DE2017482A1 - Lincomycin derivatives and processes for their preparation - Google Patents

Description

DR. JUR. DIPL-CHEM. WALTER BEIT ALFRED HOEPPENER

RECHTSANWAITE AND NOTARIES

DR. JUR. DIPL-CHEM. RJ. WOLFP DR. JUR. HANS CHR. BEIL «iCHTSANWALTE

623 FRANKFURT AM MAIN-HÖCHST AKiONSRASSf »

2017 482 to April 1970

Our number 16

The Upjohn Company Kalamazoo, me. / UNITED STATES

Lineomycin derivatives and processes for their Manufacturing

The present invention relates to new 3-mono-alkyl carbonic acid esters and 2,3-bis-alkyl carbonic acid esters of 7-halogenated lineomycin compounds of the following

Formula:

R ₂

H . J. H

H*

L 'r H /

• NH

S ^H 3

SR

H OR,

in which R is an alkyl radical with 1 to 6 carbon atoms, R. is an alkyl radical with 1 to 8 carbon atoms, a cycloalkyl radical with 3 to 8 carbon atoms or an aralkyl radical with up to 12 carbon atoms, R _{2 is} hydrogen or an alkyl radical with 1 to 8 carbon atoms, X Chlorine, bromine or iodine, R, a radical ^c _n ^H 2n + 1 ~ ° ' ^wor ~ in η is an integer from 1 to 20, and R. means the same as Rj or hydrogen, their acid addition salts and new synthesis processes.

These alkyl carbonic acid esters of lincomycin compounds have antibiotic effects. For example, the 3-mono- (alkyl carbonate) esters can be used to inhibit the growth of Staphylococcus aureus, Streptococcus hemolyticus, and Streptococcus faecalis on medical and dental equipment contaminated with these bacteria. The 2 _r 3-bis (hexyl carbonate) ester of 7-deoxy-7 (S) -chlorlincömyoin is advantageous for oral administration as an antibiotic because it does not have the bitter taste of the non-esterified compound.

The new 3-mono- (alkyl carbonate) and 2,3-bis (alkyl carbonate) esters of the 7-halogenated lincomycin compounds have the following formula I;

001144 /

ORIGINAL INSPECTED

^l 1 H

NH-

HO

OR,

II

H ,

SR

H OR;

(D

in which R is an alkyl of 1 to 6 carbon atoms, R. is an alkyl of 1 Ms 8 carbon atoms or an aralkyl of up to 12 carbon atoms and is above the plane of the pyrrolidine ring to give the trans configuration with respect to the carbonyl group , or below the ring, to give the cis configuration au; R "stands for hydrogen or an alkj ^r l with 1 to 0 carbon atoms, X is chlorine, Bro.T. or iodine and is to the left of the vertical line of the drawing to give the 7 (R) configuration, or to the right of the line to give the 7 (S) configuration

■ to surrender to figuration; R, is ^C _n ^H 2 _{n +} i ~ ° ~ ^"is ~> where η is a number of 1 means gance to 20; and R is equal to R ^ is hydrogen or The invention also relates to the Sä." Ureadditicnssalze this compound.

Examples of alkyl radicals having 1 to 8 carbon atoms siiiä. "". ethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, ur.a Cctyl and their isomeric forms. Examples of Cyc-

loalkyl radicals are cyclopropyl, cyelobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclabutyl, 2,3-dimethylcyclobutyl, 4-methylcyclobutyl and 3-cyclopentylpropyl. Examples of aralkyl radicals are benzyl, phenethyl, o6-phenylpropyl and (/ -naphthylmethyl.

Examples of alkoxycarbonyl groups, ie ⁰ _η ^Η 2η + ΐ " ^Ο groups, where η is an integer from 1 to 20, are kethoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, Octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, dodecyloxycarbonyl, tetradecyloxycarbonyl, hexadecyloxycarbonyl, octadecyloxycarbonyl, eicosyloxycarbonyl groups and isomers of the alkyl portion thereof.

The new 3-mono- (alkyl carbonate) and 2,3-bis (alkyl carbonate) esters of 7-halogenated lincomycin compounds of formula I are either in non-protonated form (as free base) or in protonated form (as acid addition salt), depending on the pH of the environment. They form permanent protonates, i.e. acid addition salts, after neutralization of the free base with appropriate acids. Salts of the 7-halo-7-deoxylincomycin-3-mono- (alkyl carbonates) can by neutralizing the free base with the corresponding acid to a pH of below about 7 »0 and advantageously about 2 to 6 are made. Corresponding acids for this purpose include hydrochloric acid, sulfuric acid, phosphoric acid, thiocyanic acid, fluorosilicic acid, Acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, pamoic acid, cholic acid, palmitic acid, Mucic acid, camphoric acid, glutaric acid, glycolic acid, Gluconic acid, lactobionic acid, phthalic acid, -

SAO OfIIQlNAL

Tartaric acid, lauric acid, stearic acid, salicylic acid, 3-phenylsalicylic acid, 5-phenylsalicylic acid, 3-H «ethyl taric acid, orthosulfobenzoic acid, cycloheiane sulfamic acid, cyclopentanopropionic acid, 1,2-cyclohexanedicarboxylic acid, 1,2-cyclohexanedicarboxylic acid, octylbylbylsulfonic acid, cyclohexanoic acid, octylbeneic acid * s acid , azobenzenesulfonic acid, octadecylsulfuric acid, picric acid and similar acids.

