride.

SMe

PHA-HH-

3H-

-SH

XIX

SMe

XX

A cooled in ice-i ^v iethanol bath solution of 5.2 g (25 »2 niM) trans -l-Hethyl-4-n-propyl-L-prolinhydro chloride and 7.16 ml (51 mmol) of triethylamine in 250 ml of acetonitrile was mixed with 3.42 ml (25.2 mol) of i-butyl chloroformate. After stirring for 20 minutes, a solution of 6.8 g (25.2 mmol) of methyl-7 (s) -mercapto-7-deoxy-a-thiolincosaminide in 100 ml of water was added. The resulting reaction mixture was then stirred at ambient temperature for 2 hours. The organic solvent was distilled off in vacuo and the residue was extracted with ethylene chloride. After drying, the methylene chloride was recovered from

909846/1201

Stand of 10.2 g distilled off. The crude oil was dissolved in 50 ml of acetone and diluted with excess HCl added. An addition of now 250 ml of acetone caused the precipitation of a rubbery solid. After trituration with 250 ml of freshly distilled acetone, this precipitate became hard, and by filtration collected. 1 g of this was chromatographed on silica gel, eluting with methanol-chloroform in a ratio of 1: 4. The fractions with antibacterial activity were combined and evaporated to dryness. This material (307 mg) was dissolved in acetone and an-? leavened. After evaporation of the solvent, 7 (S) -mercapto-7-deoxylincomycin hydrochloride was obtained in the form a glassy solid.

Analysis:

Calculated for Ο-, οΗ, .ΝρΟ ^ βρΉΟΙ:

C = 47.09; H = 7.69; N = 6.10; found: C = 47.25; H = 7.87; N = 5.60.

Antibacterial spectrum: Ύ / ml * '

Staphylococcus aureus 1.6

Streptococcus hemolyticus 0.8

Streptococcus faecalis 1.6

Bacillus subtilis 6.4

gram negative> 200

'In Hirri heart infusion broth after 20 hours determined after twofold dilution at the end point.

909846/1201

Example 2;

7 (R) -Mercapto-T-deoxylincomycin hydrochloride,

N.

ti

CH,

HS - NH

NS,

OH

XXII

Part A-2

Methyl-T-iSj-chloro-T-deoxy-a-thiolincosaminide.

CH,

HO

HO

H ₂ N

Cl

SMe

XXIII

OH

3 A- 0

\ 0H / Nj / SMe

OH

XVII

A suspension of 197.2 g triphenylphosphine in 1.5 l of anhydrous acetonitrile was mixed with 52.5 g of chlorine

909846/1201

-3O--

offset. With stirring, 18.75 g of methyl α-thiolincosaminide (U.S. Patent 3,179,565) were added and, after 2.5 hours at ambient temperature, 50 ml of methanol were added. The mixture was concentrated to a thick syrup, the concentrate was diluted with methylene chloride and extracted three times with water, and the aqueous extracts were washed twice with methylene chloride. The extracts were then made alkaline with sodium hydroxide and extracted repeatedly with methylene chloride. The organic extract was dried and evaporated in vacuo and the residue was chromatographed over 1.1 kg of silica gel, eluting using chloroform-methanol (4: 1). The main fraction, selected on the basis of its thin layer chromatogram, weighed 4.4 g. After recrystallization from methanol-water gave 2.73 g of methyl-7 (fc>) - chloro-7-deoxy-.alpha.-thiolincosaminid having a melting point of 178 and 181 ⁰ G.

Analysis:

Calculated for CgH ₁₈ GlHO ₄ S:.

C = 39.77; H = 6.67; H = 5.16; S = 11.80;

0 = 13.05;

found: C = 39.91; H = 7.02; F = 5.57; S = 11.99;

O = 13.33.

part B-2

Methyl 7 (S) -chloro-7-deoxy-a-thiolincosaminide-2-0, 3-0, 4-0, H-tetraacetate.

