IL33548A - Galactopyranosides as lincomycin intermediates - Google Patents

Description

GALACTOPYRANOSIDES AS LINCOMYCIN INTERMEDIATES T'-fPTfa^ may a»»i»a »τοη oa»ire Β»Τ»ΟΤ¾ΚΊ»Β¾Ρ^Κ¾ The present invention relates to novel processes for the production of certain octopyranosidee which are useful as intermediates in the preparation of lincomycin and isomers and analogues thereof; and to certain octopy-ranosides compounds and intermediates produced thereby.

In particular the invention relates to processes for the preparation of 6-»amino—6»8-dideoxy-I-erythro or L-threo-D-galacto-octopyranose compounds of the general formulas wherein R2 and are hydrogen or alkyl of not more than 12 carbon atoms and wherein Y is hydrogen, S-alkyl of not more than 12 carbon atoms, or 7 30H^CH20R, wherein R^ is as previously defined.

Hovel compounds and intermediates produced thereby have the general formulae: 0H5 and aoid addition salt forms thereof, wherein K2'¾ are as defined abovej and acid addition salt forms thereof* wherein is alkyl of not more than 12 carbon atoms, OHLCH^OH or CH^CH^OR^, wherein R^ is alkyl of not more than 12 oarbon atoms) wherein R. is as above defined. and aold addition salt foms thereof, wherein R^and are as defined above and is aliyl of from 3 to not more than 12 carbon atoms> and acid addition salt forms thereof, therein is as defined above? wherein Ac ie alkanoyl or aralkanoyl of not more than 12 carbon atoms.

Compounds having the general formula I above are useful in the preparation of lincomycin and isomers and analogues thereof which process is described and claimed 23907 from which this ..application was ,; divided ou in our copending application No/.2980265 SeriaiJla*_J^JJ-S^QS.).

Examples of alkyl of not more than 20 carbon atoms are methyl,ethyl,propyl,butyltpentyl,hexyl,heptyl,octyl,nonyl, decyl,undecyl,dodecyl#tridecyl,tetradecyl,pentadecyl,hexadeeyl, heptadecyl,octadecyl,nonadeeyl,and eicosyl and the isomeric forms thereof, Examples of cyloalkyl are cyclopropyl, cyclofutyl, cyclopentyl, cyclohexyl,cycloheptyl,cyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclobutyl,4-me hyl-cyclobutyl, and 3-cyclopentylpropyl. Examples of aralkyl are benzyl, phoiiethyl, et-phenylpropyl, and a-naphthylmethyl.

The compounds of Formula I can be obtained in a variety of ways.

Thus according to the present invention there is provided a process which comprises removing the Ac group from a compound having the general formulas wherein Rg and are hydrogen or alkyl of not more than 12 carbon atoms, Y is hydrogen, S-alkyl of not more than 12 carbo atoms or SOH^GH^OR^ wherein is as above defined and Ac is aoyl of the general fonnula: wherein R is alkyli&eae- of not more than 20 carbonfrfcoms, cycloalkylddene of 3 to not more than 8 carbon atoms or aralkyl-ideiie of not more than 12 carbon atoms, is hydrogen, alkyl of not more than 20 carbon atoms, cycloalkyl of 3 to not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms by hydraainolysis to form a compound of the general formulas wherein Rg, and Y are as defined above.

Also the invention provides a process which comprises removing the Ac group from a compound having the general formulaϊ wherein ¾2 is alkyl of from 5 to not more than 12 carbon atoms, JBHgCHgOH or is alkyl of not more than 12 carbon atoms and Ac is alkanoyl, aralkanoyl of not more than 12 carbon atoms or acyl of the general formul wherein 2 is a protective hydrocarbyloxycarbonyl group which is removable by hydrogenolysis, R is alkylidese- of not more than 20 carbon atoms, eycloalkylideae of 3 to not more than Θ carbon atoms or aralkylidene of not more than 12 carbon atoms and is hydrogen†alkyl of not more than 20 carbon atoms, cycloalkyl of 3 to not more than 8 carbon atoms, or aralkyl of not more than 12 carbon atoms by hydrazinolysis to form a compound having the general formula;: HO wherein R^2 is as defined above.

The hydrazinolysis advantageously is effected by heating the antibiotic under reflux with an excess of hydrazine, say for 20 hours or more. The desired 6-amino-*&UIO 6,8-dideoxy-l-thio-D-erythro-a-3-galacto-octopyranoside can be isolated by distilling off the excess hydrazine and crystallising from a pcLar solvent such as ethanol.

Other 6-amln.o-6,8-dideoxy-l-thic .D-erythro-a-3-galacto-octopyranosides and starting materials can be prepared by the following representative sequences? Ac is alkanoyl or aralkanoyl of not more than 12 carbon acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, and the isomeric forms thereof, and benzoyl, phenylacety 1 , 5-pheny lpropionyl , -phenylbutyryl , -phenyl aleryl and the isomeric forms thereof.

The process is effected as follows: Methyl a-thlolinco- saminide is N-acylated, the methyl N-acyl -α-thiol incosaminlde (IX) then O-acylated with thiobenzoyl chloride, and the resulting thiobenzoyl ester (X) is brominated to form compound Xl which on treatment with a base is converted to compound XII. Treatment of compound XII with mild alkali (aq. carbonate -bicarbonate) gives compound XIII which on alkylation with an alkyl halide yields compound XIV.

Hydrolysis of the benzoyl and thiobenzoyl groups and hydra-zinolysis of the N-acyl group gives compound 11 lb. In a like manner compounds in which Y is 2-hydroxyethyl or 2-alkoxyethyl can be prepared by reacting compound XIII with ethylene ch lor hydrl n or a 2 -a Ikoxyethy 1 hal I de. . wherein R and are as given above and Z is a protective hydrocarbyloxycarbonyl group which is removable by hydrogenolysis* can be alkyl of 3 to not more than 12 carbon atoms, or ^^ΟΒ^ΟΗ^ΟΗ^ wherein is as given above.

The starting compound, A, is dissolved in water as a soluble salt, e.g, , the hydrochloride, and bromine is added with cooling, advantageously to between about <-10 and 20°C.

A satisfactory procedure is to cool the aqueous solution to abou^o e. and the bromine la added dropKiae, The stoichiometric amount of bromine is 1 mole for each mole of stating compound, though more or less can be used.