The new 3-mono- (alky! Carbonic acid) - and 2,3-bis- (alkyl carbonic acid) esters of the 7-halogenated lincomycin compounds are prepared by mixing the corresponding 2,3-dihydroxy compound of the formula II

CH-

NH-

(II)

I OH

in which R ₁ H ₁ , R ₂ and X have the meaning given for formula I, in solution in an amine base of formula III

009844/1384

(ΠΙ)

in which the radicals Rc independently of one another are hydrogen, Methyl, ethyl, propyl, butyl, or an isomeric form thereof mean, with a corresponding halocarbonic acid alkyl ester made of formula IV,

(IV)

in which η has the meaning given above and Y is fluorine, chlorine, bromine or iodine.

The starting compounds of the formula II are prepared according to the US Pat. Nf. 3,380,992 and Belgian Patents Nos. 676 154, 676 202 and 705 364. If the desired 7-halogenated lincomycin-3-mono (alkyl carbonate) - or 2,3-bis (alkyl carbonate) compound of the formula I is a compound in which R _{2 is} hydrogen, a simultaneous undesired acylation on VN atom is prevented by first shielding this 1'-N atom with a protective group which can later be removed by hydrogenolysis. Groups suitable for this purpose are, for example, trityl, ie triphenylmethyl groups, diphenyl (pmethoxyphenyl) methyl, bis (p-methoxyphenyl) phenylmethyl, benzyl or p-nitrobenzyl and hydrocarbyloxycarbonyl groups. Examples of the latter are tertiary butoxycarbony groups; Benzyloxycarbonyl groups represented by the formula below

00Q8U / 1364

■ in the W. hydrogen, an allyl or alkyl radical nib not more than 4 carbon atoms, such as phenyloxycarbonyl, p-tolyloxycarbonyl, p-ethylphenyloxycarbonyl and p-allylphenyloxycarbonyl and the like «After the inventive esterification of the lincomycin compound with protected 1 ¹ -N -Atom, the protective group is replaced by hydrogen with hydrogenolysis (according to the process described in US Pat. No. 3ο380,992), and the desired 3-cono (alkyl carbonate) or 2,3-bis (alkyl carbonate) is obtained ) -ester of the 1'-N-hydrogen-substituted lineor.iyeinverbindungen of the formula I.

The amine bases of the formula III are known and can be prepared according to processes published in the literature. Typical amine bases that can be used in the process of the invention include 3-ethylpyridine, 4-isopropylpyridine, 5-butylpyridine, 3-ethyl-4-methylpyridine, 3 »4-diisopropylpyridine, 3- ^ etliyl-4-dipropyl- 5-propylpyridine, 3 "5-dimethyl-4-sec. · ^r butylp5 ridin and the like.

The alkyl carbonates of the formula IV are known and a big one. A variety of these carbonates have been made by known methods; many of them are commercially available. To the esters (IV), which "at the process according to the invention can be used include! »ethyl chlorocarbonate, ethyl bromocarbonate, propyl iodocarborate, Butyifluorocarbonate, pentyibromocarbonate, Hexyl iodocarbonate, heptyl fluorocarbonate, undecyl chlorocarbonate, Tridecyl bromocarbonate, tetradecyl iodocarbonate,

Q098U / 196

Pentadecyl fluorocarbonate, hexadecyl chlorocarbonate, Hep.ta-; decyl bromocarbonate, octodecyl iodocarbonate, nonadecyl fluorocarbonate and the like as well as their isomeric forms.

The new 7-halo-7-deoxylincQmycin-3-mono- (alkyl carbonate) - and 2,3-bis (p.lkylcarbonat) -e8ter of the formula I are prepared by simply adding the free base or the acid addition salt of a corresponding 3-Hydroxy compound (II), dissolved in an amine base (III.), Mixed with a corresponding alkyl halocarbonate (IV). If desired, inert solvents can be added. The reaction can be carried out at about -5o ⁰ C to +50 ⁰ C in a satisfactory manner without heating the reaction mixture is required. The nature of the end product, ie whether it is a 3-mono (alkyl carbonate) ester or 2,3-bis (alkyl carbonate) ester, is determined by the molar ratio of the carbonic acid ester of the formula IV to the 2.3 -Hydroxy-7-halo-lincomycin compound _; certainly. If this ratio is about 2 to about 1, the reaction product is completely or primarily the 3-mono (alkyl carbonate) ester, but if the ratio is about 5 to about 1, the reaction product is completely or primarily the 2 , 3-bis (alkyl carbonate) esters. The monoesterification of the 3-hydroxy group with the practical exclusion of the other hydroxyl groups of the 7-halogenated lincomycin compound under the conditions given above was unexpected because (1) a considerable excess of the above halocarbonate over the amount required for the monoesterification is used and a reaction is formed several polyesters was to be expected, and (2) the 3-hydroxy group is only one of several secondary hydroxyl groups, such as ζ "Β" of the 2-, 3- and 4-

Θ09844/1964

Hydroxyl group is so a choice in. Direction a 3-monoesterification could not be foreseen. A diveresterification of the 2- and 3-hydroxy groups below practical exclusion of the other hydroxyl groups under the conditions given above was also possible not to be expected, since (1) a considerable excess of the above halocarbonic acid ester over the amount required for diveresterification used and a further reaction with the formation of a tri- (alleyl carbonate) ester was to be expected; (2) the Esterification is selectively limited to the 2- and 3-position, whereas it was to be expected that the 4-hydroxyl group, which is also a secondary hydroxyl group is, would also be esterified, so that apart from the bis (alkyl carbonate) esters, one should pay off Yields of 2,4- and 3 »4-bis (alkyl carbonate) esters should be expected. Instead, the process of the present invention essentially produces only the 2,3-bis (alkyl carbonate) ester obtain.