909846/1201

CH,

SMe

- 31 -

Gl

AeMH

XVII

XXIV

A solution of 2 g of methyl 7 (S) -chlor-7-deoxyethioline cosaminide in 5 ml of acetic anhydride and 5 ml of pyridine was kept at 26 ° C. for 5 hours. After diluting with egg water, a crystalline product was obtained which was filtered off. The yield of crude product with a melting point of 174-198 G (with decomposition) was 2 _tons 17 g. Chromatography over silica gel, eluting using cyclohexane / ethyl acetate in a ratio of 1: 2, separated 1.08 g of methyl 7 (b) chloro-7-deoxy-a-thiolineosaminide tetraacetate, which after several recrystallizations from acetone - water melted at 249-252 ° C and a value fxjj) + 235 ° on gravel.

Part C-2

N-thioaoetyl-2,5,4-tri-0-acetyl-7 (S) -chlor-7-aesoxv-athioline cosaminide.

109846/1201

CH ₃

Cl

- 32 -

Il

XT)

CB

AcO

-Cl

OAc

XXV

SMe

OAc

XXVI '

A mixture of 4.63 g of methyl-7 (S) -chloro-7-desoxyoc thiolincosaminid-tetraacetate and 2.22 g of phosphorus - pentasulfide in 55 ml of dioxane was heated for 1 hour under reflux. The solvent was evaporated in vacuo and the residue dissolved in methylene chloride. After washing twice with dilute alkali and then washing with water and drying over sodium sulfate, the solvent was distilled off to give a crystalline residue of 4.7 g. This. The residue was recrystallized from ethyl acetate-Skellysolve B (technical ^ hexane) and the first crystal yield 1.73 g with a melting point of 2O8-216 ° C and as
second crystal yield 0.81 g with a melting point
obtained from 206 to 212 ⁰ C, bringing the overall yield
Was 2.54 g (53.2%). Part of it gradually became from ethyl acetate - Skellysolve B, acetone - water
and ethyl acetate - Skellysolve B uinkrystallized and
afforded an analytical sample with a melting point of 208-210 ⁰ C, using a small amount to 218 ⁰ C remained as Peststoff and a rotation of -259 ° (CHCl · *).

909846/1201

Analysis:

Calculated for

0 = 47.58; H = 6.10; N = 2.92; S = 15.37;

found:

G = 47.60; H = 6.06; N = 3.05; S = 13.05.

Part D-2

Methyl-7 (R) -mercapto-7-deoxy-a-thiolincosaminide-2-0, 3-0, 4-0, N-tetraacetate.

S "

Il

CH ₃ C-NH-

CH ₃

AcO /

τ Cl

CH,

HS

XXVI

AcHW

XXVII

SMe

OAc

A solution of 870 mg of thioamide from Part C-2 in 20 ml of dimethylformamide and 10 ml of water was refluxed for 1.5 hours. The solvent was distilled off in vacuo , and the residue was purified by chromatography over silica gel, eluting with cyelohexane-acetone (2: 1). The product fraction of 619 mg was recrystallized from ethyl acetate. The yield of methyl-7 (R) -mercapto-7-deoxy-a-thiolincosaminide-tetra-

909846/1201

ORiGlNAL INSPECTED

acetate with a melting point of 245-247 ° C and / ~ α + 212 ° (CHCl ₅ ) was 300 mg.

Analysis;

Calculated for C ₁₇ H ₂₇ IfOgSp!

0 = 46.66; H = 6.22; N = 3.20; S = 14.66; found: C = 46.44; H = 6.22; N = 3.1b ;. S = 14.38.

Part E-2
Methyl-7 (R) -mercapto-7-deoxy-oi-thiolincosaminide.