Advantageously a slight excess, say from 5 to 20f° excess, of bromine is used. The thloglycoside is thus converted to sugar, P, in which the pyranose form Pa is in equil* ibrium with the aldose form Pb. This sugar can be Isolated if desired but ordinarily this is neither necessary nor desirable, In the presence of acid, e.g., hydrochloric acid or other strong non-oxidizing acid such as p-toluene-sulfonic acid, and sulfonic acid type anion exchange resins, the mercaptan R^E reacts with the sugar P to form 2062A the thiogl ycoside G. Effective conversion is obtained by introducing the mercaptan, R0SH, into the aqueous solution i resulting from the bromination and treating the resulting ¾ system, which will ordinarily be a two phase system because of the insolubility of the mercaptan with hydrogen chloride * gas or concentrated . hydrochl or i c acid advantageously with o cooling to a temperature between about -10 and + 20 C. A . satisfactory procedure is to cool the reaction mixture to 0° C. and to bubble into it hydrogen chloride gas. It is ^ advantageous, especially with the longer chain mercaptans, * to partially solubllize them by the addition of tetrahydro- ' furan to the reaction mixture. Advantageously from 15 to parts of tetrahydrofuran for each part of water is used.

The temperature of the reaction may be allowed to rise, o advantageously not higher than about 55 C, during the addition of hydrogen chloride gas. After cooling to about o C., the tetrahydrofuran is removed under vacuum. The reaction mixture can be worked up in the usual way which may include solvent extraction at an acidic pH, solvent extract- ion at a basic pH, fractional liquid-liquid extractions such as counter current distribution or partition chromatography, crystallization, and the like. Concomitantly some dithio- acetal of Formula B (Sequence A-2) may be formed which after separation can be cyclized as described above to form more of the desi red thiogl ycoside G.

The β-epimers of the above can be prepared by the following representative sequence: ■ Ac and Aci can be alkanoyl or aralkanoyl of not more than 12 carbon atoms as given above . f he process Is effected as follows: treating methyl N-acyl-a-thlollncosaminide (IX) with mercuric chloride In a warm aqueous solution to obtain a mixture of 6-acylamino-6,8-dideoxy-D-erythro-a-D-galacto-octopyranose or N-acyl-a-lincosamine (XVa) and N-acyl-3-lincosamine (XVB); acylatlng this mixture with an acylatlng reagent selected from acyl halides and acid anhydrides to obtain a mixture of N-acyl-1,2,3,4,7-penta-O-acyl-a- and β-lincosamine (XVIa and XVI0); treating compound XVIa or compound XVI0 or a mixture of compounds XVIa and XVI0 with hydrogen bromide in acetic acid to obtain 6-acylamino-2,3,4,7-tetra-0-acyl-la-bromo-l,6,8-tri deoxy-D-erythro-D-gaiacto-octopyranose or N-acyl-2,3,4,7-tetra-O-acyl-la-bromo-l-deoxylincosamine (XVII); treating compound XVII successively with thiourea, a mixture of potassium carbonate and sodium bisulfite in water, and an alkyl iodide to obtain alkyl N-acyl-2,3,4,7-tetra-O-acyl-0-thiolincosaminide (XVIII); treating compound XVIII with dry ammonia gas in methanol to obtain alkyl N-acyl-0-thiolinco-saminide (XIX). Hydrazinolysis of compound XIX or of compound XVIII gives the alkyl 0-thiolincosaminide (Illc). In a like manner compounds in which Y (formula III) is 2-hydroxyethylthio or 2-alkoxyethylthio can be prepared by reacting compound XVII with ethylenechlorhydrin or a 2-alkoxyethyl halide, Compounds of Formula III where Y is hydrogen can be obtained by the, following representative sequence: The procesB is carried out as follows: methyl Nracyl- a-thiolinoosaminide (IX) (or methyl N-acyl-e-thiolincosaminide) is treated with acetone in the presence of sulfuric acid to form methyl N-acyl-3, -0-isopropylidene-o-thio incosam- 12 carbon atoms according to the alky1 hallde used to alkylate. When desired the 2-hydroxythio group can be preserved by protecting it with a trityl group. Thus compounds XXV or XXVIX where Y is 2-hydroxyethylthlo can be reacted with trityl chloride (triphenylmethylchloride) chlorodlphenyl-(p-raethoxyphenyl)methane, or chloro-bis-(p-methoxyphenyl)phenylmethane, to convert Y to a 2-trityloxy-ethylthlo and the trityl group removed by mild hydrolysis, for example with '.80 aqueous acetic acid/ after the alkylatlon . The 2-hydroxy group can be alkylated with a different alkyl group.

In carrying out this process 6-acyiamino-6,8-dideoxy-D-erythro-D-galacto-ootopyranose compound of formula XXV is suspended in dry acetone. An acid catalyst, such as sulfuric acid, p-toluenesulfonic add, o-toluenesulfonic acid, p-ethylbenzenesulfonic acid, or the like, is added to the suspension, with sulfuric acid preferred. The acetone is generally used in large excess, such as a volume of 20 to 200 times the amount of compound XXV. The acid catalyst is used in a quantity between 0.25 and 50 by weight with respect to the acetone , The reaction can be carried out between 10°C. and the reflux temperature of the solution, but is generally carried out at room remperature. The reaction time is between 15 minutes and 6 hours, depending on the temperature, after which the reaction mixture is neutralized to terminate the reaction. The inorganic salts precipitated by the neutralization are removed by filtration, and the filtrate is evaporated to give a mixture containing crystalline solids. This mixture is separated with water into a water-soluble and water-Insoluble fraction the water-soluble material Is compound XXVII; the Insoluble ^ fraction Is the oxazollne derivative thereof (XXVI).

The water-insoluble oxazollne derivative (XXVI) can be" J converted to compound XXVII by heating with water. After this hydrolysis is complete, the product is obtained by • A. evaporating the solution until crystallization occurs. · The alkylatlon of compound XXVII is performed with an alkyl halide, preferably an alkyl chloride, bromide or iodide, in the presence of a strong base. As alkylating agents, methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, and propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl chlorides, bromides · and iodides and any of the branched-chain alkyl chlorides, bromides or iodides having up to 12 carbon atoms can be used As a base, aikoxides, such as sodium methoxide, potassium methoxide, potassium isopropoxide, potassium tert-butoxlde, sodium tert-butoxide, and sodamide and the like can be used. The alkylatlon can be performed at a temperature between 0° and 50° C. using inert solvents such as benzene, toluene, dioxane, tetrahydrofuran, and the like. After the reaction Is terminated (usually between 1/2 hour and 3 hours) the reaction mixtur is filtered to remove solids, such as sodium or potassium chloride, bromide or Iodide, and the filtrate is evaporated in vacuo to a syrupy residue. The three products therein, namely compound XXVIIIa, compound XXVIIIb, and compound XXVIIIc, are separated by conventional methods, for example, by chromatography or by counter-current distribution. The removal of he N-acyl and isopropyli-dene groups is effected as described above for sequence C. it will be understood that 2-0-, and 7-0-* and 2,7-di-0- Ac can be alkanoyl or aralkanoyl of not more than 12 carbon atoms as given above.