The time required for the 3-monoesterification or 2,3-divergent disruption to complete depends on factors such as the reaction temperature, the particular reactants used, the relative amount of reactants, thorough mixing, and the like. It lies therefore it will be understood that the optimal reaction time will vary for any combination of reaction conditions. Usually, reaction times in the range of about half an hour to about 48 hours are suitable. If desired, for example to save time, the course of the reaction can be controlled by taking samples and the reaction mixture by methods known in the art

009844/1964

investigated, for example by using thin layer chromatography during implementation.

After the reaction between the compounds of the formulas II and IV has ended, the desired product is obtained with the formula I either as a free base or as an acid addition salt o The product is isolated according to conventional methods Processes such as filtration, solvent evaporation, Solvent extraction, chromatography, or crystallization, or a combination of these Procedure. The product obtained in this way can, for example, by crystallization from a Solvent or a suitable mixture of solvents. The product lies as free Base before, it can be done by neutralization with an acid, e.g. one of the acids indicated above can be converted to an acid addition salt. The acid addition salt, in turn, can, for example, be treated with a strongly basic anion exchange resin converted to the free base.

In order to understand the above used to describe the new compounds of formula I molecular To facilitate structure and nomenclature, the structural formula and chemical name are used for comparison of the last precursor, namely lincomycin, explained. Lincomycin, also known as methyl ~ 6,8-dideoxy-6- (trans-1 ~ methyl-4-propyl-L ~ 2-pyrrolidinecarboxamido-1-thio-D-erythro-oC-D-galaeto-octopyranoside is obtained as a product of a lincomycin-producing actinomycete according to US Pat. No. 3,086,912. It has the following structural formula:

009344/1904

8AD

CH ₃ CH ₂ CH

2 CH-

CH-

-' H

HO

NH-

HQ

OH l

NS

■ - ·. . ■■■ '■ - ■ - ■: ■■ -H OH

Example 1 ■ ■, -.

7 (3) -Chlor ^ -deoxylincomycin ^ - (pentyl carbonate) -hydro-

chloride

A solution of 9.63 g (0.02 mol) of 7 (S) -chloro-7-deoxylincoraycin hydrochloride / "also known as methyl-7-chloro-ό, 7,8-trideoxy-6- (trans-1 -raethyl-4-propyl-IΓ-2-pyrΓolidincarboxämido) -1-thio-L-threo-ÖC-D-galacto-octopyranosidiiydrochlorid is designated 7 (manufactured according to the Belgian patent 676.154 and the publication "Antimicrobial Agents and Chemotherapy - 1966" , American Society for Microbiology, 1967, p 731) in 100 ml of pyridine is cooled to about -30 ⁰ C and 6.02 g (0.04 mol) of n-Amylchlorcarbonat are added dropwise. This solution is brought to room temperature, such as a Stirred for hour, then cooled to about -30 ° C, with 2 g

009844/1964

n-Amyl chlorocarbonate is added, and the mixture is stirred for about 2 hours. The pyridine solution is poured into about 1 liter of ice water and acidified to pH 2 with concentrated hydrochloric acid. The aqueous suspension obtained is extracted twice with 250 cem chloroform each time, the chloroform extracts are combined and dried over anhydrous magnesium sulfate. The chloroform is removed ^{at 38 ° C. under reduced pressure.} The white precipitate obtained is shaken with 750 ml of anhydrous ether, filtered, dried in ^{air for about one hour and then dried under vacuum at 45 ° C. for about 16 hours.} 6.75 g of the 7 (S) -chloro-7-deoxylincomycin-3- (pentyl carbonate) hydrochloride obtained as a crude product are added to between 700 ml of ether and 460 ml of an aqueous buffer solution with a pH of 2.2 in a 2 liter Separating funnel with a capacity · After vigorous shaking of the funnel, the ether layer is removed and discarded. The aqueous layer is extracted again with 800 ml of ether and the ether extract is removed and discarded. Then the aqueous layer is extracted with 780 ml of chloroform (in two fortions) and the chloroform extracts are combined, dried with anhydrous sodium sulfate and under vacuum at about 500C Evaporated to dryness. The residual pale yellow oil is taken up in 80 ml -chloroform which was then saturated with anhydrous hydrogen chloride (and re-evaporated in vacuo at about 50 ⁰ C to dryness. In this case, one 2.65 g of 7 is deoxylincomycin -chloro-7 (S) -3- (pentyl carbonate) hydrochloride as a white solid.

analysis

calcd for C ₂₄ H ₄₄ N ₂ O ₇ SCl ₂ IC = 5O, O8 / H = 7.71 / N = 4.87 / C1 = 12.32 found for 1.8J * H ₃ O correctedί C = 48.24 / H »7.6O / N = 4.61 /

01 = 13.17

009844/1964

ORlQtNAL INSPECTED

-hydro-

chloride has antibacterial activity against Staphylococcus aureua equivalent to 180 micrograms of lincomycin per mg. The relative molar CDeq is O ₉ JT times that of lincomycin when administered subcutaneously to mice infected with this organism.

7 (3) -Chlor-7-deo3cylinoomyoin-3- (pentyloarbonate} hydrochloride is converted to the free base by treatment with a strongly basic ion exchange resin Exchange Resins ¹¹ , 2nd edition (1958) t John Wiley and Sons, Ine, pages 88 and 97 »described process by chloromethylation of polystyrene, which is optionally vernetat with bivinylbenzene, and quaternization according to the on page 84 of the above publication by Bunin described Process with trimethylamine or according to the process with dimethylethanolamine described on page 97 of the above publication by Kunin obtained traded 7

7 (3) -Chlor-7-deoxylincomycin-3H- (pentyl carbonate) will thereby converted into other salts of the acids listed above

Following the procedure of Example 1, except that 7 (S) -Chlor-7 ~ deoxylincomyoin instead of the hydrochloride used, 7 (3) -chloro-7-deoacylinoomyoin-3- (pentyl carbonate) is obtained

009 »** / 198 *

Following the procedure of Example 1, except that 7 (H) -Chlor-7-beoxylincomyoin or its acid addition salts are used as the starting material, 7 (R) -chloro-7-deoxylincomycin-3- (pentyl carbonate) or its is obtained Acid addition salts.