CH

HS
AcHN

AcQ

XXTII

CH *

HS

'HO

XXYIII

SMe

OAc

SMe

8 g of tetraacetate from part Ώ-2 were refluxed in 70 ml of hydrazine hydrate for 2 hours. The solution was evaporated to dryness under 1 mm pressure and 50 ml of 2-propanol were added to the residue with heating and stirring. Rapid crystal formation occurred. The solution was cooled and filtered. After drying, 51/2 g of a bluish-gray solid with a melting point of 152-165 ° C. were obtained; this solid

909846/1201

gradually darkened (it sintered) and decomposed, at 186 G. Thin-layer chromatography on silica gel using systems of chloroform-methanol in the ratio of 4: 1 or 2: 1 gave two main products and only a trace of material which was treated with 4eetylhydrazine ran. The smaller of the two main products in terms of quantity ran in thin-layer chromate graphy with the 7 (S) isomer (part BI), while the larger of the two products (the 7 (R) isomer) ran somewhat more slowly. The product as well as the mother liquors smelled strongly of H _? S. An attempt at chromatography resulted in decomposition and poor recovery “This is why this product was used in the next stage, in which the separation of a pure product turned out to be less complicated.

Part F-2
7 (R) -Mercapto-7-deoxylincomycin hydrochloride.

XXVIII

HS

PHiüra

XXIX

SMe

2.72 ml (20 mmol) of lesobutyl chloroformate were at -5 ° of a solution of 4.14 g (20 mmol) of trans -l-kethyl-4-npropvl-L-proline and 5.6 ml (40 mfaol) of triethylamine in 250 nil itoetonitrile added. After listening for 10 minutes

909846/1201

was treated with a solution of 5.2 g of methyl-7 (R) -mercapto-7-deoxy-a-thiolincosaminide from part E-2 in 130 ml of water. The resulting mixture would stirred for two hours. The acetonitrile is distilled off

and the aqueous solution is extracted with methylene chloride. The solvent was evaporated to leave a residue of 6.26 g. obtain. Thin-layer chromatography (CHCl, -MeOH 4: 1) showed mainly two substances effective against S. lutea. The smaller spot was not separated from the 7 (S) -isomer by thin layer chromatography. The larger spot had a slightly lower Rf value. Chromatography over silica gel, eluting using methanol-chloroform in a ratio of 1: 4, gave a fraction of 5 * 96 g of high quality 7 (R) -mercapto-7-deoxylincomycin hydrochloride. A middle section of this fraction was dried at 50 ° C. to carry out an elemental analysis. It gave the value foeJ ^ . + 125 ° (H ₂ O). _: ', _

Analysis:. ■ _ ■ -. · -.

Calculated for C _n OH ^ N ₀ Or-S ₀ :

C = 51.15; H = 8.11; N = 6.63; found: C = 51.18; H = 8.16; N = 6.96.

Antibacterial spectrum: T / ml ⁺ '

Staphylococcus aureus 3.2 - 6.4

Streptococcus hemolyticus 6.4

Streptococcus faecalis 6.4

Bacillus subtilis ■ 50 ■ - =

. ^ ram-negative " y 200

⁺ ^ Determined in brain-heart infusion broth after 20 hours after two-fold dilution at the end point.

909846/1201

Example 3:

TiRj-Mercapto ^ -deoxylincomycin hydrochloride. Part A-3
7 (S) -chloro-7-deoxylincomycin hydrochloride.

A solution of 50 g of lincomycin hydrochloride, 120 g of triphenylphosphine and 500 ml of acetonitrile in a 3 liter flask equipped with a stirrer was cooled in an ice bath and 500 ml of carbon tetrachloride were added all at once. The reaction mixture was then stirred for 18 hours without ice being added to the cooling bath. The mixture was evaporated to dryness in a water bath at a temperature of 50-60 ° under vacuum, after which a clear, pale yellow, viscous oil was obtained. The same volume of water was added and the mixture was shaken until the oil had completely dissolved. The resulting suspension of white pesticide (0 * PO) was filtered through a sintered glass mat, discarded, and the mixture was removed by adding 6% aqueous sodium hydroxide The pH was adjusted to 11. The resulting slurry was extracted four times with 300 ml of chloroform each time, the aqueous phase was discarded, the combined chloroform extracts were washed once with 100 ml of a saturated aqueous sodium chloride solution and the sodium chloride phase was discarded. Ehase was evaporated to dryness in a water bath at a temperature of 50-60 C under vacuum, the residue old. the same volume of methanol is added and the resulting solution is refluxed for one hour. The methanol solution was in a 50-60 C warm water bath under vacuum