Compounds of Formulae XXXI and XXXII wherein Ac represents a trans-4-propyl-l-methyl-L-propyl group and their preparation are described and claimed in our 23^02 co-pending application Ho. -29883/65--(Serial-Hej--_bil6-t-^06-) and compounds of Formula I can also be prepared from -these by removing the isopropylidene group and then the Ac group or alternatively first removing the Ac group and then the isopropylidene group* Alternatively the above sequence can be applied to any of the 6~amino-6,8-dideoxy-D-erythro~D-galacto-octopyranose compounds of Formula I(o N-acylates thereof) disclosed above, To illustrate the procedural steps for this process reference is made for convenience and illustrative purposes only to the starting compound being lincomycin that is to say a compound wherein Ac represents a rans-4-prop l-1-methyl-L-propyl group as referred to above.

Thus lincomycin is reacted with acetone to form the 1 -0-isopropylidene derivative XXa by the procedure described above for sequences C and D. As the starting compound is lincomycin formation of the oxazoline XXVI is minimized.

The 3»4-O-isopropylidene-lincomycin, XXa is then oxidized with chromic acid to form the 7-dehydro derivative, XXX, which in turn is reduced with borohydride to a mixture of 3,4-0-isopropylidene-lincomycin and 3♦4-0-isopropylidene-epilincomycin (XXXI). The two epimers can be separated by fractional liquid-liquid extractio · for example, counter-current distribution or partition chromatography, or by adsorption or gradient chromatography, or the mixture can be converted to a mixture of lincomycin and epilincomycin ( XXII) and the two epimers then separated by like procedures. Removal of the 3,4-O-isopropylidene group can be effected by mild hydrolysis as described above for sequence C, to give epilincomyci (XXXII) whic in turn can be deacylated with hydrazine as described above to form the desired methyl epi-a-thio-lincosaminide(methyl-6-amino-6,8-dideoxy-l-thio-L-threo-a-I>-galacto-octopyranoside) or the hydrazinolysis can be effected first and the removal of the isopropylidene group last as described for sequence C.

Thus furthermore according to the present invention there is provided a process which comprises reacting a compound of the formula: with acetone to form a compound of the formula: oxidising with chromic acid the compound of Formula AL to form a compound of converting the obtained compound to a compound of the formula (AN) by a borohydride reduction, and removing either the ieopropylidene group first by acid hydrolysis, and then the Ac group by hydrazinolysis or alternatively removing the Ac group first by hydrazinolysis and then the ieopropylidene group by acid hydrolysis to form a compound of the formula: wherein is hydrogen or alkyl or not more than 12 carbon atoms; Ac is alkanoyl or aralkanoyl of not more than 12 carbon atoms and Y is hydrogen, S alkyl of not more than 12 carbon atoms, S ι τΟΗ^ΟΗ^ΟΗ or S , ,ΟΒ^ CHgOalkyl wherein the alkyl is of not more than 12 carbon atoms· Methyl 6-amino-6,8-dideoxy-l-thio-D-erythro-a-I)~ galacto-octopyranoside also designated as methyl-a-thiolincosaminide or MTL and its preparation is described and claimed in our British Patent Specification No. 1,008,647 and ethyl-6-amino-6,8-dideoxy-l-thio-D-erythro-a-D-galacto-octapyranoside known also as ethyl-a-thiolincosaminide or ETL and the preparation thereof is described and claimed in our British Patent Specification No. 1,097,926.

The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting. The parts and percentages are by weight and the solvent ratios are by volume unless otherwise specified.

Immediately. The reaction was continued with occasional heat- ■o . Ing to 40 C. for a period of 3 days. Thin-layer chromato- graphy then showed the absence of etartlng material. The t precipitate of mercuric chloride mereap ide (CIHgSMe) was . removed by filtration. The colorless filtrate, together with aqueous washes of the precipitate, was stirred magnetically at room temperature, and the excess of mercuric chloride was removed by the addition of pyridine in small portions until ' the precipitation of the insoluble mercuric chloride-pyridine complex was complete. After storing the mixture in the o . , refrigerato a 0 C. for 3 hours, the solid was removed by filtration, the precipitate was washed well with cold water, and ■ * the combined filtrate and washings were stirred with a small amount of silver carbonate until the solution was neutral to pH paper. The eolution was thereupon filtered through a "Mlllipore" filter (Milllpore Filter Corporation, Bedford, Massachusetts), the filter was washed thoroughly with water, and the washings were added to the colorless filtrate. Excess silver ion was precipitated by saturating the solution with . hydrogen sulfide and removing the silver sulfide by filtration. The silver sulfide was washed with water, the washings were added to the filtrate, and the solution was lyophillzed to give a colorless amorphous solid, which was a mixture of 6-aceta- mldo-6,8-dldeoxy-P-erythro-q- and β-D-galacto-octopyranoses (N- acetyl-a-lincosamlne and N-acetyl-0-lincosamine) .

C. N-Acetyl-l,2,3, ,7-penta-0-acetyl-3-lincosamine The crude mixture of N-acetyl-ct-lincosamine and N-acetyl- 3- lncosamlne of part B was slurried in 00 ml. of pyridine and 200 ml. of acetic anhydride and stirred magnetically overnight at room temperature. The resulting colorless solu- o 1 ram, Hg pressure to a pale yellow syrup which was dissolved In a mixture of water and chloroform. The aqueous layer was extracted with chloroform and the chloroform extracts were L combined, washed with dilute sulfuric acid (2 N) , then twice ' with water, with saturated aqueous sodium bicarbonate, with water until neutral, and finally dried over anhydrous sodium * sulfate . The resulting chloroform extract was then evaporated o on a rotating evaporator at 3 C. and 15 mm. Hg pressure to give a colorless solid which was dissolved in hot ethyl acetate . To this ethyl acetate solution was added Skelly solve B hexanes until a so l i d bega to crystallize . The solid was removed by filtration and twice recrystalllzed from ethyl acetate -Skellysolve B hexanes to give N-acetyl-l, 2,3* 4,7-penta-O-acetyl-e-lincosamine (9.27 g. ) of melting point 227-' ' · ' \Q ■ ' ' " ■ as 0 23Ο C and rotation [o 3D + 35 (0, 0,832, chloroform) .