Example 2 Further 3-monoalkylocarbonates

. The procedure of Example 1 is followed, particularly with regard to the ratio of halocarbonic acid ester to that used as starting material 7-halogenated lincomyoin compound or 1 * -protected-7-halo-lincomycin compound, however, instead of n-amyl chlorocarbonate, another alkyl halocarbonate is used, such as, for example

(1) methyl bromocarbonate

(2) ethyl fluorocarbonate (3). Ptopyl iodocaybonate

(4) butyl chlorocarbonate

(5) hexyl bromocarbonate (6) octyl fluorocarbonate

(7) decyl iodocarbonate

(8) Bodecyl chlorocarbonate

(9) tetradeoyl bromocarbonate

(10) hexadecyl fluorocarbonate

(11) hexadeoyl iodocarbonate

(12) Ootadeoylochlorocarbonate

(13) nonadecyl bromocarbonate

(14) eicosyl chlorocarbonate

The following connections are obtained in each case!

009844/1984

(1) 7 (S) -Chlor-7-deoxylincomyc ± n -3- (methyl carbonate) hydrochloride

(2) 7 (S) -chloro-7-deoxylineoinycin-3- (ethyl carbonate) hydrochloride

(3) 7 (S) -chloro-7-deoxylinconiycin-3- (propylcarbonate) hydrochloride

(4) 7 (S) -chloro-7-deoxylinconiycin-3- (butyl carbonate) hydrochloride

(5) 7 (8) -0Κ1θΓ-7-αβοχγϋηοοπνοίη-3- (ΐιβχγΐχοΒ ^ οηΒΐ) hydrochloride

(6) t (S) -Chlol> 7-dβoxyίincoπgrcin-3- (ootylcarbonat) -hydrochlorld

(7) 7 {S) -chloro-7-deoxylincomycin-3- (decylcarbonate) hydrochloride

(8) 7 (S) -Chlor-7-deoxylincomycin-3- (dodecyl carbonate) hydrochloride

(9) 7 (S) -Chlor-7-deoxylincomycin-3- (tetradecyl carbonate) hydrochloride

(10) 7 (S) -chloro-7-deoxylincomycin-3- (hexadecyloarbonate) hydrochloride

(11) 7 (S) -Chlor-7-deoxylincoaaycin-3- (hexadecyl carbonate) hydrochloride

(12) 7 (S) -chloro-7-deoxylinconiycin-3- (octadecyl carbonate) hydrochloride

(13) 7 (S) -Chlor-7-deoxylinoonycine-3- (monodecylcarbonate) hydrochloride

■ {'14) 7 (S) -Ohlor-7-deoxylincomycin-3- (eicopylcarbonat) hydrochloride

etc."

009844/1964

If the method der'fünf above "paragraphs .and" of Example 1 and, as appropriate the Pätentsehrift in US 3,380, -392 Hydrogen described © - Iyseeerfahren for removing the carbobenzoxy Sehutziimd'verwendet -Man instead of ten in Example 1 ' 7 (S) -GhlOr ~ 7 ™ & eo ^ lineomycin hydrochloride and "n-Aniylöhlorcarbonats""other lineomycin derivatives and alkyl halogen carbonates, such as: · '

(1) . 7 (S) -Bromo-7-deoxylincorj, ycin / ~ methyl-7-bromo - 6.7 »8 ~ ■ trideoxy-6-- (trans- i ~ jtietii.yl ~ 4-n-prop "yl- L- 2-pyrrolidinecarboxamido) -i-thip-I-thx'eoc> C-i> -galacto-octopyranoside ' / and pentyl fluorocarbonate.,

f 2} 1'-Desmethyl-1 ^f -carbobenaoxy-4'-n-pentyl-7 (S) -chlor-7-d © bxyiincornycin / "rneth _t yi, - 7-chloro - &, 7,8 -trideoxy-

carboxaruido) ~ i-tliio- "if-'t.ivr & o -]> - galacto ~ oc topyranosi &J'unu. Äexyl chlorocarbonate with'hydrogenolysis,

_(i)?. 1 ^f -Desmethyl-I ^l _i -iaobnt vX-7 (R) -ch.lor-7-deoxylinconiyo jn / "me thy ~ i 7-chldr-S 8- trideöxy-6- ( trans-1 -isobutyl- ~ 4-n-propyl-ir-2-pjrroliaincarboxamido ') - 1-'thio-B-erythro-CC-ij-galacto ^ nOtopyrarioaid 7'υχιά hexyl bromocarbonate,

('4) 4 ^? - "Despropyl ~ 4 '^ hept, y 1 ^; -1 " «desmethy 1-1.' -cyclohexyl ^: ■ 7 (E- ") -" Chlo.r-.7 - * - deo ^ all ':> lir _f c pmycin / ^ methyl-7-ehlor-6-ϊ "7> β-- trid'eöxy-6- (ci e «-x ;; i Ciiohexyl-4-heptyl-L-2-pyrrolidincarbQxamido} -1 - ;; iric ™ D ~ 'erythro · -. O0 ~ galacto-octopyranoside 7 ' ¹ ^ ¹ O. Octyl fluorocarbonate,