909946/1201

Evaporated to dryness. The residue consisted of a clear, pale yellow, viscous oil, to which an equal volume of water and 10 ml of 37 # aqueous HCl were added and then shaken until the oil had dissolved and a white solid (further 0, PO ) remained in suspension. This suspension was filtered through a sintered glass mat at a pH of 1-2 and the solid discarded. The filtrate was extracted twice with 100 ml of carbon tetrachloride, the carbon tetrachloride phase was discarded, the aqueous phase was adjusted to pH 11 by adding 6 η aqueous sodium hydroxide and extracted four times with 300 ml of chloroform each time. The combined chloroform extracts were washed three times with 100 ml of saturated aqueous sodium chloride solution, the sodium chloride phase was discarded, the chloroform extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated to dryness in a 50-60 water bath under vacuum. The residue obtained was 45 g of clear, colorless, glass-like material of which about 95% consisted of 7 (S) -chloro-7-aesoxylincomycin. 100 ml of ethanol were added to the crude product with heating until a clear solution was obtained. 150 ml of ethyl acetate were then added, then filtered through a glass mat and the filtrate was adjusted to pH 1 by adding saturated ethanolic HCl. Crystallization soon occurred. The resulting material was ^{stored at 0} ° C. for 18 hours and then filtered through a sintered glass mat. The solid was dried for 18 hours at 60 C under vacuum to give 35 g (67 ■ t-LGSS yield) 7 (E) -chloro-7-de8Oxylincomycin hydrochloride in foxo einee Jtthanolaolvates. After umkrietallisation from aqueous acetone (7 ml Η ,, Ο to

9098 * 6/1201

300 ml of acetone) an analytical sample was obtained following analysis:

Analysis:

Calculated for C ₁ ^ H ₅₅ ClN ₂ O ₅ S.HCl.H ₃ O:

C = 45.18; H = 7.37; S = 6.70; H ₂ O = 3.77; found: C = 45.09; H = 7.74; S = 6.45; H ₂ O = 4.24. '

/ "α 7 ^H 2 ° + 145. ■

Part B-3
7 (S) -chloro-7-deoxylincomycin triacetate.

25 g of 7 (S) -chloro-7-deoxylinconiycin hydrochloride were dissolved in 125 ml of pyridine and 125 ml of acetic anhydride with heating. After 17 hours at ambient temperature, water was added with cooling until no further exothermic effect was detectable. The solution is concentrated under vacuum, the residue is dissolved in 250 ml of water, and 20% aqueous sodium hydroxide is added with cooling and stirring until the solution on the reagent paper reacted alkaline. The solid was filtered off, washed with water and dried at 50 ° C. under vacuum. As yield was obtained 28 g of 7 (S) -chloro-7-desoxylincomycin triacetate, the liquefied by heating in a molten bath at 116-120 ⁰ C.

Correspond to ie aIkvI-, cycloalkyl- and AralKvl-6-acylaminosov: ie -b-tliioacvl-aüiino-ö.e-diiesbxy-l-thiö-

909846/1201

BATH ORIGINAL

D erythro -AD -galacto -octopyranoside obtained by substitution of the lincomycin in Examples 1 and .by other alkyl, cycloalkyl or aralkyl-6,8-di deoxy-6- (trans -l-methyl-A-propyl -L ^ -pyrrolidincarboxainido) -l-thio-I> -erythro -oc-D- galacto- octopyranosides, in which alkyl radicals, e.g. ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, Nonyl, uecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadeoyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl radicals or their isomeric forms; Cycloalkyl radicals, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Gyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclobutyl, 2-methylcyclobutyl or 3-cyclopentylpropyl radicals and arylalkyl radicals, for example benzyl -, 3-phenylpropyl or 1-naphthylmethyl radicals. For example, one wins the ethyl, propyl, butyl, pentyl and hexyl-6-acylamino and -6-ifchioäcylamino-6,8-dideoxy-1-thio-D- erythro -qD -galaoto octopyranoside and the corresponding 6-acylamino- and o-thioacylamino-T-halogen-ojTje-trideoxy-l-thio-L- threo -qD- a'alacto- octopyranoside, if instead of des'lincomycins ethyl, propyl, butyl, pentyl or . Hexyl- "6,8-dideoxy-6-acylamino- and -6-thioacylamino-1-thio-D- erythro -qD -gälact ο -octopyranosi de can be used.