Anal . . Calod. for CaoH8e 0ie: C, 50.52; H, 6.15; N, 2.95 .

Pounds C, 50.40; H, 6.42; N, 3 »04.

The ethyl acetate -Skell solve B hexanes filtrate from the first crystallization was allowed to stand at room ^ temperature, whereupon colorless prismatic needles of N-ace tyl-1 , 2, 3, 4 , 7-pen ta-0-ace tyl-a-llncosamlne separated ■' o m.p . I69-172 C . The melt resolidified on cooling in the o form Of hexagonal platelets which then melted at 237-238 C ; after recrystalllzation f om ethyl acetate-Skeilysolve B o hexagonal platelets were obtained melting at 240-240.5 C.

SB O and having a rotation of [α]β + 132 (c, 0.9842, chloroform) « - Anal . Calod. for CaoHae Oia; Q » 50,52; H, 6.15; N, 2.95 Pounds Cp .62 H, 6.08; N, 3.02.

The N-acetyl-l, 2, 3* , 7-penta-0-acetyl-a- and β-lincosa-mines can also be separated by counter current distribution, using a system of water:acetone:methyl ethyl ketone : eyelohexane in a volume ratio of 3; 5; . In 900 transfers, approximately 5 of each of the 2 anomers could be isolated in the pure state, the partition coefficients being for the a-anomer, 0.75; for the 3-anomer, 0.66 , D, 6-Acetylamino-2, 3, 4, 7-tetra-0-acetyl -l-bromo-l,6,8-tri- deoxy-D-erythro-q-D-ga 1 acto-octopyranose (N-Acetyl -2, 3* 4, 7- tetra-O-acetyl - 1-bromo-l-deoxy-a- I i ncosami ne) ' XXXVI Two grams of N-acetyl-1, 2, 3, 4, 7-penta-0-acetyl-e-lincosamine of part C was stirred magnetically with a solution of anhydrous hydrogen bromide in acetic acid in 5 ml · of acetic acid (saturated at 0 ) at room temperature (about 25 C.) for about 3 hours. All of the solids dissolved within one hour. The pale yellow, viscous solution was diluted with 0 ml. of chloroform, poured onto ice and stirred for 10 minutes. The chloroform layer was separated, the aqueous solution was extracted thoroughly with chloroform, and the combined chloro-form extracts were washed with water until the aqueous wash was neutral to Congo red paper, and dried over anhydrous sodium sulfate. The chloroform was thereupon evaporated in a rotatory evaporator at 35°C. and ]5 mm. Hg pressure to give an almost colorless amorphous solid. After three crystallizations of the solid from chloroform-Skellysolve B, colorless, prismatic needles of N-acetyl-2, 3, 4,7-tetra-0-acetyl-la-bromo-l- deoxylincosamine were obtained which had a melting point of < 188-189° C and a rotation of [a]*9 + 231° (0, 0.8132, chloroform) . Ί Anal. Calcd. for CieHaeBrNOio: C, 43.56; H, 5.28; N, 2.82; Br, 16.IO.

Found; C, 43.68; H, 5.39; N, 2.88; Br, 17.22. E. Methyl N-acetyl-2, 3, 4,7-tetra-O-acetyl-0-thio- lincosaminide.

Two grams of N-acetyl-2,3, 4, 7-tetra-0-acetyl-la-bromo- ·· 1-deoxylincosamine of part D was dissolved in 25 ml. of acetone which had been dried previously over potassium car- · bonate, and to this eolution was added 350 mg. of thiourea. After warming briefly on a steam bath until the solids had dissolved, the colorless reaction mixture was left overnight at room temperature. ' To it was then added a solution of 680 mg. of potassium carbonate and 86Ο mg. of sodium bisulfite in 10 ml. of water, followed by 900 mg. ( 0.40 ml.) of methyl iodide. The mixture was kept in a stoppered bottle which was shaken mechanically at room temperature for 3 hours. The reaction mixture was then extracted thoroughly with chloro-form, the combined extracts were washed twice with water, dried over anhydrous sodium sulfate, and the solvents were removed on a rotating evaporator at 40° C. and 15 mm. Hg pressure.

In this manner I.38 g. of colorless, amorphous solid was obtained, which upon thin-layer chromatography was shown to be a single compound. This solid was dissolved in hot ethyl acetate which was thereupon diluted with Skellysolve B hexanes to give 880 mg. o colorless platelets of melting point 268-272° C. Hecryetalllzation from the same solvents gave methyl N-acetyl- 2»3»4»7-tetra-0-acetyl-e-thlolincosaminide of melting point 272-273° Q. and rotation [α]ξ3 + 51° (c, 0.6800, chloroform).

•Anal, Calcd. for CxeHaeNOioS: t C, 9.2S-«, 6.51; N, 5.02 S, 6.92.

Pound: C, 49.15;, H, 6.23; N, .00;. S, 6.4l.

P. Methyl N-acetyl-e-thiolincosaminide ■* Ten ml. of methanol was saturated with dry ammonia gas at a temperature between 0 and .5° C. Into this saturated solution was added at room temperature 1 g. of methyl N-acetyl-2,3»4,7-tetra-0-acetyl-3-thiollncosaminide. The mixture was* allowed to stand at room temperature for three hours and then taken to dryness on a rotating evaporator at 40° C. and 15 mm. Hg pressure, and the solid thus obtained was recrystallized three times from ethanol to give methyl N-aoetyl-0-thiolincoe-aminide. 0. Methyl β-thiolincosaminide A solution of 1 g. of methyl N-acetyl-e-thiolincosaminlde in 10 ml. of hydrazirie hydrate was refluxed for 24 hours.

Excess hydrazine was then removed in a stream of dry nitrogen on a steam bath, The crystalline residue was recrystallized from 5 ml, of water, the crystals were collected, washed with cold water, and dried in vacuo to give methyl β-thiolincos-aminlde.

