BE705365A - - Google Patents

Description

  

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  -New derivatives of lincomycin, analogs and isomers, and methods of preparation-
The present invention relates to new compounds and to the processes for preparing them, and in particular to
 EMI1.1
 7-chloro-7-deoxylinecmyciraer to 9-chloro-7-deoxyepilincoaaycine, analogs and isomers, and the processes by which these various compounds and like products are prepared.



   The new compounds of the invention can be represented by the following developed formula:

 <Desc / Clms Page number 2>

 
 EMI2.1
 in which R is an alkyl having not more than 20 carbon atoms, advantageously not more than 8 carbon atoms, a cycloalkyl having 3 to 8 atoms. of carbon at most, and an aralkyl of 12 carbon atoms at most, advantageously of 8 carbon atoms at most, and Ac is the acyl radical of an L-2-pyrroidinecarboxylic acid substituted in position 4,. having the formula:

     
 EMI2.2
 formulas in which R1 and R denote an alkylidene of at most 20 carbon atoms (in particular methylene), advantageously 8 carbon atoms at most, a cycloalkylidene of 3 to 8 carbon atoms at most, and an aralkylidene of 12 carbon atoms at most, advantageously 8 carbon atoms at most, and R3 denotes hydrogen or HR2. nes example $ of alkyls containing not more than 20 carbon atoms (R, HR1 and HR2) soht: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl and their isomeric forms.

   Examples of cycloalkyls are: cyclopropyl, cyclobutyl, eyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclobutyl, 2-methyl-

 <Desc / Clms Page number 3>

 
 EMI3.1
 cyclobutyl and 3-cyclopentylpropyl. Examples of aralkylea are benzyl, phenethyl, 3-phenylpropyl and 1-naphthylmethyl. Of
 EMI3.2
 examples of nlkrlidene, cycloalkylidene and aralkylidene (R1 and R2) groups are methylylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, octylidne,,
 EMI3.3
 nonylidene, d6cylidepe;

   undècylidéne, doddcylidène, tridécyli- Dene tdtrad6cylidène, pentadécylidène, hexadécylidène, heptadécylidène, cetadécyiidène, nonadécylidène, etcosyl3.dène, andmixtures isomeric forms, cyclopropylidene, cyclobutylidene, cyclopentylidene, aya7.ohexylidèns, cycloheptylidene, cyclooetylidêne, 2-cyclo- .propyléthylidène, 3 -cyclop ntylpropylidene, benzylidene, 2-phenyl-ethylidene, 3-phenylpropylidene, and 1-naphthylmdthylene.



     @     The. New compounds of the invention, of formula I, as well as other related compounds, can be prepared by replacing with chlorine the 7-hydroxy radical of a compound of the formula:
 EMI3.4
 
The replacement is advantageously carried out by mixing the starting compound of formula II with thionyl chloride, and heating. In the process, Ac and R can be cons-
 EMI3.5
 tituated by any radical which is not reactive with. thionyl chloride but, for the preparation of the compounds of the invention, Ac and are as given previously. Title 1 vention, Ac and R are as given above.

   By way of example, when a compound of formula IIA (Ac in formula II
 EMI3.6
 is that of fortnulejh acid) is used as the starting compound, a new compound of the formula IA is obtained. When

 <Desc / Clms Page number 4>

 this compound or the starting compound (formula IIA) is hydrogenated with an effective catalyst to saturate an olefinic double bond, a compound of the formula In is obtained in the form of a mixture of cis and trans epimers, according to the formulas given below -after:
 EMI4.1
 which, if desired, can be separated by countercurrent distribution or chromatography.



   When R3 in formulas B, IB and IIB is hydrogen, it can be replaced by suitable alkylation or the like. Advantageously, this replacement is. performed by regulating the component of formula B. IB or IIB, wherein R3 is hydrogen, with an oxo compound (an aldehyde or a ketone), and hydrogenating the product @. resultant addition with a catalyst effective to saturate an olefinic double bond. Platinum or palladium can be used as a catalyst. Suitable oxo compounds have the formula R4R5CO where R4R5O = is the same as R2 given above.

   Examples of suitable oxo compounds are: formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, acetone, isobutyl methyl ketone, benzaldehyde, phenylacetaldehyde, hydrocinnamaldehyde, acetophenone, propiophenone, butyrophenone, 3-methyl-2-methyl phenone, 3-methyl-2-methyl phenone, 4-phenone -5-phenyl-3-pentanone,

 <Desc / Clms Page number 5>

 
 EMI5.1
 ayclapentansprapiorialdhyde, CyclObeXanoacetAlddhyde, cycloheptanecarboxaldehyde, 2, 21àimethylayalopropylacetaldehydefl, 2,2dimethylayclopropyl methyl ketone, cyclopentyl methyl cdtpne, cyclobutyl methyl oetone, cyclo-methyl oetone, 4-cyclo-metancone, cyclo-methyl oetone, 4-cyclo-metancone, etc.



  The starting compounds of formula II are prepared
 EMI5.2
 by acylation of a compound of the formulajii,
 EMI5.3
 in which R is as defined above, with a 4-substituted L-2-pyrrolidinecarboxylic acid of formula A or B. This acylation and the similar acylations in question here can be carried out by. processes already well known in practice for the acylation of amino sugars.

   The starting acid of formula A can be prepared by reacting a 4-oxo compound of formula:
 EMI5.4
 
 EMI5.5
 in which Z is a hydrooarbyloxycarbocyl protecting group which can be separated by hydr09 "nolY.8, a trityl, it is ..'- 4: Lrt? 'a txiphenyixethyl, a diph.6nyl (p-metthoxyph'nyl) m6t .hy1e, a bio- {p-! nôthoxyphenyl) phenylm6thyl, benzyl or p-nitrobenzyl, with a Wittig's agent, for example an alkylidénetriphenylphosporane See, for example, Wittig et al., Ber. 87, 1348 (1954) ) 1
 EMI5.6
 Trippett, Quarterly Reviewaµ XVII., N * 4, page 406 (196317.

 <Desc / Clms Page number 6>

 
 EMI6.1
 Examples of hy <9eooarbylo:

  tycaxonylej) t (S) are butoxy t etiary carbonyl, daa groupJ "bennyloxycarbonyls of forlll.1 + e 1
 EMI6.2
 
 EMI6.3
 in which X denotes hydrogen, nitro, methoxy, chloro or bromo, for example carbobenzoxy, p-nitrocarbobenzoxy, p-brymocarbobenzoxy et'p-chlorocarbobobenzoXY1 and phenyloxycar- groups,. bonyles of the formula:
 EMI6.4
 wherein X1 is hydrogen, allyl or alkyl having not more than 4 carbon atoms, for example the phenomenon
 EMI6.5
 nyloxycarbonyl, p-tolyloxycarbonyl, p-ethylphenyloxycarbonyl, p-allylphenyloxycarbonyl, etc.



   In the implementation of this process, the acid is added)
 EMI6.6
 4-oxo-'L-2-pyrrolidinecarboxylic (formula C) to a freshly prepared wittig reagent. The Wittig reagents used here can be generally represented by the following formula:
 EMI6.7
 Rlr .: p c6g5 3 in which R 1 is as defined above. These Wittig agents are prepared by reacting an alkyl mg cycloalkyl- or aralkyltriphenylphoaphoniua halide, with a base such as sodium amide or sodium or potassium hydride, or sodium metalate. sodium or potassium, dimethyl sulfoxide, etc.

   For example, the elimination of the acid chlo-
 EMI6.8
 from an alkyltriphenylphoaphonium halide produces alkylidenetriphdnylphosphorane, which is produced by

 <Desc / Clms Page number 7>

 phosphoranes is described in detail by Trippett, Quart. Rev. S XVII, N 4, page 406 (1963) @. The reaction is generally carried out in an organic solvent, for example benzene, toluene, ether, dimethyl sulfoxide, tetranydrofuran, etc. at temperatures between 10 ° C. and the reflux temperature of the reaction mixture.

   The product thus obtained, namely a 4-alkylidene-, 4-cycloalkylidene-, or 4-aralkylidene-1-protected-L-proline which has the following formula: @
 EMI7.1
 is recovered from the reaction mixture in a common manner, generally by extraction from aqueous solutions of the reaction mixture. The crude product can be purified by common means, for example recrystallization, chromatography or formation and recrystallization of readily formed derivatives, such as amino salts of the amino acid, for example the dicylohexylamine salt, etc., and liberation of amino acids from these compounds.

   By hydrogenation of an acid of formula D in the presence of a catalyst, for example platinum, which is effective in saturating a double bond, but which is ineffective in carrying out hydrogenolysis, a compound of the following formula is obtained:
 EMI7.2
 

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 Platinum deposited on a support, for example darbone or an anion exchange resin, such as Dowex-1, which is a crosslinked resin of polystyrene trimethylbenzylammonium in the hydroxide ring, can be used. If desired, the starting compounds of formula V can be acylated with acids of formula C, D or E, to form compounds IIC, IID and II, respectively.

   Compound IIC can then be converted to compound IID by treatment with Wittig's reagent and compound IID can be hydrogenated to compound IIE by the methods given above. Hydrogenation, both of acid D and
 EMI8.1
 of acetelID, gives a mixture of cis and trans epimers which, if desired, can be separated by countercurrent distribution or chromatography. The starting acids of formula B in which R3 is hydrogen are obtained when. The acid of formula D or E is subjected to hydrogenolysis over a palladium catalyst, for example palladium on carbon.



  Likewise, compounds of formula IID and IIE are converted to compounds of formula IIB, wherein R3 is hydrogen, by the same method. The starting acids of formula B, where R3 is hydrogen, as well as compounds of formula IIB, where R3 is hydrogen, can be converted to compounds of formulas B and IIB, respectively, where R3 is HR, by the methods given above. The starting acids of formula A are obtained by treating an acid of formula D with a solution of hydrobromic gas in acetic acid to separate the Z group, and then treating the N-hydrogen with a HR group by the method given above.

   Compounds of formulas IID and IIE are converted to compounds of formulas IIA and IIB by the same method.



   Some of the starting compounds of formula II are
 EMI8.2
 obtained by biosynthesis. The lincomycin, namely 6,8-dideoxy-6- (trans-1-methyl-4-propyl-L-2-pyrrolodinecarboxamido) -l-thio-Ddrythro-aD-ga3.aato-ortopyranoeide, is obtained at

 <Desc / Clms Page number 9>

 title of elaboration product of an actinomycete producing
 EMI9.1
 lincomycin according to U, S.A patent no. 3,086,912. She aâla
 EMI9.2
 following structural formula: '-1 CHa CHa BIH HO- 1111 H1H MV ""' "" * q) rli 1 vi c H - ### '<RR e- "1 r where R and R3 are methyl and R1H is propyl.

   The
 EMI9.3
 lincomycin B, namely methyl 6,8-dideoxy-6- (trans-1-methyl-4-ethylle62-pyrrolidinacarboxamido) -l-thiv-D-erythro- -D-galacto-octopyranoside (formula VI in 1. which and R3 are methyl and -R1H is ethyl), is also a development product of the same microorganism, when cultured according to the method described in US Patent No. 3,086,912.

   The lincomyci-
 EMI9.4
 ne C (8-âthyl-S-demethyllincomvcine) t namely 6,8-dideoxy-6- (trana-1-methyl-4-propyl-L-2-pyrrolidinecarboxamido) -1-thio-D- 'rhythmro- Ethyl D-9alacto-octopyranoside (formula VI where R is ethyl; ep -R1H is propyl and R. is methyl), is obtained when the process according to US Pat. No. 3,086,912 is carried out in the presence of an addition of ethioni-.
 EMI9.5
 born.

   Lincomycin D, namely 6,8-didenoxy-6- (trans-4-ethylL-2-pyrrolidinecarboxamido) -l-thio-D-ethyl - D-galacto-octopy-ranoside of methyl (formula VI in which R is methyl, -R1H is ethyl and R3 is hydrogen), is obtained when the fermentation according to US Pat. No. 3,086,912 is
 EMI9.6
 carried out in the presence of a 1e -MTL, 6-amino-6,8-diddde! soxy-D-erythro-1-thio-4-D-galacto-octopyranoside / methyl, namely a compound obtained by the hydrazinolysis of lincomycin according to U. S.A. patent no. 3,179,595.

   N-demethyllincomycin B, at its
 EMI9.7
 see methyl 6,8-dideoxy-6- (tra.s - ethyl-L-2-pyrrolidonecarboxamido) - 1-thio-D-errthro-p-D-gaiacto-octopyranoside (formula

 <Desc / Clms Page number 10>

 
 EMI10.1
 VI where R is methyl, -R1H is ethyl and R is hydrogen) is also produced when [alpha] -MTL is added to the fermentation according to U.S. Patent No. 3,086,912.

   Similarly,
 EMI10.2
 lincomycin In, namely ethyl, 8-dideoxy-ô- (trens4-pro $ yL-2pyrrolidineoarboxamido) -1-thio-D-erythro- E -D-galaoto-octo) yraÀoside (formula VI in where R is ethyl, -R1H is propyl and R3 is hydrogen), is produced when the closure according to US Pat. No. 3,086,912 is carried out in advance.
 EMI10.3
 presence of an addition of -ETL, namely 6-amino-6 # 8-didemoxy-
 EMI10.4
 Ethyl 7.-thio -D-erythro-o-D-galacto-oetopyranoside, which is a compound obtained by the hydrazinolysis of lincomycin C.