(4} 4 ^! -I) espropyl-4 '-n-peiitj-1-1'-desmethyl-1' -carbobenzo.3cy ~ 7 (S) ~ chloro-7 ~ &'e.öKylittdoiny c in hydrochloride / ~ me thy 1-7 - ChIOr-0,7 j 8-triöeow ^ -ei trans-1-carbobenzoxy-4-npentyl ~ Ir-2 ~ pyrroliaineo, rboxaraido) ™ 1-thio-L-threo-o6 ~

0098A4 / 1S84

“AD ORIGINAL

galacto-octopyranoside hydrochloride 7 and hexadeoyl chlorocarbonate with hydrogenolysis,

(6) 1 · -De ame thy 1-1 · -oarbol2enzoxy-7 (S) -ohlor-7-deoxylincomyoinhydrociilorid / ^ me thy 1-7-ChIoI ^ -0.7 »8-trideoxy-6- (transi-earbobenzoxy-4-n-propy 1-Ir-2-pyrrolidincartooxamido) -1-thio-Ir-threo-! οζ-D-galac to-octopyranoside hydrochloride 7 and hexyl chlorocarbonate with hydrogenolysis,

(7) 1'-Desmethyl-1'-carbobenzoxy-7 (S) -chlor-7-deoxylincomycin / ^ ratthyl-7-cKbr-6,7 »8-trideoxy-6- (trans-1-carbobenzoxy-4- n-propyl-II-2-pyrrolidinoarboxamido ) -i-thio-L-threb-c ^ -D-galacto-octopyrenoside 7 and hexadecyl fluorocarbonate with hydrogenoly * - «·,

(8) S-desmethyl-3-ethy 1-7 (3) -chloi> -7-d * oxylinoomycin citrate / "ethyl-7-chloro-6,7,8-trid * oxy-6- (traue-1- methyl- ^ n-propyl-Ir-S-pyrrolidincarboxamido) -1-thio-L-threo-oc-galacto-octopyranoiidcitrat J and heptadecyljοdcarbonat,

(9) 1 '-Desmethy 1-1 • -äthyl- _l 7 (S) -chlor-7-deoxy lincomycin / "methyl-7-chloro-6,7» 8 * -trideoxy-6- (trans- 1- ethyl-4-n-propyl-Ir-2-pyrrolidincarboxamido) -1-thio-Ii-threo-

i ■ ^y

oC-D-galacto-octopyranosidJ ^ and hexyl chlorocarbonate,

(10) 1'-desmethyl-1 ^f -äthy1-7 (S) -chl9r-7-deoxylincomycin /"methyl-7-chlor-6.,7»e-trideoxy-o-(trans-1-äthyl-4 -n-propyl-Ir-2-pyrrolidincarboxamido) -it ^ iio-Ir-threoö6-galacto ~ octopyrano8id 7 and hexadecylohlordarbonat,

{11) 4 ⁱ ~ Despropyl ~ 4 ^l -n-pentyl- ~ 1 '-desmethyl-1' -carbobenz-

6 9 7 »8-trideoxy-6 ~ {trans-1-oar'bobenzoxy-4 ~ n-pentyl-L-2-pyrrolidxnoarboxyamido) -1-thio-L-threo-C £ ~ D-galacto-oetopyranoside-7 and hexyl fluorocarbonate with

0098U / 1864

Hydrogenolysis,

(12) 4 · -D «epropyl-4 ^f -n-pintyl-1 · -carbobtnzoxy-7 (S) -chlor- 7-deoxylincomycin / ~ jnet! Iyl-7-ohior-6,7,8-trideoxy- 6- (transi-oarbobenzoxy - ^ - n-pentyl-I ^ -pyrrolidine-

carboxyamido) -1 ~ thio-Ir-threo- ct-D-galacto-octopyranoaid ^ and Htxadecyl fluorocarbonate with hydrogenolysis,

(13) i'-DeBmethyl ^ '- despropyl- ¹ _t 4 ^f -diisobutyl-7 (S) -chloro-7-deoxylincomycin / ~ methyl-7-chloro-6,7 »8-trideoxy ~ 6- (trana -1,4-diisobutyl-Ii-2-pyrrolidinecarboxamidoJ-i-thio-L-threo-oC-D-galacto-octopyranoside 7 and laiiryl fluorocarbonate,

(14) 1 ' -Deem * thy 1-1' -linoomycinphoAplMlt ^ methyl-t-chloro ^ e, 7 , 8-tride oxy-6 "- (trana-1-oarbob · llzoxy-4-n-pΓόpyl-IΓ -2-pyrrolidincarboxamido) -1-thio * - & - threo-O6-cl> -galac to-oc topyranosidphoBphat 7 and n-imyl chlorocarbonate with hydrogenolysis,

(15) 1 '-'desmethyl-1' -carbobenzoxy-? (R) -bromo-7-deoxylin-

comycin / ^r * methyl-7-bromo-6 ₁ 7 , 8-trideoxy-6- (eis-1 caJC boben2oxy-4-propyl-Ir-2-pyrrolidine-carboxamido) 1-thio-D-erythro-ot-B- galacto-octopyranosid ^ un & Palmitylchlorcajrbonat with hydrogenolysis,

(16) S-Deamethy1-S-propy1-1'-desmnethy1-6,7,8-trid6oxy ™ 6-chloro-7-deoxylineomycin / ~ propyl-7 ~ chloro-6,7,8-trideoxy ~ -6- (trans-1-carbobenzoxy ~ 4-propyl-Ir-2-pyrrolidinoarboxamidoJ-i-thio-Ir-threo-OC-B-galactooctopyranoside "J and hexadecyl bromocarbonate with hydrogenolysis,