The acylamino and thioacylamino groups can L-7-pyrrolidinecarboxamido- substituted in the 4-position and L-2-pyrrolidine-thiocarboxamido groups of the general formula:

909846/1201

R-.

or

HR _n

mean, wherein R-,, R ₂ and R ^ have the meaning given above. Preferably, R ₁ and Rp can be methylene, ethylene, propylene, butylene, pentylene or hexylene radicals and R, a hydrogen atom or HRp radicals in each. Combination mean. When 7-epilincomycins were used above instead of the lincomycins, the same compounds with the opposite configuration in the 7-position were obtained.

Part C-3

7 (3) -0bloro-7-deoxy-thiamidolincomycin triacetate.

4 g of 7 (S) -chloro-7-deoxylincomycin triacetate

909846/1201

■ - 42 -

were mixed with 100 ml of benzene and 25 ml of the solvent were alidistilled. The mixture was clarified by filtration, removing a small amount of cloudy precipitate. The benzene was distilled off, the residue was dissolved in 100 ml of dioxane, 4 g of phosphorus pentasulfide were added and the mixture was refluxed for 1.5 hours. A further 4 g of phosphorus pentasulphide and, after a further four hours of refluxing, a further 4 g of phosphorus pentasulphide were added as a third addition. The mixture was finally refluxed for a further two hours and then the solvent was distilled off in vacuo. The residue was dissolved in methylene dichloride and washed twice with dilute sodium hydroxide solution. The organic phase was dried and the solvent was distilled off. The residue of 8.6 g was chromatographed over 500 g of silica gel, eluting with cyclohexane-acetone (2: 1). A fraction of 880 mg was obtained which contained 7 (S) -chloro-7-deoxythiamido lincomycin triacetate and other substances. This material was chromatographed over 100 g of silica gel, eluting with chloroform-methanol (40: 1). A fraction of 320 mg was obtained, the melting point of which after crystallization from methanol was 178-181 ° C. The yield was 120 mg of 7 (S) -Chlor-7-deoxy thiamidolincomycin triacetate.

For a sample prepared as described above and found at 179
get analytical data.

put samples that melted at 179-180C

909846/1201

- 43 - Analysis:

Calculated for C ₂₄ H ₅₉ ClN ₂ O ₇ S ₂ :.

0 = 50.82; H = 6.93; N = 4.94; · S = 11.31; found: G = 50.75; H = 7.08; N = 4.88; S = 11.55.

■ - ■ - .. » Part D-3

7 (R) -Mercapto-7-deoxylincomycin.

This was replaced in the procedure of part C-2 Methyl 7 (S) -chloro-7-deoxy-a-thiolincosaminide tetra acetate by 7 (S) -chloro-7-deoxythiamidolineomycin triacetate and received 7 (R) -toercapto-7-deoxylincomycin-2-0, 3-0, 4-0-triacetate, which after saponification with aqueous potassium hydroxide at pH 10.5 with that of part F-2 gave identical ^ (Rj-mercapto ^ -deoxylincomycin.