   S-ethylS, N-didemethylincomyc3ne B, namely 6,8-didexoxy-6- (trana-4- Ôthyl-L-2-pyrrolidineaarboxamido) -1-thio-D-erythro- -D-galaeto- octopyranoside of ethyl (formula VI where R is ethyl, -R1H is ethyl, and R3 is hydrogen) is also obtained when -ETL is added to the fermentation according to U.S. Patent No. 3,086,912 . The N-desm6thyles products described above,
 EMI10.5
 which are obtained when adding α, -MTL and B-ETL to the fermentation process of U.S. Patent No. 3,086,912, are examples of compound IIB, in which R33 is hydrogen.

   By the process described above, replacement of N-hydrogens produces compounds of formula IIB in which R3 equals HR2,
 EMI10.6
 for example the 6,8. * dideoxy-6- (trans-1-ethyl-4-propyl-L-2-. pyrrolidinecarboxam1do) -1-thio-D-erythro-D-qalacto-octopyranoide, 6 , Ethyl 8-dideaxy-6- (trans-1-methyl-4-ethyl-L-2-pyrrolidinecarboxamido-1-thio-D-erythra- -i3-galaato-octopyranoside, 6,8-dideoxy-6- (trans-1-ethyl-4-ethyl-L-2-pyrrolidinecarboxamida) -1-thio-D-erythro-: ethyl D-galacto-octopyranoside and 6,8-dideoxy-6- (trans-1-ethyl -4-ethyl-L-2-pyrrolidinecarboxamido) - methyl 1-thio-D-erythro-a -D-galaoto-octopyranosida.



   Lincomycin or any of the starting compounds of formula II having the D-erythro configuration can

 <Desc / Clms Page number 11>

 be converted to the L-threo configuration by oxidation of the 7-hydroxy group to a 7-oxo group, and reduction of the latter to a 7-hydroxy group. A suitable method for this is illustrated by the following sequence
 EMI11.1
 
For example, lincomycin by treatment with acetone in the presence of p-toluenesulfonic acid is converted to la
 EMI11.2
 3,4-0-isopropylidenelicomyoine which, by oxidation with chromic acid, gives 7-dehydro-3, -0-isopropylideneincomycin, namely 6,8-dideoxy-3,4-O-isopropylidene-6- (trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxamido)

  Methyl-1-thio-D-glycero-α-D-galacto-octanopyranos-7-uloside, which on treatment with sodium borohydride / is converted to epilincomycin, namely
 EMI11.3
 6,8-dideoxy-6- (trans-methyl-4-propyl-L-2-pyrrolidinecarboxa-

 <Desc / Clms Page number 12>

 
 EMI12.1
 Methyl mido) -1-thio-L-threo-a-D-golacto-octopyranoside. Any of the starting compounds of farmule II, having a D-erythro configuration, can be converted to the corresponding L-threo configuration by this method,
 EMI12.2
 since the bionynthetically produced lincomycins, as well as the amino sugars derived therefrom, are methyl or ethyl thioglucosides, it is sometimes desirable to convert them to higher or lower glucosides.

   It is sometimes also desirable to convert any of the compounds of formula I, II or V to higher or lower glycosides. This can be effectively accomplished by reacting the compound to be converted with a mercaptan of the formula R6SH, wherein R6 is an alkyl group of at most 20 carbon atoms, but different from R, and cyclizing the resulting dimercaptal. By way of example, compounds of formula I and II, upon reaction with a mercaptan of formula R6SH, produce dithioacetalas of formula
 EMI12.3
 formulas in which X @@ sign the hydroxyl radical or chlorine and which, by treatment with an acid or by heating,

   in the presence of an acid or not, are recycled into a compound of the following formula
 EMI12.4
 

 <Desc / Clms Page number 13>

 
The process can be applied directly to any of the starting material of formula II, i.e.
II1, IIB, IIC, IID and IIE, The resulting products can be subjected to hydrasinolysis to form compounds of the following formula:
 EMI13.1
 which can be N-acylated as described above, with acids of the formula A, B, C, D and E, to give compounds of the formula XII where X is the hydroxy radical.

   The process can also be applied to the starting compounds of formula V. For example, [alpha] -MTL, by treatment with ethyl mercaptan, followed by cyclieation as described above, is converted to a-ETL.



   Another method of preparing compounds of formula XII or of formula XIII consists in brominating the starting material (formulas I, II or V) and then reacting the product with a marcaptan in the sequence given below:

 <Desc / Clms Page number 14>

 
 EMI14.1
 
The starting compound XIV is dissolved in water in the form of a soluble salt, for example the hydrochloride, and bromine is added with cooling, preferably to a temperature of between about -10 and 20 ° C.

   It is sufficient that the aqueous solution is cooled to about 0 C and the bromine is added dropwise The stoichiometric amount of bromine is 1 mole for each mole of the starting compound, although one can use of * greater or lesser quantities. Advantageously, a slight excess, for example a 5 to 20% excess of the bromine, is used. Bromine initially replaces the RS- group and the resulting intermediate hydrolyzes to the sugar in which the pyranose form XVa is in equilibrium with the aldose form XVb.

   In the presence of an acid, for example hydrochloric acid or other strong non-oxidizing acid, such as p-toluenesulfonic acid, and anion exchange resins of the sulfonic acid type,

 <Desc / Clms Page number 15>

 
 EMI15.1
 Mreaptan R68M reacted with More XV to form thioglucoside XVI. at the same time, a certain amount of diacetal can be formed which, after separation, can be cycli-
 EMI15.2
 * As described above to form an additional amount of the desired XVX thicqllxconide.



  The mechanism by which thionyl chloride achieves
 EMI15.3
 whether the substitution of 7-hydroxy by chlorine is not well understood. ".- r '.-.-.: ...,: This mechanism is such that a' configuration change occurs ... '* Hence,, a
 EMI15.4
 7-hydroxy compound of the D-erythro configuration gives) .. a 7-chloro compound of the L-thr4o configuration. For example, 7-chloro-7-disoxylincomycin, which is derived from lincomycin and has D-erythro configuration,?. aai ::, configuration 1, -thréo. However, it has been established by experiments that the process passes through a series of intermediates following the sequence given below.
 EMI15.5
 

 <Desc / Clms Page number 16>

 In these formulas, Ac and R are as given previously.

   Intermediate XVIIa is the 3,4-cyclic sulfite of the material. start II and it has the following formula 1
 EMI16.1
 wherein X is the hydroxy radical.Intermediate XVIIb is the corresponding 3,4-cyclic sulfite of the compound 7-chloro (formula I) and is represented by the formula XVIIa, wherein X is chlorine.

   Intermediate XVII can be a bis-sulfite of the 3,4-cyclic sulfite of the compound 7-chloro, which can be represented by the formula:
 EMI16.2
 If desired, each of the three intermediates, XV, XVIIb and XVIII can be isolated during the reaction. All that is necessary, however, to effect the substitution of 7-hydroxy with chlorine is to mix the starting compound of formula II or V,

 <Desc / Clms Page number 17>

 advantageously in the form of a salt by addition of acid, for example the hydrochloride, with thionyl chloride, advantageously in the presence of an inert solvent, with moderate heating, advantageously at the temperature of reflux, until the desired substitution of the 7-hydroxy group by chlorine is achieved.

   Advantageously, the reaction is carried out in an inert atmosphere, for example under nitrogen. Carbon tetrachloride can be used effectively as a solvent, but other inert solvents can also be used, such as chloroform, methylene chloride, ethylene chloride, ether, ether. benzene, etc. A satisfactory method is to stir the reaction mixture at room temperature for a substantial period of time, for example for about 1 to 18 hours or as long as necessary. to get a reasonably clear solution,

   and then raising the temperature to a value between approximately 50 and 100 ° C., for example up to the reflux temperature (77 ° C. for carbon tetrachloride). At the end of the reaction, usually after heating under reflux for about 1 to 5 hours, the reaction mixture is allowed to cool, preferably under nitrogen. Any material which separates on cooling is collected and dried.

   The solvent is separated by vacuum distillation at a vessel temperature, preferably below about 35 ° C, and the material which precipitates is collected and dried, then treated with ethanol to convert any residual sulphite intermediates. The collected material is then further purified by solvent extraction and / or recrystallization. tion, and it can be recovered in the form of the free base or in the form of a salt by addition of acid.



   The proportions of the reagents can vary widely.



   If, however, the stoichiometric amount is considered, at least 3 moles of thionyl chloride are required for each mole of the

 <Desc / Clms Page number 18>

 Starting compound. Any greater amount can be used, but ordinarily it is not necessary or desirable to use more than about 10 times excess. Advantageously, an excess of about 2 to 3 times is used. The amount of the solvent is not critical and can vary widely depending on practical techniques. Usually, about 15 to about 30 volumes of the solvent for each part of the solid starting compound will suffice. The proportion of the "solvent relative to the thionyl chloride is however important because of the solubility of the product in this thionyl chloride.

   If the solvent / thionyl chloride ratio (v / v) is high, the desired product precipitates on cooling the reaction mixture and the processing of the product is simplified. For example, with carbon tetrachloride, a mixture of products precipitates directly. upon cooling of the reaction mixture, if the volume / volume ratio of carbon tetrachloride to thionyl chloride is kept greater than about 10 to -1.



   The compound of formulas IA, IB, IIA, IIB and V exists in the protonated form or in the non-protonated form depending on the pH of the environment. When the protonated form is contemplated, the compound is termed as an acid addition salt and, when the non-protonated form is contemplated, it is termed as the free base. Free bases can be converted to salts by adding stable acids by neutralizing this free base with the appropriate acid to a pH less than about 7.0, and preferably to a pH of about 2 to 6. .



  Suitable acids for this purpose are the acids: hydrochloric, sulfuric, phosphoric, thiocyanic, fluosilic, hexafluororarsenic, hexafluorpohosphoric, acetic, succinic, citric, lactxic, maleic, fumaric pamoic, cholic, palmitic, mucic, camphoric, cholic, palmitic, mucic, camphoric, cholic, palmitic, mucic, camphoric, cholic, palmitic, mucic, camphoric, cholic, palmitic, mucic, camphoric, cholic, palmitic, mucic, camphoric, cholic glycolic, phthali-

 <Desc / Clms Page number 19>

 as, tartaric, lauric, stearic, salicylic, 3-phenylsalicy-, lic, 5-phenylsalicylic, 3-methylglutaic, orthosulfobenzol- que, @ @ cyclopentanepropionic, 1,2-cyclohexanedicarboxylic 4-cyclohexanecarboxylic, octadecinecarboxylic, octadecanecarboxylic

       methanesulfonic, benzenesulfonic, helianthic, Reinecke's, dimethyldithiocarbamic, cyclohexylsulfamic, hexadecylsulfamic, octadecylsulfamic, sorbic, monochloroacetic, undecylenic, 4'-hydroxyazobenzene-4-sulfonic, octicodecylsulfamic, sorbic, monochloroacetic, undecylenic, 4'-hydroxyazobenzene-4-sulphonic, octicodecylsulfic and similar acids, picylsulfic acid



   The acid addition salts can be used for the same purposes as the free base, or they can be used to improve this free base. For example, the free base can be converted to a water insoluble salt, such as picrate, which can be subjected to purification processes, eg, solvent extractions and washes, chromatography. , fractional liquid-liquid extractions, and crystallization, and then this salt can be used to regenerate the free base form by treatment with alkali, or to prepare a different salt by metathesis.

   The free base can be further converted to a water soluble salt, such as the hydrochloride or sulfate, and the aqueous solution of the salt can be extracted with various water-immiscible solvents, before regeneration of the form. free base by treating the acidic solution thus extracted, or it can be converted to another salt by metathesis. The free bases of formulas IA, IB ,. IIA, IIB and V can be used as buffers or as antacids. The compounds of formulas I, II and V react with isocyanates to form urethanes and they can be used to modify polyurethane resins.

   Long chain compounds, i.e. those in which HR2

 <Desc / Clms Page number 20>

 is an alkyl of up to 8 carbon atoms, has surface active properties and can be used as wetting and emulsifying agents. The salt on addition of thiocyanic acid, when condensed with formaldehyde, forms resinous materials of interest as pitting inhibitors, according to U.S. Patents 2,425,320 and 2,606,155. Free bases are also good vehicles for toxic acids.

   For example, salts by addition of fluosilicic acid are useful as moth repellants according to U.S. Patents No.
1,915,334 and 2,075,359, and salts by addition of hexafluoroarsenic acid and by addition of hexafluorophosphoric acid are useful as parasiticides according to U.S. Patents No.
3,122,536 and 3,122,552.
 EMI20.1
 



  Analogs close to 7-ahloro-7-deaoxylincomycin *, that is to say in which -R1H is a cis or trans alkyl of at most 8 carbon atoms, R3 is methyl or ethyl, R is a alkyl of 8 carbon atoms or less, have anti-bacterial properties and some are comparable or superior to lincomycin and can be used for the same purposes as lincomycin. The corresponding compounds where R3 is hydrogen have similar antibacterial properties, and in addition, they have improved gram-free activity.



  The other analogs and isomers have similar antibacterial properties but to a lesser degree and can be used for the same purposes as lincomycin, where larger amounts are not detrimental.