009844 / 19.84 '

SAD OFIiGiNAL

i A

(17) 1'-desmethyl- 1 '-ä thy 1-4' -dispropyl-4'i-rn-pentyl-, 7 (3) -chlor-7-deoxylin.comycIn / ~ niethyl-7-clilor-

pyrrolidiricarboxamido) -1 — Hzfcfio-Ir-three- οί rD- ^ galac to oc "t" opyräxib "s ± a ^ 7 ttiicl Teträdeeylfluorearboriat, ..

then " ή & χι gets the haclifeteheri'de" * 'connections "-. · (ι) • 7 ( ^! S) - l3rom-V-deÖxylihcoinyc' ± n-3 ^; - ^; (pe-n: iiylDarboaat -). r ''

( 2) 1 • -desmetlTy-1- ^ '-despro'py ^; l-4 · '-ii-pentyl-? CS) ~ Gh3iOr Xylineoraycin> -3i-Chex-yl carbonate) _r · ■■■ ",,; - ..

(3) 1'-Desniethyl-1'-isobutyl-7 (β) -chloro-7-deoxylin

(4) 4 * • ^ • Sespropyl-4 ^l i-h'e.ptyl-1 ', - dasjnetliyl-1 V

: i) 1. DesmetlTyl-4'-despropyl-4'-n-pentyl ~ 7 (S) -ch.lor

7-deoxylincomycin-3- (hexadecyl carbonate) -hyaro- '. ■ "chlbri ^f d _t ^; " ■. · - ·''"..·", ■■ .- ■ -., - · ■ -.- .--- ■ · ■ ",, ^ ··. ::; ■

carüdnat) ~ «iiydro: clilorid, · -. . . , -

(T j 1 'Descetliyl-7 (S) -chlor-7-deoxylincoiny6iii-3-Cli.exa eecyl carbonate) _t ^; . . . _; . . , .'_ ..

(a). -S-2) esmetiiyl-S-ethyl-7 (S) -chlor-7-deoxylincoKycin 3- (Iieptadecyl carbonate) citrate,

(9) 1'-Desuethyl-1. -Ethyl-7 (S) -chloro-7-deoxyincomy ™ cln-3- (liexyl carbonate),

009844/1964

(10) 1 "-desmethy1-1" -äthyl ^ Sj-Ghlor - ^ - deoxylincomycin-3- (hexadecyl carbonate),

(11) 4 ^t -despropyl-4'-n-pentyl-7 (S) -chlor-7-deoxylin ~ coraycin-3- (hexyl carbonate),

(12) 4 ^ espropyl-4 · -n-pentyl ^ 7 (S) -chlor-7-deoxylineomycin-3- (hexadecylcarbohat),

(13) 1 • -desmethyl-4 ^l- desjropyl-1 ' _f 4'-diisobutyl-7 (S) -chloro-7-deoxylincomycin-3- (lauryl carbonate),

(14) 1 ^l -desraethyl-7 (S) -chlor-7-deoxy lincomycin-3- (pentyl carbonate) phosphate,

(15) 1 * -I3esmethyl-7 (R) -broin-7- ^r deoxylincOiDycin-3- (palinityl carbonate),

(16) S-DeBmethyl-S-propyl-1 • -desmethyl-7 (S) -chlor-7-deoxylincomycin-3- (hexadecyl carbonate),

(17) 1'-Desmethyl-1'-ethyl-4'-dispropyl-4'-n -pentyl-7 (S) -chlor-7-deoxylincomycin-3- (tetradecyl carbonate).

If the method of the immediately preceding paragraph is used, and instead of the syridine used in Example 1, another amine base, such as 3-methylpyridine, 4-propylparidine, 5-butylpyridine, 3-methyl-4-ethylpyridine, 3,4 -Dibutylpyridine, 3-ethyl-4-isopropylpyridine, 3-propyl-4-isobutylpyridine, 3-AtOyI-S-PrOPyIPy ^ dIn ,, 3,5-Dimethy 1-pyridine, 3-isopropyl-5-sec * -bu- #Lpyridine, 3 »4,5-Trlmettiylpyridin, 3 _f 4-dibutyl-5-propylpyridin, 3-ethyl-

009844/1904

4-propyl-5-t) utylpyridine, 3> 5-diethyl-4-methylpyridine, etc. , the above-mentioned compounds are also obtained.

Example 3

7 (S) -Chlor-7-deoxylincomyein-2,3-bis (hexyl carbonate) -

hydrochloride

7 (S) -Ohlor-7-deoxyiinoomyoinhydroohloridmonohydrat (9.63 g, 0.02 mol) is dissolved in 150 ml of AR-Eyridin and cooled to ⁰ C -3q. n-Hexyl carbonate (Eastman White Label) is added dropwise with thorough stirring. The reaction mixture is slowly warmed to room temperature and stirred for one hour. The solution is cooled again, a further 10 g of n-hexylochlorocarbonate are added, and the solution is warmed to room temperature. The mixture is poured into 1500 ml of biswater which has been brought to a pH of 2 with concentrated hydrochloric acid, carefully stirred and extracted twice with 750 ml of ether each time. The ethereal solution is dried with anhydrous magnesium sulfate and concentrated on a steam bath. The resulting precipitate (syrup) is carefully dried in vacuo and shaken vigorously with 500 ml of anhydrous ether. The dark yellow precipitate obtained is * resuspended in 500 ml of ether and filtered. 7 (S) -chloro-7-deo3 "ylincomycin-2,3-bis (hexyloarbonate) hydrochloride is obtained in the form of white crystals, which ^{are dried at 50 0} O in a vacuum drying cabinet for three days.