By substituting the methyl iodide of part E by ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl iodides and the isomeric forms thereof the corresponding aikyl N-aoetyl-1,2,5*4,7-tetra-O-acetyl-e-thiolinoosarainides, alkyi N-.acetyl-0-thlolincoeaminides, and alkyl 0-thiolincosamlnidee are obtained,.

By substituting 2°hydroxyethyX iodide for the methyl iodide of part E, 2- ydroxy-ethyl ET-acetyl-2g »4 , 7-tetra-0~acGtyl~3-thiolincocarainidep 2-hydroxyethyl N~acetyl-,8=-thiolincosaminide 9 and 2-= hydroxyethyl β-thiolincosaminide are obtained„ By using a 2-alkoxyethyl iodide the corresponding 2= alkoxy thyl compounds are obtained„ The alkyl of the alkoxy can be methyl9 ethyl„ propyl„ butyl9 pentyl, hexyl, heptyl, decyl, undecyl9 or dodecyl or the isomeric forms thereof.

I 6->Amino-lt6,8-trideoxy-D-erythro-D-galacto-octo pyranose (l-deoxylincosamine) XXXIX A. Methyl N-aoetyl-3, -0-isopropylidene-fJ-thiolincosam- inlde A suspension of 5.3 g. of finely-powdered methyl N-acetyl-0-thiolincosaminide was etirred for 30 minutes at room tem-perature with 500 ml. of acetone and 5 ml. of concentrated sulfuric acid. After 30 minutes another 5 ml. of concentrated sulfuric acid was added, and the solution was stirred for another half hour at room temperature. A suspension of 150 g. of barium carbonate in 100 ml. of water was added, and the mixture was stirred until neutral. The barium sulfate and excess carbonate were removed by filtration, and the precipi-tate was washed with acetone. The filtrate and washings were combined and evaporated to dryness in vacuo at 40° C.

The residue was treated with acetone .ether (10: l) and insoluble materials were removed by filtration. The filtrate was evaporated to dryness and the residue was dissolved in 100 ml. of ethanol. Removal of the alcohol by heating in vacuo left a gummy material which was dissolved in 20 ml. of warm water containing a small amount of sodium carbonate. After removal of some insoluble material by filtration, the filtrate was cooled. The crystals which formed were collected after stand-ing in the refrigerator for 4 hours, washed with cold water, and dried in vacuo to give methyl N-acetyi-3#4-0-isopropyl- idene-3-thiollncosaminide .

B. N-Acetyl-3,4-0-lsopropylldene*-'l-deoxy- , lincosamine *' Five grams of methyl N-acety 1-3, *0-isopropylidene-0-thiolincosamlnide was heated under reflux for 7 hours with * 35 ml. of loosely-packed Raney nickel in 150 ml. of ethanol, The mixture was thereupon filtered and the catalyst was washed with a total of 400 ml. of boiling ethanol. The filtrate and washings were oombined and evaporated to dryness*, leaving a partially crystalline residue. This residue was puri ied by counter current distribution in a system of butanol ;water to give N-aoetyl-3,4-0-isopropylidene-X-deoxy» lincosamine. ~ £. 1-Deoxylinoosamine One gram of N-acetyl-J^-O-isopropylidene-l-deoxylinoosamine in 5 ml, of hydrazine hydrate ( 98-100$) is heated under reflux for 21 hours. The excess hydrazine hydrate is distilled in vacuo. The residue is stirred with acetonitrile and again evaporated. Five ml. of water is added and the pH adjusted to 2 with hydrochloric acid. After 3-5 hre. at 26° the solution is diluted with 10 ml. of water . and excess silver carbonate added, The mixture is then filtered and the filtrate lyophilized. The resulting residue ia crystallized from water to yield l-deoxylincosamine. 2-Hydroxyethyl 6-amino-7-0-raethyl-6* 8-dideoxy-l thlo-D-erythro-g-D.gaiacto-ootopyranQBlde ( 2- hyd A. 2-Hydroxyethyl a-thiooelestosaminide hydrazine solvate A mixture of 5 g. (0.0094 mole) of celesticetin (Example 3, U S, Patent 2,928,844) and 25 ml. (excess) of hydrazine hydrate was heated under reflux for 21 hours. The excess hydrazine was removed by distillation in_ vacuo and the residue was crystalliz-ed from 35 ml, of absolute ethanol. white crystals ( 1 .2 g.) of 2-hydroxyethyl a-thiocelestosaralnide hydrazine solvate were obtained which melted at 98-108° C , Recrystaliization from, absolute ethanol gave 0.65 g. having an optical rotation of [a]gs · + 243° (c <» 0.8, water); an infrared absorption spectrum in Nujol mull at the following frequencies: 3400, 1630, l600, 1460, 1450 (sh), 1305/.1275, 1260, 1200, 1115, 1085, 1055, 1010,.978, 950, 925, 910, 873, SoO¾20, 705, 690, and 680 cm 1 j an equivalent weight of 161 with two basic groups having. pKas in the region of 7.5; and the following elemental analysis: ; Calculated for CiiHaa OeSrNaH*: C, 40,11; H, 8.26; N, 12.76; >S, 9.7 : Pound: C, 40.15; H, 8.04; N, il.69; S, 9.56.

B. 2-Hydroxyethyl c^thiocelestosaminide hydrazine solvate Desalicetin (Example 1, U. S. Patent 2,851,463) (10 g.) was dissolved in hydrazine hydrate (100 cc.) and heated under - reflux in an oil bath at 1650 C. for 18 hours. The almost colorless solution was concentrated to dryness on a steam bath, first at 15 mm. and finally at less than 1 mm., giving a solid residue which was triturated with acetonitrile, filtered, and washed with the same . solvent. Crystallization from ethanol gave colorless needles (2.64 g.) of 2-hydroxy- ethyl a-thlocelestosaminide hydrazine solvate. Recrystallization from the same solvent gave crystals of 2-hydroxyethyl a-thio- celestosaminide hydrazine solvate which had an equivalent , weight of 168 with two basic groups having pKas in the region of 7·5ί an optical rotation of ta]p5 - .·.+ 248° (c » 1, 95^ ethanol); and the following elemental analysis: Calcul ted for CiiHaaNOeS'NalU: C, 40.11; H, 8.26; N, 12.76; C. 2fHydroxyethyl a- hiocelestosaminide A solution of 2 g, of 2-hydroxyethyl a-thlocelestosaminide hydrazine solvate, prepared as in part; A or part B, in 30 ml. of dimethylformamide was concentrated to a volume of about ml. and then diluted with 10 mlt of diniethylformamide .