   The following examples illustrate the process and products of the present invention but do not constitute a limitation thereof. The parts and percentages are given by weight and the proportions of solvent are given by volume, unless otherwise indicated.

 <Desc / Clms Page number 21>

 



  EXAMPLE 1
 EMI21.1
 7-chloro-o7-desoxylincomycinel7-chloro-6,7; a-tridêsoxy-6- <tan8l-methyl-4-propyl-L-2-pyErolidineoarboxamido) -1-Eheo-L-teo-a-Dgalaoto-ootopyranoside methyl ±?
 EMI21.2
 A. Free base
A suspension of 221.0 gr (0.5 mole) of lincomycin hydrochloride in 5 liters of carbon tetrachloride was. stirred well at 25 under nitrogen. 900 ml of thionyl chloride was added all at once and stirring continued for 2 hours. During this period, the solid dissolves and a clear solution is obtained. The reaction mixture is heated
 EMI21.3
 at reflux for 2 hours, then the heat source. removed and nitrogen is bubbled through the amber solution until the temperature of the reaction vessel drops to 25.

   About 4 liters of liquid are separated off by vacuum distillation at a reaction vessel temperature below 35. The yellow solid which precipitates during this distillation is rewashed and dried. This solid is dissolved in approximately 300 ml of methanol, then it is cooled to 25, made basic (pH 11) with a dilute aqueous solution of caustic soda (2N), then diluted to approximately 1200 ml with water and conveniently extracted with ether. The ethereal extracts are combined, washed with a small amount of water, dried over anhydrous magnesium sulfate and filtered.

   By evaporation of a small amount of

 <Desc / Clms Page number 22>

 Combined ethereal extracts, the free 7-chloro-7-deoxylincomycin basa is obtained as a yellow amorphous solid.



  B. Hydrochloride
Addition of hydrochloric gas to the filtrate from Part A results in the precipitation of 7-chloro-hydrochloride.
 EMI22.1
 7-deoxylincomycin which is separated and recrystallized from ethanol and ethyl acetate. A 32% yield of white crystalline 7-ehloro-7-deoxylincomycin hydrochloride is obtained, solvated with about a molecular proportion of water.



  Analysis: Calculated for C18H33C1N245S.HC1.H2? 1 Ci 45.18; Hi 7.371 Cls 14; 821 Nt 5.861 4t 6.70o H2O s 3.77 Found s Ci 44.70; Hi 7,651 Cli '.' & 4,271 Ni 5,781 Sa 6,45t H20 s 3,85. ôcD2 ¯ + 1300 (Cs 0.9858 g / 100 ml). Activity about 4 to 8 times that of 11ncomycine Antibacterial spectrum: identical to that of lincomycin.



  EXAMPLE 2.



  7-chloro-7-deoxvlindomvcine free base
The process of Example 1, part A, was repeated,
 EMI22.2
 except that methylene chloride was used instead of ligor as the extraction solvent. and that the combined extracts were filtered and evaporated to dryness. We thus obtained
 EMI22.3
 a yield of 64% of the free base of I-ehloro.7-ddsa, rylincomy ce
 EMI22.4
 cine as a yellow adjnorphic solid. 15 g of amoxphe solid was adsorbed. on 30 g of a wilica gel in methylene chloride, then adchis tteiparde on a column with a diameter of 3 inches comprising 1500 g of silica gel.

   The column is then eluted with a mixture of methanol and chloroform in the proportions of 1 to 19, and this in portions of 200 ml, after a production head of 2 liters. Fractions 26, 27 and 28 are combined and evaporated to dryness, yielding 1.04 gr.

 <Desc / Clms Page number 23>

 
 EMI23.1
 of essentially pure 7-chloro-7-d <aoxylin <: omyeine free base forms an amorphous solid with an antibacterial spectrum of the same type and magnitude as the hydrochloride.
 EMI23.2
 of 7-chloro-7-deaoxylàomyoino of Example 1.



  EXAMPLE 3 7-ahloro-7-deaoxylinoomyain * C 7-chloro-.6,7,8 "trideaoxy''6'.tran '' 1-methyl-4-propyl-L-2-pyrrolidin * aarboxamidp) -1- thào-> threo-aD galacto-octopyranoBided'ethyl7
 EMI23.3
 A, Substitution by chlorine
A suspension of 1 g of lincomycin C hydrochloride in 25 ml of carbon tetrachloride and 4.5 ml of chloride
 EMI23.4
 of thionyl 'was stirred under nitrogen for 2 hours at 25 ° C. A clear solution was thus obtained in about 15 minutes. The reaction mixture is then heated at reflux for 2 hours and evaporated to dryness in vacuo to give a yellow solid which is dried in vacuo at 40 C for 18 hours.



  The product is then dissolved in about 15 ml of hot ethanol, made basic with caustic soda as in Example 1 and diluted to 300 ml. with water. The aqueous solution is extracted 5 times with 100 ml portions of ether.

   The
 EMI23.5
 ethereal extracts are Vâmass6s, dried over sodium sulfate, filtered, saturated with hydrochloric gas and evaporated to a brown residue which, on recrystallization twice from a mixture of ethanol and ethyl acetate (dissolved in a minimum quantity of ethanol and addition of ethyl acetate until

 <Desc / Clms Page number 24>

 cloudiness) gives 200 mg of 7- hydrochloride
 EMI24.1
 chloro-7-deaoxylincomycin C as white crystals which have the same activity and the same spectrum as the hydrochloride of '7-eh.oro-i-dgsoliomycin of Example 1, B.

   Preparation of lincomycin C
 EMI24.2
 Lincomycin C is obtained * by reacting 4 * lincomycin with ethanethiol (ethyl meroaptan) to form diethyl dithioaceta, 1, and heating the exaction mixture in the presence of p-toluenesulfonic acid or heating to fusion . The following process is illustrative.
 EMI24.3
 



  Bl. 6,8-dideoxy-6- (trans-1-methyl-4-propyl-L2-pyrrolidine-oa boXamido) -D-drythro-D-galacto-: aldehydo-octote diethyl dithioacetal
 EMI24.4
 In a bottle & 3 cola, with a capacity of 1 liter, we place concentrated hydrochloric acid (150 cm3) and ethanethiol (50 cm3, previously cooled to 0), then 15.0 gr of lincomycin hydrochloride, After stirring magnetically at room temperature for 5 hours, the reaction mixture
 EMI24.5
 tion is diluted with an equal volume of ice water "" lIt ruu "JI \" "" Ù.11'1 "'JL' '' 'M] la ..,. and the solution is extracted & melted with Skellysolve , B (technical hexane), these extracts being rejected.



   Most of the acid is neutralized by the careful addition of solid caustic potash (100 gr) keeping the temperature of the well stirred reaction mixture between
 EMI24.6
 20 and 30 C by cooling in aaetone aarboglaae +

 <Desc / Clms Page number 25>

 The solid potassium chloride is separated by filtration and the solid is washed well with chloroform. Chloroform is added. additional to the filtrate (about 150 cm3) and the mixture *, stirred by magnetic means, is adjusted to pH 10 by the addition of aqueous caustic soda (2N). The chloroform layer is separated, the aqueous layer is extracted thoroughly with chloroform and the combined extracts are washed twice with water and dried over anhydrous sodium sulfate.

   Removal of the solvent at 30 ° C. in vacuo gives a semi-solid residue which, on recrystallization from acetone, gives 55.41 g of 6,8-dideoxy-6- (trans- 1- methyl-4-propyl-L-2-pyrrolidinecarboxamido) -D-erythro-D-galacto-aldehydo-octose diethyl dithioacetal in the form of colorless flattened needles, with a melting point of 130-132. Concentration of the mother biters gives an additional amount of material (1.50 g), with a melting point of 129-131 *. (Total yield of 6.91 gr, or 42.4%).



  Analysis: Calculated for C21H42N2O6S2
C: 52.25t H: 8.77; Ni 5.811 S: 13.29%
Found: C152.38; H: 8.71; -if 5.931 S: 13.46% 32. Cyclization to licomycin C.



   (a) A part of the -diethyl dithioacetal from part B1 and a part of p-toluenesulfonic acid monohydrate are refluxed in 25 parts of acetonitrile until significant antibacetial activity is obtained. The reaction mixture is cooled and evaporated to dryness, then chromatographed on silica gel using a solvent mixture formed from ethyl acetate, acetone and water in a ratio of 8/5 / 1. Fractions 102 to 131 show antibacterial activity. Among these fractions, fractions 105 to 125 are combined, dried to dryness and crystallized from acetone acidified with hydrochloric acid,

   then recrystallized by dissolving in water and adding acetone to give crystals of

 <Desc / Clms Page number 26>

 lincomycin C hydrochloride, melting point 149-153.



   (b) The diethyl dithioacetal from part B1 was heated to 2600 for about 3 minutes and the ethyl mercaptan odor was noted. The product, on chromatography as in part B2 (a), gives lincomycin C.



   C. Preparation of lincomycin C by fermentation The lincomycin C hydrochloride was prepared as follows @
FERMENTATION @ @
A lying soil culture of Streptomyces lincolnensis var. Lincolnenais, NRRL 2936, was used to inoculate a series of 500 ml Erlenmeyer flasks, each containing 100 ml of a seeding medium consisting of the ingredients: Yeastolac 1 10 gr Glucose Monohydrate 10 gr.



    N-Z-amine B 11 5 gr Tap water, quantity sufficient to make 1 liter (1) Yeastolac denotes a protein hydrolyzate of yeast cells (11) N-Z-amine B denotes an enzymatic ingestion casein from Sheffield.



   The pre-sterilization pH of the seed medium is 7.3. Growth takes place for 2 days at 28 ° C. on a rotary Gump shaker operating at 250 revolutions per minute.



   A 5% inoculum of the stocking described above (5 ml) is added to each of the 30 Erlenmeyer flasks of 500 ml which are used and which each contain 100 ml of the following small fermentation: Glucose monohydrate 15 gr Starch 40 gr Molasses 20 gr Wilson peptone liquor n 159 1 10 gr Corn maceration liquor 20 gr Calcium carbonate 8 gr

 <Desc / Clms Page number 27>

 Bacon Oil 0.5ml Tap Water, Amount Enough to Make 1 Liter (1) Wilson Peptone Liquor No. 159 is a preparation of enzymatically hydrolyzed proteins of animal origin.



   At the time of inoculation, DL-ethionine is added to a final concentration of 2 mg / ml.



   The shaken flasks are harvested after 4 days of fermentation at 28 ° C. on a rotary Gump shaker operating at 250 revolutions per minute. They assay 200 mcg / ml in a S. lutea test, which is described below. The total beer solids obtained is about 20 g / liter.



   PURIFICATION
The total beer (235 liters) from fermentation with DL-ethionine is filtered at harvest pH, using filter aid if necessary. The mycelial cake is washed with water and then discarded. The filtered beer and the water wash liquid (275 liters) are stirred for 45 minutes with 12.5 kg of activated charcoal and 2.5 kg of diatomaceous earth. The mixture is filtered and the filtrate is discarded. The charcoal cake is washed with 60 liters of water and the water is discarded.

   The cake is washed with 70 liters of a 20% aqueous acetone solution and the washing liquid obtained is discarded :,. The cake is then eluted twice with 100 liter portions of 90% aqueous acetone. The eluates are combined (215 liters), and the solution is concentrated (18 liters), This concentrate is adjusted to pH 10.0 with a 50% aqueous solution of caustic soda and it is extracted 3 times with portions of 20 liters of methylene chloride. The methylene chloride extracts are combined (60 liters) and then concentrated to give an oily preparation (7.14 gr) containing lincomycin and lincomycin C in equal amounts and both in the form of the base li - bre.

   This preparation is then dissolved in 200 ml of methylene chloride. The solution is clarified by filtration and in-

 <Desc / Clms Page number 28>

 continuation concentrated until secity empties us. The residue is dissolved in 100 ml of 1N methanolic hydrochloric acid. This methanolic solution is then mixed with 3.2 liters of ether and stirred.

   The resulting crude, colorless, precipitated, lincomycin hydrochloride and lincomycin C hydrochloride are isolated by filtration and dried, the production is 7.14 gr grading 940 mcg / mg with respect to Sarcina lutea (The test with respect to Sarcina lutea is carried out on agar-agar buffered at pH 6-8 with a phosphate buffer of pH 7.0 [0.1M], A unit volume [0.08ml] of solution containing the material to be tested is placed on a 12.7 ml test disc which is then placed on an agar plate seeded with the microorganism to be tested). Thin layer chromatography shows the presence of both lincomycin hydrochloride and lincomycin C hydrochloride in approximately equal amounts.



   The crude lincomycin C hydrochloride (7.0 g) is dissolved in 20 ml of water and 20 ml of butanol, the pH is adjusted to
4.2 with IN HCl and the solution is dispensed into a countercurrent dispensing apparatus for 1000 transfers. A. analysis by thin layer chromatography shows that the fractions in tubes 135 to 190 contain lincomycin C. These fractions are combined and the solution is concentrated, then dried thoroughly to give 2.44 g of hydrochloride. lincomycin C titrating 1400 mcg / mg vis-à-vis your Sarcina lutea.