Yield: 8g (55.7 #).

0098A A / 196 4

calculated for

C a 53.55; H - 8> 14; N-- 3.90? Cl = 9.88; Equivalent weight «717 * 80;

Found (corrected for H ₂ O):

C »53.47; H «8.28; N -4.14; S, Cl = 9.89; Equivalent weight ■ - 714.

Example 4

Other 2,3-bis (alkyl carbonates)

The procedure of Example 3 is followed by considering the molar ratio of halocarbonate to the 7-halo-lineomyoin compound or 1 »-protected-7-halo-lincomyoin compound with the exception that the 7-halo-lincomycin starting compounds given in Example 2 are used and alkyl halocarbonates and the corresponding 2,3-bis (alkyl carbonate) esters of the 7-halogenated lincomycin compounds receives. By treating

(1) 7 (S) -Bromo-7-deoxylincomycin with propyl fluorocarbonate

(2) 1 »-desmethyl-1 · -carbobenzoxy-4'-despropyl-4 * -n- pentyl-7 (S) -chlor-7-deoxylincomycin with decyl iodocarbonate;

(3) S-desmethyl-S-ethyl-.7 (S) -chlor-7-deoxylincomycin citrate with hexadeoyl chlorocarbonate;

009844/1964

(4) 4'-BeBpropyl-4 * - "tfwpentyl-1 · -carbobenzoxy ^ CS) -chlor-7-deoxylincoinycin hydrochloride with hexadecyl fluorocarbonate or the like

accordingly, the following ver-rs are obtained bindxingeni

(1) 7 (S) - bromo-7-deoxylincömycin-2,3-bio- (propyl carbonate),

(2) 1 '^ Besmethyl-l · -earbobenzoxy-4' -despf opyl-4 ¹ * -n-pentyl-7 (S) -chlor-7-deoxylincomycin-2,3-bi- (dexyl carbonate),

{3) S-desmetliyl-S-ethy 1-7 (S) -chlor-7-deoxylincomycin * 2 , 3-bifl- {hexadecyl carbonate) citrate,

(4) 4 '.- Despropyl-4 ^l -n-pentyl ~ 1 «-carbobenzoxy- ^ iSj-chloro-7-deoxylincomycin-2,3-bi- (hexadecyl carbonate) hydrochloride and the like *

009844/1964

Claims (29)