Ether was added until cloudiness resulted^ and 500 mg. of 2- hydroxyethyl a-thlocelestosaminide was deposited.. The cry- stalllne 2->hydroxyethyl a-thlooelestosamlrilde had an optical rotation of [a] s + 262° (c «» l, *in water); an infrared absorp tlon spectrum at the following frequencies: 3 00 (sh), 3250, ί 1600, 1400, 1325, 1310, 1290, 1240, 1195* ll60, 1150 (sh), 1110, 1100, 1075, 1045, 1038, 1005, 980, 920, 895, 862, 825* 796, 740, 711, and 690 cm j ei equivalent weight of 297 and a pKa' of 7.2; and the following elemental analysis: Calcu ated for CnHssNOeS: C, 44.43;, H, ··80; N, 4.715 ,3, 10.78 ■ ■ ' , ' "/ Pound: C, 44.20; H, 7.78; N, 4.97; -S, 10.68, XLIII A.2-Hydroxyethyl N-ace yl-3,^-0-1so ro ylidene-a-thio- celeetosaminide .

To a solutidn of 14 g. (0.047 mole) 'of 2«^hydroxyethyl a- t thiooelestosaminide in 50 ml. of ethanol was added 14 ml. of *· · . ί acetic anhydride. The reaction mixture was stirred for 1/2 hours, refrigerated overnight, and evaporated to dryness in vacuo. The residue, 2-hydroxyethyl N-acetyl-a-thiocelestoe* aminide, was .slurried with ether and dried under reduced pressure.

The thus-obtained dried material was dissolved in 1500 ml. of acetone and 15 mi. of concentrated sulfuric acid was added to the solution ith stirring. The mixture was stirred for about 2 hours and then neutralized by adding dry ammonia. The mixture was filtered and the filtrate was evaporated to dryness, leaving 2-hydroxyethyl N-acetyl-3,4- -isopropylidene- a-thlocelestosaminide as an oil.

B- . N-Aoetyl-2,4-0-isopropylidene-7-0-methyl-l-deoxy- lincosamine The oil of part A was dissolved in 500 ml. of ethanol, 150 ml. of loosely-packed Raney nickel in ethanol was added thereto, and the mixture was heatjed under reflux for 10 hours.

. . . Thereafter the mixture was filtered, the catalyst was washed with 1 liter of boiling ethanol and the combined filtrate and washings were evaporated to dryness. An oil resulted which was distributed (500 transfers) in the system 1-butanol:water. A peak fraction, K » 0.82, obtained by evaporation of pooled tubes 2ΟΟ-25Ο, gave 4.6 g. (33#) of N-acetyl-3,4-0-isopropyl- idene-7-0-methyl-l~deoxylincosamine which crystallized upon drying; melting point, 198-205 C; rotation (a]*s + 71 (c » 1, 50j£ ethanol).

Anal. Calcd. for Ci H2sN0e: C, 55.43; H, 8.51; N, 4.62; Methoxyl, 10.63.

Found: C, 55.05; H, 8.28; N, 4.70; Methoxyl, 10.4 . t B-2 Potassium metal (l.l6g.) was dissolved in 100 ml. of tert-butyl alcohol. The solvent was removed as completely as4 possible by distillation (unless specified all distillations are at atmospheric pressure) and finally by vacuum distillation at 15 mm. Hg pressure. To the dry solid residue was added 100 ml. of dry benzene and the benzene was removed by distillation to leave a fine powder. To the thus -obta i ned powdery potassium tert -butox ide was added 200 ml. of dry benzene, and the mixture was stirred magnetically at room temperature until an opalescent solution resulted. To this solution was added 5 g. of N-acetyl -3,4-0-isopropyl idene-1 -deoxyl i ncosami ne, prepared according to part B of Example 5» and the mixture was then stirred overnight at room temperature. To this mixture was added 2. g. (I8.6 ml.) of methyl iodide and the mixture was stirred at room temperature for 2 hours. The mixture was filtered to remove potassium iodide, and the iltrate was distilled in vacuum at about 35°C. to give a colorless syrupy material which was subjected to counter current distribution in a system of ethyl acetate: ethanol: water in a ratio of 4.1:2. The fractions containing N-acetyl-3,4 -0-i sopropy 1 idene-7 -0-methy 1 -1 -deoxy 1 i ncosami ne, as determined by thin-layer chromatography, were combined, evaporated to dryness and the residue was crystallized to give pure N-acetyl -3*4 -0-i sopropy 1 idene-7 -0-methyl -1-deoxy-1 i ncosami ne.

£. T-O-Methyl-l-deoxylincosamine Following the procedure of Example <2J part C, N- acetyl-3, -0-isopropylidene-7-0-methyl-l-deoxylincosaflrine is 0 converted to 7-0-methyl-l-deoxylincosamine.

Example jr~ 2-Hydroxyethy'l a-thiolincosaminide A. Methyl N-acetyl-2,2, ,7-tetra~0«-thionobenzoyl-a- thiolincosaminide Methyl N-acetyl-a-thiolincosaminide (IX), dissolved in dry pyridine, is treated with an excess of thiobenzoyl chloride (l80# excess) at 0° C. and the reaction mixture allowed to stand overnight at room temperature with the exclusion of atmospheric moisture. Following the removal as completely as possible of volatile material at 30° C. under high vacuum, the reaction product is extracted with chloroform, the extract washed with water, dilute sulfuric acid (N), water, saturated aqueous sodium bicarbonate-, with water again, and dried over anhydrous sodium sulfate. Removal of the chloroform in vacuo yields the .product, methyl N-acetyl-2,3, ,7-tetra-O-thionobenzoyl-a-thiolincosaminide (X), which 2A can be recrysta 11 i zed from acetone or ethyl acetate by the addition of Skellysolve B (technical hexane).