   500 mg of this preparation are dissolved in 2 ml of water, 1 ml of methanol and 100 ml of acet @ ne. The solution is clarified by filtration. The filtrate is mixed with ether until crystals appear. The mixture is allowed to stand at room temperature for 1 hour. The crystalline incomycin C hydrochloride (cubes) is separated from the supernatant by decantation. These crystals are recrystallized in 1 ml of water,
1 ml of methanol, 80 ml of acetone and 20 ml of ether; the production is 250 mgr of crystalline lincomycin C hydrochloride (cubes),

 <Desc / Clms Page number 29>

 The supernatant * (obtained as described above) is allowed to stand at 5 ° C. for 4 hours.

   The crystalline lincomycin C hydrochloride (needles), which precipitates, is filtered off and dried; @ the yield is 150 mr of crystalline lincomycin C hydrochloride (needles), melting point 151-157 ° C.



   D. Alternative Method of Preparation of lincomvcine C
Lincomycin hydrochloride (8.85 gr, 0.02 mole) was dissolved in 20 ml of water, and cooled to 0 and stirred, while adding drome (3.52 gr; 0.022 mole) dropwise. over a period of 1 minute. Ethanethiol (25 ml) was added and the mixture was stirred at 25 for 2 hours. The two-phase system, colorless, clear (ethanethiol is relatively insoluble in water) and cooled in water. ice bath and bubbled hydrochloric gas therein for about 5 minutes. The lower aqueous phase turns red. The reaction mixture is then extracted three times with 100 ml portions of SkellysolveB and an aqueous solution of caustic soda is added to bring the aqueous phase to pH 11.

   The basic phase is conveniently extracted with chloroform. The chlorofrom extracts are washed with saturated sodium chloride solution, dried and evaporated in vacuo to give 6.2 g of a white solid. 4.8 g of this solid are chromatographed on 800 g of silica gel by the method of Example 2, using methanol-chloroform (1/7) as solvent system. After 800 ml of production head, 80 fractions of 25 ml each are collected.



  Fractions 40 to 58 are combined and evaporated to dryness and the residual oil is recrystallized from acetone to give 0.5 g of a material identical to the diethyl dithioacetal of part B1. Fractions 65-75 are combined, evaporated to dryness and dissolved in a mixture of 5 ml of methanol and 400 ml of diethyl ether. Hydrogen chloride gas is added and the white solid which precipitates is collected.

   By recrystallization from aqueous acetone, 0.5 g of hydrochloride is obtained.

 <Desc / Clms Page number 30>

 of lincomycin C, identical to that of part C.
 EMI30.1
 E.Other 7-chloro-6,7,8-trideoxy-6 (trans-1-methyl-4propyi-L-2-pyrrolidinecarboxamido) -1-thio-L-tflr'oa-D-cralacto-octoovranosides from â k 1
By substituting the ethanethiol in part B1 and in part D I, for example, with other alkyl mercaptans, for example propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl , hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosylated mer-captans and their isomeric forms;

   by cycloalkyl mercaptans, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 'cycloheptyl, cyclooctyl, 2-methylcyclopentyl, 2, 3-dimethylcyclobutyl, 2-methylcyclobutyl' and 3-cyclopentylpropyl mercaptans; or by aralkyl mercaptans, for example benzyl, phenethyl, 3-phenylpropyl and 1-naphthylmethyl mercaptans, one obtains
 EMI30.2
 the corresponding alkyl, cycloalkyl and aralkyl 6,8-dideoxy-6- (trans-1-methyl-4propyl-L-2-pyrrolidinecarbaxamido) -1-thio-D-erythro-aD-galacto octopyranosides, which, by treatment with proceeded from Part A, are converted to, alkyl, cycloalkyl and aralkyl
 EMI30.3
 Corresponding 7-chloro-6,7,8-tridesoxy-G- (trans-1-methyl-4-propyl-L-x-pyrrolidi necarboxamido) -l-thio-L-thrdo-a-D-galidacto-octanopyranosides.

   The compounds thus obtained (both compound 6,8didesoxy and compound 7-chloro-6,7,8-trideoxy) in which the alkyl is propyl,.: Butyl, pentyl and hexyl (which obtained respectively when using propyl, butyl, pentyl, and hexyl mercaptans) are particularly effective as antibacériens agents, having the same spectrum as lincomycin and an activity equal or greater.



  EXAMPLE 4
 EMI30.4
 7-chlora-5,7,8-tridesoxy-8- (trans-i-aikyl-4-butyl-L-2-pyrrolidine carboxamido) -1-thio-L-threo-a-D'galacto- * oatopyranosides methyl.

 <Desc / Clms Page number 31>

 
 EMI31.1
 



    R3 = methyl or ethyl.



   Part a
A suspension of 116 mgr of the free base of 6.8-
 EMI31.2
 methyl didebxy-6- (trans-1-ethyl-4-butyl-L-2-pyrrolidineearboxamido) -1- thio-D-erythro-aD-galacto-octopyranoside in 3 ml of carbon tetrachloride and 0.7 ml of Thionyl chloride was stirred at 25 C until a clear solution was obtained (about 15 minutes) and then allowed to stand at 25 C for 2 hours. The reaction mixture is then heated at reflux for 2 hours and then evaporated to dryness in vacuo to a yellow solid which is treated as described in Example 3.

   The product does crystallize however. no aorta as the crystallization solvents are evaporated to give 17 mg of hydrochloride
 EMI31.3
 te of 7-chloro-6,7,8-tridesocy-6- (trans-1-ethyl-4-butyl-L-2-pyrrolidineoarboxam $, do) -1-thio-L-threo-aD-galacto-octopyranoside of methyl as a tan-colored amorphous solid, which exhibits 8 times the activity of lincomycin against gram-taking bacteria, and 16-64 times the activity of lincomycin against non-gram-taking bacteria.



   When replacing the cis epjmary, we get
 EMI31.4
 7-Chloro-6,7,8-trideoxy-6- .ois-1-ethyl-- butyl-L-2-pyrrolidinecarboxamido) -1-thio-L-threo-a-D-galacto- - hydrochloride
 EMI31.5
 Methyl octopyranoside, having the same antib4cterial spectrum.

 <Desc / Clms Page number 32>

 
 EMI32.1
 



  Los do the substitution of the 1-methylm analogues, we obtain the hydrochlorides of 7-chloro-6,7,8-tridAsoxy-6 "(ois- and trana-1-methyl-4-butyl-L-2-pyrolidinecarboxamido) - Methyl 1-thio-Lthreo-D-galacto-octopyran08idee.



  The cis and trans epimers used as starting materials in the previous example were prepared in the following manner.
 EMI32.2
 B. 4-Butylidene-1-carbobenzoxy-L-proline and its cyclohemylamine alone, ¯-.



   Sodium hydride (19 g) in the form of a 53% suspension in mineral oil is heated with 350 ml of dimethyl sulfoxide at a temperature of 70-75 C until the reaction is complete. total (about 30 minutes). After cooling to 30 ° C., 16.2 g of butyl bromide are added. triphenyl phosphonium and the resulting reaction mixture is stirred for 1 hour to ensure complete reaction. A solution of 26 g of 4-keto-1-carbobenzoxy-L-proline in 100 ml of dimethyl sulfoxide is added and the resulting reaction mixture is heated at 70 C for 3 hours. The reaction mixture is cooled to 25 ° C. and 1 liter of a 2.5% aqueous solution of potassium bicarbonate is added thereto.

   This mixture is washed twice with 700 ml portions of ether and then the ether is discarded after exhaustion with 150 ml of a 2.5% aqueous solution of potassium bicarbonate. The bicarbonate solutions are combined and acidified with 4N hydrochloric acid. The acidified mixture is extracted with 4 portions of 500 ml of ether. The combined ethereal extracts are washed successively with 250 ml of water, 3
 EMI32.3
 250 ml portions of aalutian: aqueas, sodium bisulfite aturde and 250 ml of au, then dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo gives 24 g of an oily residue which is 4-butylidene-1-carbobenzoxy-L-proline.



   This residue is dissolved in 31 ml of acetonitrile and treated with 18 ml of dicyclohexylamine, then refrigerated. Screams-; rates are collected, washed with acetonitrile and dried

 <Desc / Clms Page number 33>

 vacuum-packed, giving 21 g (46.8%) of crystalline dicyclobexylamine salt, melting at 136-140 C.

   After 2 recrystallizations from acetonitrile, an analytical sample is obtained which
 EMI33.1
 melts at 142-144ec and has an L57D rotation. -4 '(c -0.99, CEÇ1 Analysis Calculated for C29H44N2O4 Ci. 71.861 H: 9.15; N: 5.78
Found Ci 71.69; H; 9.30 N: 5.74
 EMI33.2
 10 g of the dicyclohexylamine salt of 4-butylideno-1- @ carbobenzoxy-L-proline are shaken with ether and a 5% excess of aqueous caustic potassium hydroxide until no solid remains. The layers are separated and each is back washed.

   The aqueous alkaline layer is combined * with the backwash liquid from the ethereal layer and acidified with 4N hydrochloric acid. The mixture is repeatedly dissolved with ether and the ethereal extracts are combined, dried over sodium sulfate and evaporated in vacuo to give
 EMI33.3
 6.3 gr (93%) of 4-butylideno-1-carbbenzoxy-L-proline in the form of an oil.



  C. 4-butvl-1-carbobenzoxv-L-iM'oliM!
The oil from part B is hydrogenated in 200 ml of methanol over 2.1 g of a 10% platinum catalyst. of Dowex-1, under a pressure of 40 pounds of hydrogen. The catalyst is separated by filtration and the filtrate is evaporated to give 6.3 g of 4-butyl-1-carbobenzoxy-L-proline in the form of an oil. The product contains about 2 parts of cis-4-butyl-1-carbobenzoxy-L-proline for each part of trans-4-butyl-1-carbobenzoxy-L-proline.



   If desired, the hydrogenation of the 4-ylidene group can be delayed to any subsequent phase, even to the final phase, during the process.



   By substituting butyl triphenylphosphonium bromide in part B with other triphenylphosphonium bromides

 <Desc / Clms Page number 34>

 substituted, wherein the substituent is methyl, ethyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl dodecyl, tridecyl, tetradecyl :, pentadecyl, hexadecyl, heptadecyl,
 EMI34.1
 octadecyl, nonadecyl, and e1a08y1e and their isomeric forms, including clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-cyclopropylethyl, and 3-cyclopentylpropyl, benzyl,
 EMI34.2
 phenethyl, 3-phenylpropyl and 1-naphthyInethyl, 4alkylidene-, 4-cyaloalkyl3, dene- and 4-ara, kylidene-1-carboben $ oxyw are obtained.



    The corresponding L-prolines and the corresponding 4-alkyl-, 4-cycloalkyl-, and'4-aralkyl-1-carbobenzoxy-L-prolines. For example, when butyl triphenylphosphonium bromide is substituted by ethyl-, propyl =, isobutyl-, pentyl-, and hexyltri- bromides
 EMI34.3
 phenylphosphonium, one obtains -ethyl, .dne-1aarbobenztsy-proline, 4-propylidene-1-carbobenzoxy-L-proline, 4-isobutylidene "1-carbobenzoxy-L-proline, 4-pentylidene-l-carbobenzoxy-L-proline and 4-hexylidene-1-carboEenzoxy-L-proline, and cis and trans 4-ethyl-1-carbobenzoxy-L-proline, 4-propylZ-aarbob, enaaxxy-L-proli. ne, 4-inobutyl-1- carbobenzoxy-L-proline, 4-pentyl-1-carbobenzoxy- 'L-prolina and 4-hexyl-1-carboµbenxoxy-L-proline.



   D. Methyl 6-mino-6,8, -didesoxy-1-thio-D-erythro-a-D-galacto-octopyranoside ([alpha] -MTL)
A solution of 40 g of the free base of lincomycin (US Patent No. 3,086,912) in 20 ml of hydrazine hydrate (98-100%) is refluxed for 21 hours = the excess hydrate is separated. hydrazine under vacuum and nitrogen at a steam bath temperature, leaving a residue. The residue, which is a pasty mass of crystals, is cooled, acetonitrile is added and the mixture is stirred until that the crystals are in suspension. The crystals are collected on a filter, washed with acetonitrile and with ether.

   The yield of the white crystalline α-MTL free base, after vacuum drying at room temperature, is 21 g (84%). A re-

 <Desc / Clms Page number 35>

 crystallization is carried out by dissolving the free base of a-MTL in hot dimethylformamide and adding one volume
 EMI35.1
 equal to ethylene glycol dimethyl ether.



  Methyl 6-amino-6,8-dideoxy-1-thio-D-èrîthroa-D-galacto-octopyranoside free base has a melting point of 225-228 C, optical rotation of -7 25 a - ' -276 '' (c- - 0.768, water) and a pKa 'value of 7.45.
 EMI35.2
 Analysis: s Calculated for s C9Hl9NOSS 1
C: 42.71 H: 7.56; Ni 5.531 S: 12.66 Found: C: 42.6; H: 7.49; Ni 5.75; S: 12.38.