The trans-l-methyl-4-propvl-L-proline can through other prolines substituted in the 4-position der Formula A and B are substituted. Other oc-thiolincosaminides of the formula IX can also be used. .- ■■ --- .. ·. :

9098A6 / 1201

Claims (15)

Claims; 1. Compound of the general formula Ac ¹ NH AcO OAc SR
OAc in which R is an alkyl radical with not more than 20 carbon atoms, a cycloalkyl radical with 3 to at most 8 carbon atoms or an aralkyl radical with not more than 12 carbon atoms, Ac is a hydrogen atom or an acyl radical of a carboxylic acid with not more than 18 carbon atoms and Ac ^{1 is} a hydrogen atom , the Ac radical or an acyl radical of an L-2-pyrrolidine-carboxylic acid substituted in the 4-position. 2. A compound according to claim 1, characterized in that Ac and Ac * of the formula are hydrogen atoms and R is a lower alkyl radical. 3. A compound according to claim 1, characterized in that Ac and Ac ^{1 of} the formula are acetyl radicals and R is a lower alkyl radical. ■ 4. Connection according to claim. 1, characterized in that that R of the formula is a lower alkyl radical ', 909846/1201 JLc is a hydrogen atom and Ac 'is an ayl radical of the formula HR ₂ denote in which R, and R ₂ denote alkylidyne groups with not more than 20 carbon atoms, cycloalkylidyne groups with 3 ″ to max. 8 carbon atoms or aralkylidyne groups with not more than 12 carbon atoms and R denotes a hydrogen atom or a HRp group; 5. A compound according to claim 4, characterized in that Ac ^{1 of} the formula is a l-methyl-4-propyl-L-2-pyrrolidine-carboxacyl radical and R is a methyl or ethyl radical. 6. A compound according to claim 4, characterized in that it is in the 7 (S) configuration and Ac · of the formula a trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxacyl radical and R is a methyl radical. 7. A compound according to claim 4, characterized in that it is in the 7 (R) configuration and Ac ^{1 of} the formula is a trans -1-methyl-4-propyl-L-2- 909846/1201 pyrrolidincarboxacyl radical and R a methyl radical! 8. Compound of the general formula GH, HN HOy) α Koh A \ / S OH in which R has the meaning given in claim 1, 9. A compound according to claim 8, characterized in that R of the formula is a methyl or ethyl radical means. 10. Process for the preparation of a compound of the general formula Il R ₄ -C -NH characterized in that one connects the 909846/1201 general formula It R ₄ -C-NH- Ac Gl SR OAc in which R is the remainder of a mercaptan, Ac is the acyl group a carboxylic acid, R ₄ -C- the acyl group of a carboxylic acid and R ₄ -C- mean the S-isologue of R ₄ -C-, heated with water in dimethylformamide. 11. Process for the preparation of a compound of the general formula HS "ENT HO sR OH characterized in that one connects the general. Porm.el: -. ■ ■, _: . . . - _; . 9 0 9 8 A 6/1 2 Ö1 CH, OH S Il R ₄ -C-NH- AcO , OAc SR OAc in which R is the remainder of a mercaptan, Ac is the acyl group Il a carboxylic acid and R ^ -C- the acyl group of a carboxylic acid means which subjects to hydrazinolysis. 12. Process for the preparation of a compound of the general formula CH, HS «I. R-C-HH HO .CH SR OH Il in which R is the remainder of a mercaptan and R-C- is the acyl group of one substituted in the 4-position 909846/1201 Pyrrolidine-carboxylic acid, characterized in that that one is a compound of the general formula CH, BHr SH with a pyrrolidinecarboxylic acid substituted in the 4-position acylated. 13. Process for the preparation of a compound of the general formula QH, HN- HO SR OH in which R is the remainder of a mercaptan, thereby characterized in that one is a solution of a compound 909846/1201 the general formula CH, NH, HO Gl OH SR OH heated in the presence of an acid acceptor. 14. The method according to claim 13 »characterized in that that an anhydrous sodium carbonate is used as the acid acceptor. 15. Process for the preparation of compounds of the general formula QH, NH. HO SH , 0H SR OH in which R denotes the remainder of a mercaptan, characterized in that one is a solution of a compound 909846/1201 the general formula HN HO SR OH heated under hydrogen sulfide pressure. Pur The Up, lohn Company Lawyer 909846/1201