J3, 2-Hydroxyethyl N-acetyl -2-0-benzoyl -5,4,7- tri.-O-'' thi onobenzoyl -a- thi ol i ncosami n i de The tetrathi onobenzoate (X) of part A is dissolved in * ethanol-free chloroform (to give a 2 to 10i solution) and treated with a solution of bromine (2 molecular equivalents) in chloroform (a l-2£ solution, vol. /vol. ) with magnetic stirring at room temperature with the exclusion of atmos-pheric moisture. After 2 hours the volatile material is o removed as completely as possible by evaporation at 50 C. and 15 mm. Hg pressure, more chloroform (ca. 100 ml. per 2 g. of starting material ) is then added and removed as before. To the residue is added acetone (ca. 25 ml. per 2 g. of starting material) and triethylamine (2 molar equivalents), and the resulting solution heated under reflux on a steam bath for 1 hr. with the exclusion of atmospheric moisture. [The initial bromination product (XI ), is thus converted to the cyclised intermediate (XI I). ] To the cooled solution is then added potassium carbonate (5 molecular equivalents), sodium bicarbonate (wt. equal to the potassium carbonate used), and water (ca. 10 ml. per g. of potassium carbonate), followed by ethylene Iodohydrin (preferably, ca. 6-10 mol ecul ar equivalents), and the stoppered mixture is shaken mechanically for 5. hrs. at room temperature. The reaction mixture is extracted with chloroform and the chloroform solution is washed with water to remove inorganic salts, and dried over anhydrous sodium sulfate. o Removal of the chloroform at 50 C. in vacuo yields 2-hydroxy-ethyl N-acetyl -2-0- benzoyl -5,4,7- tr i -0- thi onobenzoyl -a-thio- hydrazine hydrate (20-30 times the weight of the ester) for 12-36 hours and the excess hydrazine is removed by distillation under reduced pressure. The residue is triturated with aoetonitrile, and the remaining solid product is recovered by filtration, washed with acetoni tri le, and recrystal 1 i zed from ethanol to yield 2-hydroxyethyl a-thiol i ncosami nide.

By using a 2-alkoxyethyl iodide the corresponding 2- alkyloxyethyl compounds are obtained. The alkyl of the alkyloxy can be methyl* ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, deoy , undepyj., or dodeoyl or the isomeric forme thereo . g the ethylene Identical with that obtained from llnoomycln C In Example 2 Is obtained. By substituting propyl, butyl/ pentyl, hexyl, heptyl, ootyl, nonyl, undecyl, and dodeoyi iodides and the isomeric forms thereof, there are obtained the corresponding alkyl a^thlpllncosamlnides.

Example 'rj*: 2-0- and 7-0-Aikylatlon of alkyl o- and 0- XLVIII A.. Methyl N-acetyl-3, -0-isopropylidene-a-thiolincos- aminide and the oxazolin derived therefrom Sixteen grams of methyl N-acetyl-a-thiolincosaminide was finel powdered and suspended in l600 ml of dry acetone with rapid magnetic stirring.. To this suspension was added 16 ml. of concentrated sulfuric acid. The suspended solid began to dissolve and solution was complete within, 30 to 60 minutes.

After standing for hours at room temperature (24-26° C. ), the solution was cooled overnight in a refrigerator at about 5 to 10° C . . ' The pale yellow solution was neutralized by introducing, ' with stirring, a stream of dry ammonia gas . Ammonium sulfate precipitated and was removed by filtration and washed with L acetone. The acetone washing was added to the colorless filtrate which was evaporated οη a rotating evaporator at 50° C o and 15 mm. Hg pressure to yield a mixture of syrup and crystalline solids . The syrup was dissolved by swirling the * mixture with 50 ml , of water, and the crystalline solid was collected on a filter and washed with ice-cold water. Upon drying at 60° C. and 15 mm. Hg^ pressure, 7.12 g. of solids were obtained of melting point 189-192° C. Recrystallization from acetone-Skellysolve B hexanes gave colorless needles of the oxazoline derived from methyl N-acetyl-5*4-0-ieopropylidene-a-thiolincosaminlde; melting point, 191-192.5° C ; rotation IcOj* + 126° (c, Ο.85Ο8, ethanol ) .

Anal . Calcd. for C14HS3 O9S : C, 52.95; H, 7.5 ; ίϊ, , li S, 10. lOj O, 25.20.

Pound: C, 52.77; H, 7 ,34 ; N, 4.40; S, 10. 12; 0, 25.11. The aqueous mother liquors were concentrated in vacuo to give a solid which was re crystallized from acetone; it consisted of methyl N-acetyl-5,4-0-isopropylidene-o-thiolincosaminide of melting point 178-180° C, and rotation [c]g8 '+ 189° (c, 0^5137» water) * B. Conversion of the oxazollne derived from methyl N- acetyl-3,4-0-isopropylidene a-thlollncosaminlde to methyl N-acetyl-3, 4-0-isopropylidene-ot-thiolincos- ' amlnide A solution was prepared of the oxazollne derived from methyl N-acetyl-3,4-0-isopropylidene-a-thiolincosaminide in 2,0 ml. of hot water and heated under reflux for 2 hours at which time thin-layer chromatography on silica gel revealed the conversion of the starting material to methyl N-acetyl-3,4-0-isopropylidene-a-thiolincosaminide . The water was then remoyed in vacuo at 40° C, leaving a colorless crystalline solid which was recrystallized from a small volume of hot water to give colorless needles of methyl N-acetyl-3,4-0-isopropylidene-a-thio-lincosaminide of melting point 178-180° C. and rotation [a]^s + 190° (c, 1.223, water).

C. ethylation of methyl N-acetyl-3,4-0-isopropylidene- a-thiolincosaminide Potassium metal (l.l6 g.) was dissolved in 100 ml. of t-butyl alcohol (previously dried over sodium metal) under stirring and reflux. The solvent was removed as completely as possible by distillation and finally by distillation in a vacuum of 1$ mm.. Hg. To the dry, solid residue was added 100 ml. of dry. benzene, which was removed by distillation to leave a fine powder. This was treated again- with benzene which was distilled off to insure complete removal of tert-butyl alcohol.

To the thus-obtained, powdery potassium tert-butoxide was added 200 ml. of dry benzene and the mixture was stirred magnetically at room temperature until an opalescent suspension resulted. To this was added 5 g. of methyl N-acetyl-3,4-0-ieopropylidene-a-thiolinooeaminide and the mixture was thsn stirred overnight at room temperature at the end of which time all of the solid had dissolved.