  By substituting lincomycin with other alkyls or
 EMI35.3
 cycloalkyl or aialkyl 6,8-dideoxy-6- (trana-1-methyl-4-propyl-L- 2-pyrrolidineaarboxamido) -1-thio-D-erythto-aD-qalacto-octopyrano- aids, in which the alkyl is @ ethyl, propyl, butyl, penty-
 EMI35.4
 hexyl, heptyl, octyl, nonyl, decyl, unddoyl, dodicyl, tridecyl, tetrad6cyl, pentadecyl, hexadecyl,: .eptadecyl, cetadecyl, nonad6cyl, and oicosyl ot their igomeric forms, if the cycloalkyl is cyclutyclopentyle-propocheobyl, cyclutyclopentyle-propocheobyl , cycloheptyl, cycloootyl, 2-methylcyclopehtyl, 2,3dimethylcycobuty1e :, 2-methylyclobutyl and 3-cyclopentylpropyl, and aralkyl is:

   benzyl, phenethyl, 3-phenylpropyl and 1-naphthylmethyl, one obtains the alkyl, cycloalkyl and aralkyl 6-amino-
 EMI35.5
 Corresponding 6,8-dideoxy-1-thio-D-erythro-α-D-galacto-octopyranosides. For example, substituting lincomycin with echyl-, propyl-, butyl-, pentyl- and hexyl 6,8-dideoxy-6- (trans-1-
 EMI35.6
 methyl-4-propyl-L-2-pyrrolidinecarboxamido) 71-thio-D-drythro - aD-galacto-octopyranosides, we obtain ethyl 6-amino-6,8-dideoxy-1-thio-D-erythro-aD -galacto-octopyranoside, propyl 6-amino-6,8-
 EMI35.7
 didesoxy-1-thio-D-erythro'-aD-galacto-octopyranoside, butyl. 6-aloino-6,8-dideoxy-1-thio-D-erythro-aD-galacto-Qctopyranoside, pentyl 6-amino-6 , 8-dideoxy-1-thio-D-erythro-aD-galacto-çctopyranoside and heàyl.

   - amino-6, 8-dideoxy-1-thio-D-erythro-o-D-galacto-octo-

 <Desc / Clms Page number 36>

 pyranoside.



   If desired, the method of part A can be applied to the compounds of paragraph D using hydrochloride or another salt of a strong acid, the resulting 7-chloro compounds being treated by the following steps of this example. to arrive at the end products of said example.
 EMI36.1
 



  2. 6,8-dideoxy-6- (1-carbobenzoxy-4, -b, tyiL-2-pyrrolidinecarboxamido) -1-thio-D-erythrolfi-D- '' 'free base
 EMI36.2
 
 EMI36.3
 To a solution of 6.3 g of 4-butyl-1-carbobentoxy-Lproline (the oil of the parts) in 175 ml of diotillated acetonitrile cooled to 0, 3.46 ml of triethylamine are added, then 3.34 ml of isobutyl chloroformate. The mixture is stirred, C (plus or minus 3) for 15 minutes, A solution of 6.2 g of the free base of α-MTL from part C in 85 ml of water is added and the mixture is stirred. reaction at 0 C for half an hour, then at 25 C for 1 hour.

   The reaction product is then filtered and dried to give 4.57 gr (37.7%) of the free base of 6,8-dideoxy-6- (1-carbobenzoxy-4-butyl-L-2-
 EMI36.4
 methyl pyrrol.dinecarboxamido) -x-thio-D-rhythro-a-D-galacto-octopyranodis, the miqueur-m @ re is concentrated under vacuum and an additional 4.25 g (35.2%) of product are recovered. Recrystallization from acetonitrile gives crystals of the
 EMI36.5
 Methyl 6,8-dideoxy-6- (1-carbobonzoxy-4-butyl-L-2-pyrrolidinecarboxamido) -l-thio-D-erythro-aD-galacto-octopyranoside free base, melting at 194-196 vs.

   A second recrystallization from acetonitrile gives an analytical sample, with a

 <Desc / Clms Page number 37>

 
 EMI37.1
 melt of 195.5-200 ° C, having an L ** '<-111' (c - 0.98, MeOH). Analysis @ Calculated for C26N40N2O8S
 EMI37.2
 Cs 57.75; fis 7.46? , Ni 5.131 as 5.93 Finds Ci 57.581 and 7.161 rds 5.50 ?.

   Si 6.07 F, 6,8-dideoxy-6- {4-butyl-L "2-pyrrolidinecarboxamido) -1-thio-D-erythro-a-D-galacto-octopyranoside hydrochloride,
 EMI37.3
 A solution of 7.8 g of the free base of 6,8-dideoxy-
 EMI37.4
 Methyl 6- (1'-carbobenzoxy-4-butyl-L-2-pyrrolidinecarboxamido) -1-thio-D- erythro-aD-galacto-octopyranoside coming from part E in 200 ml of methanol is shaken on two gr d 'a catalyst of 10% palladium on charcoal, under a pressure of
40 pounds of hydrogen for 17 hours. The catalyst is separated by filtration and the solution is concentrated in vacuo. The residue is dissolved in a mixture of 20 ml of acetone and 20 ml of water,. then it is acidified with 6N hydrochloric acid.

   A dilu-. tion with 4 volumes of acetone precipitates 6,8-dideoxy-6- (4-butyl-L-2-pyrrolidinecarboxamido) -1-thio-D-erythro- hydrochloride
 EMI37.5
 Methyl a .- 'D-galacto-octopyranoside which is collected by filtration and dried. The crystals, dried at 55 under vacuum, set 4.7 g and melt at 188-194 C. The analytical sample obtained by recrystallization from acetone melts at 197-199 * C and has a value - 725 ¯ +150 (water, c: 0.89).
 EMI37.6
 



  Analysis s Calculated for s C18Fi34zSïZ065.HC1
 EMI37.7
 . Ci 48.80; H:?, 96; Ni 6.32s Si 7.24 Found: (corrected for 5.54% water)
Cs 48.58; H: 8.191 N: 6.04; Si 7.36

 <Desc / Clms Page number 38>

 
This material has 8% of the antibaoteric activity of lincomycin in the 8-via assay. Lutea.



   By substituting the [alpha] -MTL by other alkyl or cyclo-
 EMI38.1
 alkyl or aralkyl 8-aminv-6, 8 āidéaoxy-lthio-Décythro-ai-galaotc-octanopyranosides, in which the alkyl is: ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl., nonyl, decyl,, undé ... cyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl and their isomeric forms;

   cycloalkyl is 1 cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloootyl, 2-methylcyclo-
 EMI38.2
 pentyl, 2,3-dimethylcyclobutyl, 2-methylcyclpbutyl and 3-cyclopentylpropyl; and aralkyl is, benzyl, phenethyl, 3-phenyl-
 EMI38.3
 propyl, and 1-naphthylm6thyle, one obtains the alkyl, cycloalkyl and aralkyl 6,8-dideoxy-6- (1-carbobenzoxy-4-butyl-L-2-pyrrolidineaarboxamidoj-1-thio-D-drythro-cs-D- galaato-octopyranodides and the corresponding alkyl, cycloalkyl and aralkyl 6,8-dideoxy-6- (4 butyl-L-2-Pyrrolidinecarboxamidp) -1-thio-D-6rythro-aD-galacto-octopyranosides.

   For example, by substituting α-MTL with ethyl, propyl, butyl, pentyl and hexyl 6-amino-6,8-deoxy-1-thicD-erythro-αD-galacto-octopyranceide4, ethyl 6,8didësoxy is obtained. .- (1-carbobsnzoxy-4-butyl.-2-pyrrolidinecarboxamido-D erythro-aD "'galacto-, ctopyranoside, propyl Cs, 8-dideoxy-fi-1-carbobenzoxy-4-butyl-L-2-pyrrolidinecarboxanddo) -1-thio-D-erythro-a "D-galacto-octopyranosida;

   butyl 6 <8-dideaoxy-6- (1-carbobenzoxy-4 * 'butyl-L - pyrrol.dinecarboxamidoa-1-thia D-erythro-cx-D-gaiacto-. octopyranoside, pentyl 6,8-didezoxy-6 -CI-carbobonzoxy-4-butylL-2-pyrrolidinecarboxamido) -1-thLo-o-erythro-oD-galacto-octopyra noside, hexyl 6,8-dïddsoxy - (1-carbo'benxoxy - butyl-Lx-Pyrrolidinecarboxamidoj -I-tho-D-erythro-ct-D-galacto-octopyranosidee ethyl 6,8-diddsoxy-6- (4-butyl-L-2-pyrrolidinecarboxàmido) -1-thio D-erythro-aD-galacto-octopyranoaide, propyl 6,8-dideoxy-6- (4- butyl-L-2-pyrrolidinecarboxamido) -1-thio-D-erythro-aD-galacto-

 <Desc / Clms Page number 39>

 
 EMI39.1
 octopyranoside, butyl 58-didsoxy- (butyl-L-2-pyrrolieiaeGar hoxamidoj-1-thio-D-erythro-aD-galaato octopyranoside, pentyl 6, 8-dideoxy-6- (4-butyl-L-2-pyrrolidinecàrboxamido) -1-thio-D- erythro-, -D-galaato-octopyranoside, hexyl 6,

  8didësoxy-5 = (4 butyl-L-2-pyrrolidineaarboxam3.do) 1-thio-D-erythro- n-galacto-octopyranoside corresponding, @
 EMI39.2
 These alkyl, cycloalkyl and aralkyl * thiolincoi3aminides @ are obtained by hydrazinolysis of S-alkyl, S-cycloalkyl and S-
 EMI39.3
 corresponding aralkyl S-demethyllincomycins which, in: their turn, are prepared by substituting the ethanethiol of preparation @ B-1 of Example 1 with other alkyl ercaptans, for example @ propyl, butyl, pentyl, hexyl , heptyl, octyl, nonyl, decyl,
 EMI39.4
 undecy1, dodecyl, tridecyl, tetraddcyl, pentadecyl, hexadgayl, heptadecyl, octadecyl, nonadecyl and eicosyl mercaptans and their isomeric forms;

   with cycloalkyl mercaptans, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
 EMI39.5
 cyclooctyl, 2-methylcyàopentyl, 2,3-dim4thylcyclobutyl, 2-methyl-cyclobutyl and 3-cyclopentylpropyl mercaptans; or by aralkyl mercaptans, for example benzyl, phenethyl, 3-phenylpropyl and 1-naphthylmethyl mercaptans. The alkyl, cycloalkyl and aralkyl 6,8-dideoxy-6- (trans-1-methyl-4-propyl-L-2-pyrroli-
 EMI39.6
 dinecarboxamido) -1-thio-D-erythro -D-galacto-octopyranosides corresponding.



   By substituting 4-butyl-1-carbobenzoxy-L-proline with other 4-alkyl-1-carbobenzoxy-L-prolines, in which the 4-alkyl is: ethyl, propyl, butyl, pentyl, hexyl, heptyl, acetabulum, nonyl, decyl, undecyl, dodecyl, tridecyl,
 EMI39.7
 tdtradecyl, pentadecyl, hexaddayl, heptad6cyl, octadecyl, nonadécyl and aicosyl and their isomeric forms by 4-cyolo-alkyl-1-carbobenzoxy-L-prolines, in which the 4-cycloalkyl is: cyclopropyl, cyclobutyl, cyclopxentyl, cyclohexyl, cyclo-
 EMI39.8
 heptyl, cyolooctyl, 2-methyloyclopentyleo 2,3-dimethylayclobu- '

 <Desc / Clms Page number 40>

 
 EMI40.1
 tyle, 4-mithyloyolobutyl and 3-cyolopentylpropylo and by 4-aralky3¯1-carbabenxoxy-L-prolines in which 4-axalkyl
 EMI40.2
 is:

   benzyl, phenethyl, 3-phenylpropyl, and 1-naphthylmethyl, we
 EMI40.3
 obtains the alkyl, oycloalkyl 'and aralkyl 6t8-diddsoxy-6- (l-carbobenzoxy - alkyl, 4-cycloalkyl, and 4-aralkyl-t-2-pyrrolidinacarboxamido) -1-thio-D-erythro - D-galacto -octopyranosides corresponding
 EMI40.4
 and alkyl, cycloalkyl and aralkyl-6- (4-alkyl, 4-cycloalkyl, 4-
 EMI40.5
 aralkyl-L-2-pyrrolidinecarboxamido) -1-thio-D-erythro- -D-galactooctopyranosides corresponding.