Claims 1. Compound of formula CH ■ NH HO a ι / H OH in which R is an alkyl group with 1 to 6 carbon atoms, R _{1 is} an alkyl group with 1 to 8 carbon atoms, a cycloalkyl group with 3 to 8 carbon atoms or an aralkyl group with up to 12 carbon atoms, R _{2 is} hydrogen or an alkyl group with 1 to 8 carbon atoms, X Chlorine, bromine 04er iodine and R * an means in which, η is an integer from 1 to 20, as well as their acid addition salts. 2. A compound according to claim 1, characterized in that R is methyl, R _{1 is} trans-n-propyl, R _{2 is} methyl, X is 7 (S) ~ chlorine and R ^ has the meaning given in claim 1 , as well as their acid 09844/1964 ■ - 25 - addition salts. 3 »Compound according to claim 1, characterized in that H denotes methyl, R .. denotes trans-n-propyl, R ₂ denotes methyl, X denotes 7 (S) chlorine and Rj denotes pentyloxyearbonyl, as well as their acid addition salts. 4. Hydrochloride of the compound according to claim 3. Compound according to claim 1, characterized in that R is methyl, R. is trans-n-propyl, R _{2 is} Me-methyl, X is 7 (S) -chlorine and R ^ is hexadecyloxyoarbonyl, and acid addition salts thereof , 6. A compound according to claim 1, characterized in that R is methyl, R ^ is trans-n-propyl, R _{2 is} hydrogen, X is a 7 (S) -GhIQr- and R ^ is as defined in claim 1 has, as well as their acid addition salts. 7. A compound according to claim 1, characterized in that R is methyl, R _{1 is} trans-n-propyl, R _{2 is} hydrogen, X is 7 (S) -chlorine and R 1 is hexyloxycarbonyl, and acid addition salts thereof. 8. A compound according to claim 1, characterized in that R is methyl, R .. is trana-n-propyl, R _{2 is} hydrogen, X is a 7 (S) -Ohlor and R- is, hexadeoyloxyoarbonyl, as well as their Acid addition salt. 0098AA / 1964 9. A compound according to claim 1, characterized in that R is methyl, R .. is trans-n-pentyl, R _{2 is} hydrogen, X is a 7 (S) -ChIoI * and R ^ is given in claim 1 Has meaning, as well as their acid addition salts. 10. A compound according to claim 1, characterized in that R is methyl, R _{1 is} trans-n-pentyl, R _{2 is} hydrogen, X is 7 (S) -chlorine and R ^ is hexyloxyoarbonyl, and acid addition salts thereof. 11. Hydrochloride of the compound according to claim 10, 12. A compound according to claim 1, characterized in that R is methyl, H ^ is israns-n-propyl, R _{2 is} ethyl, X is 7 (S) -chlorine and R, is hexadecyloxycarbonyl, and acid addition salts thereof. 13. Compound of Formula -'NH- H OR, UQS844 / 1964 in which R is an alkyl radical with 1 to 6 carbon atoms, R / an alkyl radical with 1 to 0 carbon atoms, a cycloalkyl radical with 3 to 8 carbon atoms or an aralkyl radical with up to 12 carbon atoms, Rg is hydrogen or an alkyl radical with 1 to 8 carbon atoms, X chlorine, Bromine or iodine and R-, and R * a C _n H _{2n +} ^ -OC-, group in which η is an integer from 1 to 20, and their acid addition salts. 14. Compound according to claim 13 »characterized in that R is methyl, R., is trans-n-propyl, R _{2 is} methyl, X is a 7 (S) -chlorine and R, and H, which in claim 14 have given meaning, as well as their acid addition salts, ■ 15. A compound according to claim 13 »characterized in that R is methyl, R _{1 is} trans-n-propyl, H _{2 is} methyl, X is a 7 (S) chlorine and R, and R ^ are a hexyloxycarbonyl , as well as their acid addition salts. T6. Hydrochloride of the compound of claim 15. 17. A compound according to claim 13 »characterized in that R is methyl, R. is trans-n-Pfopyl, ₉ R _{2 is} methyl» X is a 7 (S) chlorine and R ^ uc ^ R _{4 is} hexadecyloxycarbonyl mean, as well as their acid addition salts. 18 * Compound according to claim 13 »characterized in that R is methyl, R _{1 is} trans-n-propyl, R _{2 is} hydrogen, X is 7 (S) -chlorine and R ^ and R _{4 are} those in claim 13 have given meaning, as well as their acid addition salts. 009844 / 19S4 19. A compound according to claim 13t, characterized in that R is methyl, R. is trans-n-propyl, R _{2 is} hydrogen, X is 7 (S) -chlorine and R ^ and R _{4 are} hexyloxycarbonyl, and their acid addition salts . 20. Hydrochloride of the compound according to claim 19. 21. Compound according to claim 13 »characterized in that R is methyl, R. is trans-n-propyl, R _{2 is} hydrogen, X is a 7 (S) -chlorine and R ₃ R. denotes hexadecyloxycarbonyl, as well as their acid addition salts. 22. A compound according to claim 13, characterized in that R denotes methyl, R ₁ denotes trans-n-pentyl, R ₂ denotes hydrogen, X denotes 7 (S) -chlorine and R ₃ and R which are defined in claim 13 have given meaning, as well as their acid addition salts. 23. A compound according to claim 13 »characterized in that R is methyl, R _{1 is} trans-n-pentyl, R ₃ . Is hydrogen, X is a 7 (S) -chlorine and R ^ and R. are hexyloxycarbonyl, as well as their acid addition salts. · 24. The hydrochloride of the compound of claim 23. 25. A compound according to claim 13 »characterized in that R is methyl, R .. is trans-n-pentyl, R _{2 is} hydrogen, X is a 7 (S) chlorine and R ₃ and R. are hexadecyloxycarbonyl, as well as their acid addition salts. 009844/1964 26; Process for the preparation of a compound according to claim 1, wherein R _{2 is} not hydrogen, characterized in that a corresponding 2,3-dihydroxy starting compound with a halocarbonic acid alkyl ester, / wherein the alkyl radical is the same as in the compound to be prepared, in one Ratio of ester to dihydroxy compound of 2: 1, in the presence of pyridine, 3- »4- or 5-alkylpyridine, 3,4- or 3,5-dialkylpyridine or 3,4,5-trialkylpyridine. 27. The method according to claim 26, characterized in that one 7 (S) - chloro ^ -deoxylinoomjdn ^ -pentylcarbonat hydrochloride from 7 (S) -Cnlor-7-deoxylincomycin hydrochloride and n-amyl chlorocarbonate in pyridine. 28. Process for the preparation of a compound according to claim 1, in which H _{2 is} hydrogen, characterized in that a 1 »-protected form of the corresponding 2,3-dihydroxy compound, in which the protective group can be removed by hydrogenolysis, with an alkyl halocarbonate , Wherein - i the alkyl radical is the same as in the compound to be prepared, in a ratio of ester to the 1'-protected 2,3-Bihydroxyverbindun-'g of 5 ι 1 in the presence of pyridine, 3- * ■ 4- or 5-alkylpyridine, 3,4- or 3 »5-dialkylpyridine or 3,4» 5-trialkylpyridine, mixes and the protective group is removed by hydrogenolysis, 29. A method for producing a 2,3-bis (alkyl carbonate) compound according to claim 13 »in which H _{2 is} an alkyl radical having 1 to 8 carbon atoms, characterized in that a corresponding 2,3-dihydroxy starting compound with a Halohalic acid esters, the alkyl radical being the same as in the compound to be produced 09844/1964 dung, in the presence of pyridine, 3-, 4- or 5- alkylpyridine, 3,4- or 3 »5-dialkylpyridine or 3,4,5-trialkylpyridine mixes, 30, the method according to claim 29, characterized in that ^v one 7-deoxy-7 (S) -chlorlincomycin-2,3-bis (hexyl carbonate) hydrochloride from 7-deoxy-7 (S) -chlorlincomycin hydrochloride and n- Manufactures hexyl chlorocarbonate in pyridine. 31 · Process for the preparation of a 2,3-bis (alkyl carbonate) compound according to Claim 13 »in which R _{2 is} hydrogen, ■ characterized in that a 1'-protected form of the en corresponding 2,3-dihydrofoxy compound, in which the protective group can be removed by hydrogenolysis, with an _{alkyl halocarbonate f} where the alkyl radical ! is the same as in the dividing connection, in a ratio of ester to! '- protected 2,3-dihydroxy compound of 5: 1, in the presence of pyridine, 3-, 4- or ^ alkylpyridine, 3,4- or 3,5-dialkylpyridine or 3,4f5-trialkylpyridine, and the protecting group removed by hydrogenolysis. ψ For The Upjohn Company Ealamazoo, me. / UNITED STATES Recruitment Attorney