   For example, substituting the 4- µ
 EMI40.6
 butyl-1-carbobenzoxy -L-proline by 4-methyl-, 4-ethyl-, 4-pro
 EMI40.7
 pyl-, 4-pentyl-, and 4-hexyl-1-carbobenzoxy-1-polines, one obtains / the methyl, ethyl, propyl, butyl, pentyl and hexyl 6,8-didfiàxy-6-) (1-carbobenzoxy- 4-methyl-L-2 = pyrrolidinecarboxamido) -1-thÉlp-ery- thro "-D-galacto-octopyranosides, methyl, ethyl, propµ), butyl, 1
 EMI40.8
 
 EMI40.9
 pentyl and hexyl 6,8-dideoxy-6- (1-carbobenzoxy-4-ethyl-L-2¯pyrroli * l dinecarboxamido) -1-thio-D-erythro- -D-galacto-octopyranosidej3;

  methyl, ethyl, propyl, butyl, pentyl and hexyl 6,8-dideoxy-fi '
 EMI40.10
 

 <Desc / Clms Page number 41>

      
 EMI41.1
 (1-carbobenzoxy-4-propyl-L-2-pyrrolidinecarboxaôido) -1-thjo-D- erythro-aD-galacto-octopyranosidest the methyl, ethyl, pxopyl, butyl, pehtyl, and hexyl 6,8-dideoxy-6- (I-carbobenzoxy-4-pentyl- à-2-pyrrolidinecarboxamido) -1-thio-D-erythro-GD-galacto-octopy-, ranosidesi the methyl, ethyl, propyl, butyl, pentyl and hexyl 6,8dideoxy-6 - (1-carbobenzoxy-4-hexyl-L-2-pyrrolidinecarboxamido) -l-
 EMI41.2
 thio-D-erythro-a-D-galactc> -octopyranosides; methyl, ethyl, propyl, butyl, pentyl and hexyl 6, f-dideoxµl6- (4-methyl-L-2-pyirolidinecarboxamido) -1-thio-D-erythro-a-D-galacto-octopyranosides;

   the
 EMI41.3
 methyl, ethyl, propyl, butyl, pentyl and hexyl 6,8-dideoxy + 6- (4- ethyl-L-2-pyrrolidinecarboxamido) -1-thio-D-erythro-a-D-galacto-.
 EMI41.4
 octopyranosidosi methyl, 4thyl, propyl, butyl, pentyl and hexyl 6, 8didésaxy 6- (4prapyl-D wpyrrolidinacarboxam.do).-thioi7-erythrc-a-D-galactv-octopyranosidesr methyl, ethyl, propyl; butyl, pentyl and hexyl, 6,8-dideoxy-6- (4-pentyl-L-2-pyrrolidine-, carboxanido) -1-thio-D-erythro-aD-galacto-octopyranosidea and methyl, ethyl, propyl, butyl, pentyl, and hexyl 6,8-dideoxy-6- (4-hexyl-L-2-pyrrolidinecarboxamido) -1-thio-D-drythro-aD-galac-to-octopyranosides.



   If desired, the 1-carbobenzoxy compounds prepared according to part E can be chlorinated by the method of part A and the resulting 7-chloro compound can be treated by the following steps of this example to separate the 1-carbobenzoxy group and to substitute nitrogen for proline, in order to arrive at the end products of this example.
 EMI41.5
 



  Gl. Methyl 6,8-dideoky-6- (1-methyl-4-butyl-L- 2-pyrrolidinecarboxamido) -1-thio-D-erytÀro-a-D-ga-lactc-octopvranoside hydrochloride
 EMI41.6
 

 <Desc / Clms Page number 42>

 
 EMI42.1
 A solution of 2.0 g of 6,8-dideoxy- 6- (4..butyl-L-2-Pyrrolidinecaxboxamido -l..thio-D-erythro-cx..Dgalac-, to-octopyranoside methyl from part F and 2.0 ml of 37% formalin in 150 ml of methanol is shaken over 500 mg of a 10% palladium catalyst on charcoal under a hydrogen pressure of 40 pounds for 3 hours and deme. Separation of the catalyst by filtration and of the solvent by distillation.
 EMI42.2
 vacuum lation gives the hydrochloride of,

  -deoxy-6- (lmethyl-
 EMI42.3
 Partially crystalline methyl 4-butyl-L-2-pyrrolidinecarboxamido) -l-thio-D-erythro-aP-galactO-octopyranoside which by thin-layer chromatography on silica gel using a mixture of acetate ethyl, acetone and water (8/4/1) for elution and a solution of KMnO4 for detection is found to consist mainly of two materials, namely the cis epimers
 EMI42.4
 and 6,8-dideoxy-6- (1-methyl-4-butyl-L-2PYxrolidinscarbaxaaüda) -1-th3.cD-erythro-cc-Dwgaiactooctopyrnoside hydrochloride and trans in a ratio of approximately 3 to 2 .



   G2. Separation of cis and trans forms by chromatography
 EMI42.5
 Methyl 6, didecxy-6- (1-methyl-4-butyl-L- 2-pyrrolidinecarboxamido) -1-thio-D-erythro-oe-D-galacto-octopyra- noside hydrochloride from part Gl is dissolved in a mixture of methanol and methylene chloride (1/1) and 1.5 ml of triethylamine are added. To this solution, 7 g of a silica gel are added and the solvent is evaporated in vacuo, which leaves the antibiotic deposited. on silica gel, which is placed at the top of a chromatography column of 200 g of a silica gel stuffed with a solvent mixture consisting of ethyl acetate, acetone and water in a ratio from 8/4/1.

   The column is developed by elution with the same solvent and 20 ml portions are collected. Thin layer chromatography of each fraction shows that the fractions. 314 38 (310 mg)

 <Desc / Clms Page number 43>

 are the pure trans epimer, that fractions 49-74 (32 mg) are the essentially pure cis epimer, and that fractions 39-48 consisted of a mixture of the epimers. This mixture could be further separated by repeated chromatography. Each epimer is dissolved in a few drops of dilute hydrochloric acid and the hydrochloride is precipitated by adding acetone.

   In this way, 50 mg of hydrochloride are obtained.
 EMI43.1
 6,9-dideoxy-6- (trans-1-methyl-4-butyl-L2-pyrrolidinecarboxamido) - 1-thio-D-erythro-aD-galacto-octapyranoside gas-melting 135-137 'and about 150 mg of Methyl 6,8-dideoxy "6- (cisl-methyl-4-butyl-L-2-pyrrolidinecarboxamido) -l-thio-D-erythro-aD-galacto-octopyranoside hydrochloride, softening at 105 C with fusion at 175-185 C, the trans epimer recrystallized from the same: solvent melts
 EMI43.2
 at 139-141 C and lend the following analysis i 'Analysis 1 Calculated for C19F335Nx06S.HC1
Ci 49.931H: 8.16; Ni 6.131 Si 7.02 Found: (corrected for 4.07%.

   H2O)
 EMI43.3
 Cs 46.811 Ha 8.54t Ni 6.49; Si 6.67
Likewise, recrystallization of the cis epimer gives a product which softens at 108 C and again at about 189 C (solvation), with the following analysis t Analysis Found a (corrected for 4.95% water)
 EMI43.4
 Ci 50.27s and 9.00; Ni 6, OS, Si 6.65 ..



   The trans epimer is about 2.2 times as active as lincomycin in the S. lutea assay, it is about 2 times as active in the broth dilution assay, and it is 2.5 times as active in mice infected with S. aureus.



   The cis epimer is about 1/2 to 1/3 as active as the trans epimer, being about equal to lincomycin.

 <Desc / Clms Page number 44>

 
 EMI44.1
 



  Hl. 6,8-dideoxy-6- (1-ethyl-4-butyl t, -2..pyrro7.idinecarboxamidoa -.- thio-D-erythro-üD-galacto-o hydrochloride, methyl topy ranoside
 EMI44.2
 A mixture of 2.0 g of 6,8-deoxy-6-4 butyl-L-'2-pyrrolidinecarboxamido) -l-thio-P-erythro-a.-D-galaoto- 'octopyranoside methyl hydrochloride from part F, of 1.5 ml of acetaldehyde, of 150 mg of a catalyst of 10% palladium on charcoal in 150 ml of methanol is shaken under a pressure of 35 pounds of hydrogen for 5 and a half hours. The catalyst is filtered off to give a residue consisting mainly of the cis and trans epimers of 6,8- hydrochloride.
 EMI44.3
 Methyl didesoxy-6- (1-ethyl-4-butyl-L-2-pyrrolidinecarboxamido) -l-thio-D-erythi'o-a-D-galacto-'octopyranoide.



  H2. Separation te ".. 6r., M.



   As described, in part G2, the mixture of the epimers of part H1 (2 g) is chromatographed on 200 g of silica gel using, for the elution, a solvent system of ethyl acetate, of acetone. and water (8/4/1). Fractions 33-42 were found by thin layer chromatography to be pure trans epimer and they were combined, Fractions 49-64 were essentially pure cis epimer and were also combined.



  Fractions 43 to 48 constitute a mixture of epimers which '
 EMI44.4
 can be purified by chromatography. Each epimer is dissolved in a few drops of dilute hydrochloric acid. And the. Crystalline hydrochloride precipitates on dilution with a large volume of ether.



   The 415 mg crude trans epimer fraction gives. 340 mg (15.4%) of 6,8-dideoxy-6- (trans-1-ethyl-4- hydrochloride).
 EMI44.5
 butyl-L-2-pyrrolidinecarboxamido) -1-thio-D-erythro-a-D-galacto-ocotpyranoside crystalline, melting point 144-151 C.

   Recrystallization from dilute acetone raises the melting point to 148-151 C,

 <Desc / Clms Page number 45>

 The 645 mg epimer fraction gives 300 mg (14.1%)
 EMI45.1
 4o 6,8-dideoÀy-6 * (cis-1-ethyl-4-butyl-L-2-pyrrolidinecarboxamido) -l-thio-D-erythro-aD-galacto-octopyranoside hydrochloride crystalline, of fusion of 135-139 C. A recris-. Tallization in dilute acetone gives crystals with a melting point of 134-138 C.



   The trans epimer isomer shows about 1 to 1.2 times the activity of lincomycin in the titration against S. lutea, 2 to 4 times the activity of lincomycin against S. lutea. against organisms taking the gram and at most 8 times the activity of lincomycin against organisms not taking the gram.



  In mice, towards S. aureus, the trans epimer is (about 2 times as active as lincomycin. The cis epimer is about 1/2 as active as the trans epimer.



   Separation of the cis and trans isomers is not a necessary step because the 7-chloro derivatives of the mixed epimers are of interest in themselves. It is, however, desirable to
 EMI45.2
 maintain the tanner of the trans isomer at a high level since this is the most active form. By carrying out the process with this in mind, mixed epimeric products containing a ratio of trans epimer to cis epimer of 3/1 to 1/5 can easily be obtained.

   By replacing the formaldehyde and acetaldehyde of., Parts G and H with other oxo compounds of the formula R4R5CO, for example: prpionaldehyde, acetone, butyraldehyde, isobutyl methyl ketone, benzaldehyde, phenylacetaldehyde, hydrocinnamaldehyde, @ acetophenone, propiophenone, propiophenone, butyrophenone, 3-methyl-4-phenyl-2-
 EMI45.3
 butanont, 2-Methyl-5-phenyl-3-pentanone # 3-cyclopentanopropionaldehyde, cyclohexaneactalci, hy3e, oyalohe9tanecarboxaldehyde, 2,2dimethylcyclopropaneacetaldehyde, 2,2-dimethylethylyclopropyl methyl ketone, cycletone 'methyl-cyclone cyclone cyclohexanone and 4-methylcyclohexanone, and using;

   
 EMI45.4
 alkyl, cycloalkyl or aralkyl 6,8-Ùideoxy-6- (4-alkyl, 4-cyclo-

 <Desc / Clms Page number 46>

 
 EMI46.1
 amlyl-, or 4-aralkyl-L-2-pyrrolidinecarboxamido) -71-thio-D-drythro-. aD-galacto-octopyranosidos, suitable, one obtains the alkyl, cycloalkyl and aralkyl 6,8-cidôsacy-6- (1RRSCH-4-alkyl, 4-cyclo-alkyl-, and 9-aralkYl-D-2-pyrroli.âinscaxboxamido ) -Ithio-Drexytihxa
 EMI46.2
 
 EMI46.3
 corresponding o.-D-galac't.b-octopyranosides which, by treatment
 EMI46.4
 with thionyl chloride by the method of part A, give alkyl, cycloalkyl and aralkyl, 7-chloro-6,7,8-tridenoxy- '
 EMI46.5
 6- (1- R4R5CH-4-alkyl-, 4-cycloalkyl-, et'4-aralkyl <L-2-pyrrolidine- carboxamido) -1-thio-L-threo-aD-galacto-octopyranosid corxespon-, dants, in which RRSCh- is:

   propyl, isopropyl, buyl, and 4-meth 1-2-pentylei benzyl, phenetyl, 3-ph6nylpropyl, 1phenylethyl, 1-phenylpropyl, 1-phenylbutyl, 3-ethyl-4qhenyl-2-butyl, and 2-methyl-5- phenyl-3-pentylei 3-cyclopentylpropyl, 2-cyclohexylethyl, cycloheptylmethyl, 2- (2,2-di, Ymethylcyclopropyl) -ethyl, i- (2,2-dimethylcyclopropyl) ethyl, 1-cyclopentylethylethyl, i-cyciobutylethylj cyclobutyl, cyclohexyl and 4-methylcyylo-
 EMI46.6
 hexyl.

   Using formaldehyde and acetaldehyde or other
 EMI46.7
 very Albanian, for example propionaldehyde, butyxaldehyde,
 EMI46.8
 valeraldehyde or caproaldehyde with a 6,8-dideoxy-6- (4-
 EMI46.9
 alkyl-L-2-pyrrolifinecarboxamido) -1-thio-D-erythro-a-D-galacto-
 EMI46.10
 alkyl octopyranoside in which alkyl and 4-alkyl are
 EMI46.11
 methyl, ethyl, i, propyl, butyl, pentyl, or hexfl le, the preferred starting compounds of formula s
 EMI46.12
 

 <Desc / Clms Page number 47>

 wherein X represents the hydroxy radical R, HR1 and R3 represent an alkyl of not more than 6 carbon atoms, preferably of not more than 12 carbon atoms overall;

   and the configuration is that of D-erythro, are obtained and, by treatment with thionyl chloride by the method of part A, they give compounds according to the formula XXIX, in which X represents chlorine, R1 HR1 and R3 are an alkyl as defined above, and the %% configuration and that of L-threo. The 6,8-dideoxy compounds of formula XXIX, as characterized above, are active antibacterials comparable to lincomycin. The 7-chloro- compounds
6,7,8-Trideoxy of Formula XXIX, as characterized above, have the same spectrum of antibacterial activity but are significantly more active.

   Representative compounds of formula XXIX, where X is chlorine but which have the L-threo configuration, are given in the following table.

 <Desc / Clms Page number 48>

 BOARD
 EMI48.1
 
<tb>
<tb> Compounds <SEP> of <SEP> the <SEP> formula <SEP> XXIX, <SEP> in <SEP> laguelle <SEP> X <SEP> represents <SEP> the <SEP> chlorine
<tb> R <SEP> HR1 <SEP> R3
<tb> 4A <SEP> methyl <SEP> trans-ethyl <SEP> methyl
<tb> 4B <SEP> methyl <SEP> cis-ethyl <SEP> methyl
<tb> 4C <SEP> (7-chloro-7-deoxylincomycin) <SEP> methyl <SEP> trans-propyl <SEP> methyl
<tb> 4D <SEP> -7-chloro-7-deoxyallolincomycin) <SEP> methyl <SEP> cis-propyl <SEP> methyl
<tb> 4E <SEP> (7-chloro-7-deoxylincomycin <SEP> E) <SEP> methyl <SEP> .trans-propyl <SEP> ethyl
<tb> 4F <SEP> (7-chloro-7-deoxyallolincomycin <SEP> E)

   <SEP> methyl <SEP> cis-propyl <SEP> ethyl
<tb> 4G <SEP> ethyl <SEP> trans-propyl <SEP> methyl
<tb> 4H <SEP> ethyl <SEP> cis-propyl <SEP> methyl
<tb> 41 <SEP> methyl <SEP> trans-butyl <SEP> methyl
<tb> 4J <SEP> methyl <SEP> cis-butyl <SEP> methyl
<tb> 4K <SEP> methyl <SEP> trans-propyl <SEP> ethyl
<tb> 4L <SEP> methyl <SEP> cis-propyl <SEP> ethyl
<tb> 4M <SEP> ethyl <SEP> trans-propyl <SEP> ethyl
<tb> 4N <SEP> ethyl <SEP> cis-propyl <SEP> ethyl
<tb> 40 <SEP> methyl <SEP> trans-butyl <SEP> ethyl
<tb> 4P <SEP> methyl <SEP> cis-butyl <SEP> ethyl
<tb> 4Q <SEP> methyl <SEP> trans-pentyl <SEP> methyl
<tb> 4R <SEP> methyl <SEP> cis-pentyl <SEP> methyl
<tb> 4S <SEP> ethyl <SEP> trans-butyl <SEP> ethyl
<tb> 4T <SEP> ethyl <SEP> cis-butyl <SEP> ethyl
<tb> 4U <SEP> '<SEP> methyl <SEP> trans-pentyl <SEP>

  ethyl
<tb> 4V <SEP> methyl <SEP> cis-pentyl <SEP> ethyl
<tb> 4W <SEP> ethyl <SEP> trans-pentyl <SEP> methyl
<tb> 4X <SEP> ethyl <SEP> cis-pentyl <SEP> methyl
<tb> 4Y <SEP> methyl <SEP> trans-hexyl <SEP> methyl
<tb> 4Z <SEP> methyl <SEP> cis-hexyl <SEP> methyl
<tb> 4AA <SEP> butyl <SEP> transpropyl <SEP> methyl
<tb> 4AB <SEP> butyl <SEP> cis-propyl <SEP> methyl
<tb> 4AC <SEP> ethyl <SEP> trans-pentyl <SEP> ethyl
<tb> 4AD <SEP> ethyl <SEP> cis-pentyl <SEP> ethyl
<tb> 4AE <SEP> butyl <SEP> trans-butyl <SEP> ethyl
<tb> 4AF <SEP> butyl <SEP> cis-butyl <SEP> ethyl
<tb> 4AG <SEP> butyl <SEP> trans-pentyl <SEP> methyl
<tb> 4AH <SEP> butyl <SEP> cis-pentyl <SEP> methyl
<tb> 4Al <SEP> cyclohexyl.

   <SEP> trans-propyl <SEP> methyl
<tb> 4AJ <SEP> cyclohexyl <SEP> cis-propyl <SEP> methyl
<tb> 4AK <SEP> butyl <SEP> trans-pentyl <SEP> '<SEP> ethyl
<tb> 4AL <SEP> butyl <SEP> cis-pentyl <SEP> ethyl
<tb> 4AM <SEP> pentyl <SEP> trans-pentyl <SEP> ethyl
<tb> 4AN <SEP> pentyel <SEP> cis-pentyl <SEP> ethyl
<tb>
 
Intermediates for the preparation of the foregoing compounds correspond to the table above, where (1) X is the hydroxy radical; (2) R3 is hydrogen! (3) X is the hydroxy radical and R3 is hydrogen; (4) X is the hydroxy radical and R3 is the carbobenzoxy radical; (5) X is chlorine and R3 is carbobenzoxy radical;

   (6) X is the hydroxy radical, R3 is the carbobenzoxy radical, and HR1 and H in position 4 are replaced by

 <Desc / Clms Page number 49>

 the ylidene group, R1, (7) X is chlorine, R3 is the carbobenzoxy radical, and HR1 and H in the 4 position are replaced by the ylidene group, R1; (8) X is the hydroxy radical, R3 is hydrogen and HR1 and H in, position 4 are replaced by the ylidene group, R1;

   (9) X is chlorine, R3 is hydrogen, and HR1 and H in the 4 position are replaced by the ylidene group, R1, (10) X is the hydroxy radical, and HR1 and H in the posi- tion 4 are replaced by the ylidene group, R1; and (11) X is chlorine and HR1 and H in the 4-position are replaced by the ylidene group, R1 on the understanding that when X is the hydroxy radical its configuration is that of D-erythro and that when X is the chlorine, the configuration is, @ @ that of L-threo.



   When the lincomycin of part A of Example 4 is replaced by the free base of 6-amino-6,8-dideoxy-1-thio-D- @ erythro-aD-galacto-ocotpyranoside, alkyl, cycloalkyl or aralkyl, compounds of the formula are obtained:

   
 EMI49.1
 wherein R is ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl or any one of them isomeric, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cy- forms. cloheptyl, cyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclo-

 <Desc / Clms Page number 50>

 
 EMI50.1
 butyl, 2-methylyclobutyl and 3-ayclopentylpropyle benzyje, phenethyl, 3-phenylpropyl and 1-naphthylmethyl,

   which can be acylated by the methods of Example 4 to form the analogs
 EMI50.2
 of the corresponding chloro-7-deaogylinoomyoine, for example the * compounds of formula XXIX given previously, as well as the intermediates for these compounds. Example
 EMI50.3
 't-ohloro-6'i, w-trideoxy-6- (trarm -4-hutyl - 2-pyxrolidinecarboxamido) -1-thlo-L-thr60 - D-galacto-octopyrana.ide. methyl.
 EMI50.4
 A suspension of 116 mg of the stocking is stirred at 25 ° C.
 EMI50.5
 free of methyl 68-dideoxy-6- (trans-4-butyl-L-2-pyrrolidine- carboxamido) -l-thio-rl-erythro- -D-galacto-octopyranoside in 3 ml of carbon tetrachloride and 0.7 ml of thionyl chloride at 25 C until a clear solution is obtained (about 15 minutes) and the mixture is left to stand at 25 C for 2 hours.

   The reaction mixture is then heated under reflux for 2 hours and then evaporated to dryness under vacuum to give a yellow solid which is dried under vacuum at 40 ° C. for 18 hours. The product is then dissolved in about 15 ml of hot ethanol, made basic with caustic soda as in Example 1 and diluted to 300 ml with water. The aqueous solution was extracted 5 times with 100 ml portions of ether.

   We amass-

 <Desc / Clms Page number 51>

 if the ethereal extracts are dried over magnesium sulfate, filtered, saturated with hydrochloric gas and evaporated to obtain
 EMI51.1
 obtaining methyl? -chloro-6,?, 8-tridësoxy-6 (trag-4-butyl-L-2-pyrrolidinecarboxamldo) -l-thio-I '"threo" o (-D-galaoto-octopyranoside hydrochloride) as an amorphous tan solid, which has at least 8 times the activity of lincomycne.



   By substitution of the cis epimer, we obtain the
 EMI51.2
 7-Chloro-6,7,8-tridenoxy-6- (Cis-4-butyl-L-2pyrrolidinecarboxamida) 1-thio-L-threo-D (methyl a-galacto-oatopyranoside) hydrochloride, having the same antibacterial spectrum.



   The cis and trans epimers used as starting materials in the previous example were prepared as follows.
 EMI51.3
 



  B. - Methyl 6,8-dideoxy-6- (4-butyl-L-2pyxrolid: lnecarboxamido) 1-thio-D-erythro-ot-D-galacto-oatapvranoside hydrochloride is obtained by the method of Parts B to F of Example 4. If desired, the 1-carbobenzoxy compound prepared according to Part E of Example 1 can be chlorinated by the method of Part A of this Example and compound 7- resulting ohloro can be treated to separate the 1-carbobenzoxy group.



  C.- Separation of the cis and trans forms by chromatography.
 EMI51.4
 



  Methyl 6,8-diddsoxy-6- (4-butyl-L-2-pyrrolidinecarboxamido) -1-thio-D-erythro- -D-galacto-octopyranoside hydrochlorides of part S are dissolved in a mixture of methanol and methylene chloride (1/1) and 1.5 ml of triethylamine are added. To this solution, 7 g of silica gel are added and the solvent is evaporated off in vacuo, which leaves 1, the antibiotic deposited on the silica gel, which is introduced into the top of a chromatographic column of 200 g. of silica gel packed with a solvent mixture consisting of ethyl acetate, acetone and water in a ratio of 8/4/1. The column was developed by elution with the same solvent and 20 ml portions were collected. The fractions are monitored by thin layer chromatography.

   The fastest moving active fractions

 <Desc / Clms Page number 52>

 are mostly pure trans epimer, and the slower active moieties are mostly pure cis epimer. Each epimer is dissolved in a few drops of dilute hydrochloric acid and the hydrochloride is precipitated by addition of acetone, In this way, the hydrochlorides are obtained.
 EMI52.1
 of methyl 6,8-dideaoxy-6ttrana-4-butyl-2-pyrrol.dinecarboxamido- 1-thio-D-erythro- pD-galacto-octopyranoside and-of 6,8-dideoxy-6- (cia-4- butyï.-L - pyrroli $ inecarboxamido) -1-hio D-erythro- -0-galaoto-octopyranosidet EXAMPLE 6? -chloro-b ?, 8-tridësoxy-6- (trans-1-methyl-d-propy, -L- 2 "pyrrolidinecarboxamido) -1-thio-D-erythro- CC -D-galaoto-octopyranoside (methyl I-ohloro-7-deoxy-epilincomycin).



  A, 3,4-O-isoProPYlinenelincomvaine
 EMI52.2
 
 EMI52.3
 A solution of 9.8 g of lincamycin in 150 ml of acetone is added to a solution of 9.8 g of p-toluenesulfonic acid monohydrate in 100 ml of acetone, with good stirring, and avoiding exposure to humidity. The mixture is. stirred at room temperature for 1 hour, after which 100 ml of anhydrous ether is added and stirring is continued in an ice bath for half an hour. The mixture is filtered and the solid is dried in vacuo at 50.ci the yield is 13.35 g
 EMI52.4
 (85.5%) 3,4-0-isopropylideneincomycin p-toluenesulfonate.

   A further 1.15 g (7.4%) can be recovered from the mother liquors by adding 350 ml of anhydrous ether to the mother liquor from the previous filtration run and re @.

 <Desc / Clms Page number 53>

 cooling the solution for 1 hour. The 14.5 gr thus Obtained!
 EMI53.1
 . were suspended in 200 ml of ether and shaken vigorously with 125 ml of a 5% solution of potassium bicarbonate. The aqueous layer was redrawn with 2 portions of 100 ml of ether.
 EMI53.2
 The ethereal extracts are washed with 50 ml of a ** killed sodium chloride solution and then filtered through anhydrous sodium sulfate.

   The ether is evaporated in vacuo, leaving
 EMI53.3
 7.9 gr (73.1%) of 3,4-t7-isopropylidènelincomycïne which is dissolved in 25 ml of ethyl acetate and which is concentrated to about 10 to 15 ml. The concentrate is allowed to stand at room temperature for several hours and then refrigerated overnight. The crystals are filtered from the solution and washed lightly with cold ethyl acetate; the yield is 4.55 gr (42.2%) 'of 3,4-0-isopropylidene incomycin having a melting point of 126-128 C and an optical rotation of
 EMI53.4
 g75 - 101-102 '(e: 1, methylene chloride).



  B. 7-dehydro-3,4-0-isopropylidènelincomycin To a solution of 6 g (0.0135 mol) of isoprapylidene-lincomycin in 75 ml of pyridine, 12 g (excess) of oxy are added; chromic. The solution warms up to about 20 C. After 1 hour, the mixture is added to a solution containing 250 ml of ethyl ether and 250 ml of ethyl acetate. It is then filtered and evaporated to a syrup of 8.4 g. This syrup is distributed in a countercurrent distribution at 500 transfers, using
 EMI53.5
 the water / ethyl acetate / ethanol / cyclohexanone (1/1/1/1) system. 7-Dehydro-3,4-O-isopropylidénelinaomycije was isolated as the peak fraction from tubes 330-380r K, 45.

   Analysis 1 Calculated for C31H36N2O6S:
 EMI53.6
 Ce 56.72 Et 8.16t Nt 6.301 81 7.21 Found s Cs 56.371 -Et 7.62 # Na 6, S11 St 6.84.

 <Desc / Clms Page number 54>

 
 EMI54.1
 



  C..3., 4 # isooroovlidéna = µD $ lin.comsheath A 1.6 gr of -dhydro-3, 4-isoprcpy.dnel3nttocyaine. pure (Craig) in 75 ml of methanol, 400 mg of sodium borohydride are added. After 1 hour and a half, this solution is evaporated to dryness on a rotary evaporator. The residue is added to 25 ml of water and extracted 3 times with 25 ml of methylene chloride. The extract is washed back with 15 ml of water, then dried over magnesium chloride and evaporated to dryness. The residue, (1.4 g) is distributed in a countercurrent distribution at 500 transfers, using the water / acetate solvent system.
 EMI54.2
 drethyl / 6thanol / cyclohexane (1/1/1/1), and a simple maximum is observed which corresponds to theory at the value K = 1.05.

   The material in tubes 240 to 280 is isolated as a syrup.



    Analysis! Calculated for C21H38N2O6S
 EMI54.3
 Ca 56.47; And 8.50; Nt 6.27; Si "lys Found s Ci 56.241 Hi 8.541 Nt 6 # 13; Si 7.01
Thin layer chromatography shows that this material consists of two substances. One is 3,4-0-isopro-
 EMI54.4
 pylideneincomycin, while the other, which is 3,4O-isopro pylidene-epilincomycin, moves 16generally more slowly.



    D. Epilino @ mycine
The syrup from part C is stored at room temperature for 5 hours in a solution containing 60 ml of 0.25N hydrochloric acid and 40 ml of ethanol. It is then stored at 0 ° C. for 4 days. After neutralization with sodium bicarbonate, it is evaporated to 25 ml, then extracted with chloroform. The extract is washed with a little water and dried over magnesium sulphate, then it is evaporated until a residue is obtained. Thin layer chromatography of the residue shows two substances, both of which are active against S. lutea.

   The residue is chromatographed on a column of Florisil 14 inches x 3/4 inch (synthetic silicate of

 <Desc / Clms Page number 55>

 
 EMI55.1
 type described in U.8.A, n * .3g3.825), which is studied by gradient with a solvent which varies continuously from 100% SkellysolveB (technical hexane) to 100% acetone * The total volume this of 5000 ml. The two compounds are then separated.



  Fraction 1 Tubes 53-65 (40 ml sections); Epilincomycin, Titration: 450 mcg / m1.
 EMI55.2
 



  Analysis R Calculated, for C18N34N2O6 Ct 50.92, Ri 8; 551 Nt 6.601 Si 7.56 Found 1. CzSO, 19t Et ', 91t Nt 6.051 St 6.42, Fraction 11s Tubes 73-104. Lincomycin
Titration: 950 mcg / mg.
 EMI55.3
 



  2., I-é, iCh10r0 -? -. D $ oX3.inaO.vc.nesFC1,
 EMI55.4
 
7-Epilincomycin hydrochloride (0.85 g) is suspended in 17 ml of carbon tetrachloride, thlonyl chloride (4.5 ml) is added and the reaction mixture is stirred at 25 for 15 minutes. The solid dissolves to give a clear colorless solution. The reaction is then refluxed for 2 hours, then cooled to 25 and evaporated in vacuo to give a yellow solid residue. This crude product is dissolved in 10 ml of ethanol, made basic with 0.1 N caustic soda, diluted to 500 ml with water and extracted 4 times with 50 ml portions of chloroform.

   The extracts

 <Desc / Clms Page number 56>

 with chloroform copbines are washed back twice with 20 ml portions of a saturated solution of sodium chloride, then filtered and evaporated in the vacuum. The solid residue is slurried with 500 ml of ether, then filtered and hydrogen chloride gas is passed through the filtrate. The solid precipitate is recovered, dissolved in 3 ml of ethanol and reprecipitated by the addition of ether.



   The solid is collected and dried. A production of 30% (270 mg) of 7-epichloro-7-deoxylincomycin having about 2-3 times the activity of lincomycin is obtained. Thin layer chromatography on silica gel (MeOH system: CHCl3,
1/6 v / v) shows a spot having an Rf value of 0.44, compared to an Rf value of 0.52 for 7-chloro-7-deoxylincomycin.



   By replacing lincomycin in this example with the lincomycin analogs of formula II in which Z, R, R1,
R2, R3 of the Ac group are as given above, we obtain the corresponding 7-chloro-7-deoxyepilincomycin analogs of the formula:
 EMI56.1
 in which Z, R, R1, R2 and R3 of the group Ac are as given and illustrated above.

   All the compounds which have been described above have, consequently, their counterpart in the opposite configuration, that is to say the configuration deriving from the 7-epi form @ or when an inversion is carried out by the substitution of the group 7-hydroxy by chlorine, the epi compounds which have the con-

 <Desc / Clms Page number 57>

 L-threo figuration are then inverted to the D-erythro configuration. In this way.;. the two forms D @ erythro and L-threo are obtained depending on whether normal lincomycins (D-erythro) or epilincomycins (L-threo) are used.



    EXAMPLE 7.



   7-Chloro-7-deoxylincomycin hydrochloride.



   We stir and we heat! lincomycin hydrochloride (10 g; 0.0226 mol), 200 ml of carbon tetrachloride and 10 ml of SOC12 were refluxed for 4 hours, the reaction mixture was cooled to 25 ° C. and filtered. The yellow solid is dried in vacuo and then dissolved in 10 ml; about boiling ethanol. Ethyl acetate is added until cloudiness is obtained and the solution is allowed to cool. The crystals of 7-chloro-7-deoxylincomycin hydrochloride thus formed are recovered in a yield of approximately 43%.



   Although the methods of the invention have been described with reference to the preparation of specific compounds, it should be understood that the method is broadly applicable to compounds of formula II, wherein Ac and R are radicals which do not. are not reactive with thionyl chloride.

   Thus, in general, according to the present invention, Ac can be hydrogen or any acyl which is not reactive with thionyl chloride, and R can be any alkyl, regardless of the number of carbon atoms, or any other radical, for example aralkyl, such as benzyl, naphthyl methyl, and benzydryl, or any unreactive hydrocarbon radical with thionyl chloride.

** ATTENTION ** end of DESC field can contain start of CLMS **.

 

Claims (1)

'CLAIMS 1. A compound of the formula: <Desc / Clms Page number 58> EMI58.1 wherein R is an alkyl of 20 carbon atoms at the most and Ac is the acyl radical of an L-2-pyrrolidinecarboxylic acid substituted in position 4 of the formula selected from the group consisting of t EMI58.2 formulas wherein R1 and R2 are selected from the group consisting of 20 atom alkylidene. of carbon at most, cyclealkylidene of 3 to 8 carbon atoms at most, and aralkylidene of at most 12 carbon atoms, and R3 is selected from the group consisting of hydrogen and HR2. 2. A compound of the formula: EMI58.3 <Desc / Clms Page number 59> wherein R, HR1 and HR2 are lower alkyl. . . 3. A compound according to claim 2, wherein R is methyl, HR1 is propyl and HR2 is methyl! 4. A compound according to claim 2, wherein Rest is methyl, HR1 is propyl and HR2 is hydrogen. 5. A compound according to claim 2, wherein R is methyl, HR1 is propyl and HR2 is ethyl. 6. A compound according to claim 2, wherein R is 1ethyl, HR1 is propyl and HR2 is methyl, 7. A compound according to claim 2, wherein R is ethyl, HR1 is propyl and HR2 is hydrogen. 8. A compound according to claim 2, wherein R is ethyl, HR1 is propyl and HR2 is ethyl. 9. A compound according to claim 2, wherein R is propyl, HR1 is propyl and HR2 is methyl. 10. A compound according to claim 2, wherein R 1 is propyl, HR1 is propyl and HR2 is hydrogen. 11. A compound according to claim 2, wherein R is propyl, HR1 is propyl and HR2 is ethyl. 12. A compound according to claim 2, wherein R is butyl, HR1 is propyl and HR2 is methyl. 13. A compound according to claim 2, wherein R is butyl, HR1 is propyl and HR2 is hydrogen. 14. A compound according to claim 2 wherein R is butyl, HR1 is propyl and HR2 is ethyl, 15%. A compound according to claim 2, wherein R is methyl, HR1 is pentyl and HR2 is methyl, 16. A compound according to claim 2, wherein R is methyl, HR1 is pentyl and HR2 is hydrogen. 17. A compound according to claim 2 wherein R is methyl, HR1 is pentyl and HR2 is ethyl. 18. A compound according to claim 2 wherein R is methyl, HR1 is butyl and HR2 is methyl. ' <Desc / Clms Page number 60> 19. A compound according to claim 2, wherein EMI60.1 . ro is methyl, lm 1 is butyl and HR2 is hydrogen, 20.A compound according to claim 2 wherein R is methyl, HR1 is butyl and HR2 is ethyl. 21. A compound according to claim 2, wherein R is ethyl, HR1 is butyl and HR2 is methyl. 22. A compound according to claim 2, wherein R is Methyl, HR1 is butyl and HR2 is hydrogen. 23. A compound according to claim 2, wherein R is ethyl, HR1 is butyl and HR2 is ethyl. 24. A compound according to claim 2, wherein R is propyl, HR1 is butyl and HR2 is methyl. 25. A compound-6 according to claim 2, wherein R is propyl, HR1 is butyl and HR2 is hydrogen, 26. A compound according to claim 2, wherein R is propyl, HR1 is butyl and HR2 and ethyl. 27. A compound according to claim 2, wherein EMI60.2 R is butyl, HR 1 is butyl and HR2 is methyl. 28. A compound according to claim 2, wherein R is butyl, HR1 is butyl and HR2 is hydrogen. 29. A compound according to claim 2, wherein R is butyl, HR1 and butyl and HR2 is ethyl. 30. A compound according to claim 2, wherein R is cyclohexyl, HR1 is butyl and HR2 is methyl. 31. A compound according to claim 2, wherein R is cyclohexyl, HR1 is butyl and HR2 is hydrogen. 32. A compound according to claim 2, wherein EMI60.3 R is cyclohexyl, HR1 is butyl and HR2 is gethyl. 33. 7-Chloro-7-deoxylincomycin 34. 7-Chloro-6,7,8-.trideoxy-6- (trans-1-ethyl-4propyl-L-2-pyrrolidinecarboxamido) -1-thio-L- Methyl threo-oD-qalacto-oc-topyranoside. <Desc / Clms Page number 61> EMI61.1 Methyl 7-QhlOrO-6,78-tri4'.oxy-ttan'-1-'thYl-i-butYl-> 2mpyrnolidinouarbuxamido) 1-thiu-L-threo-a-D-qalaatomoctppyranouide. 36. Methyl 7chlorO-6,7, -trid68oxy * 6 (tran8-1-meth²1-.butyl-> 2-pyirolidineoaiboxamido) -1-thio-p-threo-a-D-galacégioc-topyranoside. EMI61.2 37.? -Ch.oro-6,?, 8-trideso-6-tran $ -1methyl4-pen- EMI61.3 methyl i - pyxrol, dinecarboxamido) -1-thio - thro-a D-galacto bto- pyranoid. EMI61.4 38. Le7-chloro-67r8-.daoxy-6-txans1dthyl.4-pentyl-L-2-pyrrolidinecarboxamido) -l-thic-L-thr6o.a-b-galacto.octc.- methyl pyranoside 39. The process for preparing the compounds of the formula EMI61.5 EMI61.6 in lague3e R and Ac are as defined above; comprising the reaction phase of a compound of the formula EMI61.7 <Desc / Clms Page number 62> with thionyl chloride at a temperature effective to replace the 7-hydroxy group with chlorine, R and Ac being * radicals which are not reactive with thionyl chloride, 40. A process according to claim 39 wherein R is alkyl and Ao is acyl unreactive with thionyl chloride. 41. A process according to claim 39, wherein R is alkyl and Ao is HX.H, wherein HX is a strong acid. 42. A process according to claim 39, wherein R and Ac are as defined in claim 1. 43. A process for the preparation of lincomycin D and its analogs and isomers which comprises reacting a compound of the formula EMI62.1 wherein R and R @ represent an alkyl of 20 atom. of carbon at most, cycloalkyl of 3 to 8 carbon atoms at most or aralkyl of at most 12 carbon atoms, and is a protective group removable with thionyl chloride at a temperature effective to replace the 7- group. hydroxy with chlorine to form a compound of the formula <Desc / Clms Page number 63> EMI63.1 wherein R, R1 and z have the above meaning, and the removal of the group z to form a compound of the formula: EMI63.2 wherein R and R1 are as provided above. 44. New products and processes, such as EMI63.3 or1ts.g1dessus, in particular in the examples given.