To this mixture was added 42.4 g. (18.6 ml.) of methyl . iodide and the mixture was stirred at room temperature for * 1-1/2 hours; after 1 hour, the mixture gave a neutral reaction with moist pH paper. The reaction mixture was filtered to remove potassium iodide and the potassium iodide was washed · with benzene; the benzene was added to the filtrate. The filtrate and washings were distilled in vacuo at 55° C. to give a colorless syrup which was subjected to counter current distribution in the system ethyl acetate :ethanol: ater in the ratio 4:1:2. After 500 transfers the three components, as indicated by thin-layer chromatography, had been completely resolved. The major components were methyl N-acetyl-3> 4-0-isopropylidene-7-O-methyl- -thiolincosaminide and methyl N-acetyl-3,4-0-isopropylidene-2-0-methyl-a-thiolincosaminide . A minor component was methyl N-acetyl-3,4-0-isopropylidene-2,7-di-0-methyl-a-thiolincosaminide .

Removal of solvents from combined tubes No. 2 0-310 (K=1.30 ) inclusive gave a glassy material which crystallized from ethyl acetate : Skellysolve B hexanes to yield methyl N-acetyl-3,4-0-isopropylidene-2-0-methyl-a-thiolincosaminide as short, colorless prisms of melting point 176-177° C. and rotation [a]p5 + 176° (c, 0. 6220, chloroform).

Anal . Calcd. for C15H27N0eS: C, 51757/ H, 7.79; N, 4.01; S, 9-17; OMe, 8 .88.

Pound: C, 51.82; H, 8.10; N, 4.08; S, 8.94; OMe, 8.49.

Removal of solvents from combined tubes No. 330-38 (K*2.52) Inclusive by distillation gave a glassy product which orystalllzed slowly on standing. Reerystaliiaa¾ien r& ©¾he*> gave clusters of minute, colorless needles of methyl N-acetyl- 7-0-methyl-3,4-0-isopropylidene-a-thiolincosaminide .

Similarly, evaporation of the solvents from combined 'tubes No. 410-450 (K=5.67) gave a colorless glassy product.

Recrystallization from ether gave colorless, chunky needles of methyl N-acetyl-2,7-di-0-methyl-3,4-0-isopropylidene-a- thiolincosaminide of melting point 124.5-126° C. and rotation [a] 5 + 184° (c, 0.8390, chloroform).

Anal. Caicd. for CieHae OeS: C, 52.88j H, 8.04; N, 3.8 ; S, 8.82; 0CH3, 17.08.

Found: C, 53-02; H, 7-95; N, 4.05; S, 8.73; 0CH3, 15-92. 1 . Methyl N-acetyl-2-O-methyl-a-thiolincosaminide - A mixture of 2 g. of methyl N-acetyl-2-0-methyl-3, 4-0- isopropylidene-o-thiolincosaminide in 50 ml . of 0.25 N hydro- chloric acid was magnetically stirred at room temperature (about 25° C). The solid starting material dissolved within minutes. After 1-3/4 hours, thin-layer chromatography showed the complete absence of starting material.

The strongly acidic solution was stirred with a polystyrene quaternary ammonium anion exchange resin until the colorless supernatant solution gave a neutral reaction with pH paper.

Filtration, washing of the resin with water, and removal of the water from the combined filtrate and washes in vacuo gave 1.68 g. (95$) of a colorless crystalline residue which was crystallized from methanol -ether to give long, colorless, felted needles of methyl N-acetyl-2-0-methyl-a-thiolincosaminifle of melting point 237-238° C.

Anal. Caicd. for Ci2H23 0sS: C, 46.56; H, 7 9 N, 4.53; S, 10.36 Founds C, 46.72; H, N, 4.37; S, 10.3½.

D. Methyl 2-0-methyl-a-thiolincosaminide The thus-obtained methyl N-acetyl-2-0-methyl-a-thiolin-cosaminide was heated with 6 ml. of hydrazine hydrate under reflux for a period of 22 hours. The excess hydrazine hydrate was removed by distillation in vacuo and the residue was three times recrystallized from ethanol-water to give methyl 2-0-methyl-a-thiolincosaminide.

E. , Methyl 7-0-methyl-a-th.iolincosaminide In the manner given in parts C and D, methyl N-acetyl-7-0-methyl-3,4-0-isopropylidene-a-thlolinco.saminide was hydrolyze and then hydrazinolyzed to give methyl 7-0-methyl-a-thiolifJ-cosaminide.

F. Methyl 2,7-di-O-methyl-a-thiolincosaminide In the manner given in parts C and D, methyl N-acetyl-2,7-di-0-methyl-2,4-0-isopropylidene-a-thiolincosaminide was hydrolyzed and then hydrazinolyzed to give methyl 2,7-di-0-methyl- -thiollncosaminide .

By substituting the methyl -thiolincosaminide by methyl 0-thiolincosaminide or by the other alkyl a- or 3-thiolincos-aminides given above, the corresponding alkyl 2-0-, 7-0-, and 2,7-di-0-alkyl a- and 3-thiolincosaminides are obtained.

By substituting the methyl N-acetyl-a-thiolincosaminide, by 2-hydroxyethyl a- and (3-thiollncosaminides, the corresponding alkoxyethyl N-acetyl-2-Ο-, 7-0-, and 2,7-di-O-alkyl-a and β-thiolincosaminides are obtained. By substituting the methyl N-acetyl-a-thiolincosaminide by 2-trityloxyethyl B N-acetyl-a- and β-thiolincosaminides, the corresponding 2- * trityloxyethyl N-acetyl-2-Ο-, 7-0-, and 2, 7-di-0-alkyl-a-and -thiolincosaminides are obtained. By removing the trltyl group by hydrolyzlng with 80 aqueous acetic acid and the N-acetyl by hydrazinolysls, the corresponding 2-hydroxyethyl 2-0-, 7-0-, and 2,7-di-O-alkyl-a- and β-thio-linocsaminides are obtained.

Example 8 Methyl 6-amino-6,8-dideoxy-l-thio-L-threo-a-D-galac o-octopyranoside Methyl epi-a-t iolincosaminide 0H Following the hydrazinolysis procedure as described in the Example of British Patent Specification No. 1.008,647» epilincomycin which compound and its preparation from lincomycin are described in our copending application No. 29882/65(Serial No, 1,118,306) is converted to methyl epi-a-thiolincosaminide.

The process can also be applied to other 6-acylamino-6f8^ideoxy-D-ery^hro-l ¾alacto-octopyranose compounds of the formula: OR, 3 where Ac, Y and are as given above to form the corresponding epimerss which can be alkylated y e proceure given above to provide compounds of the formula? There oan thus be obtained 6-amino-6,8-dideox -I-threo-D-galacto-; 6-amino-2-0-alkyl~6,8-dideoxy-L-threo-l)-galacto-; 6-amino-7-0-alkyl-6,8-dideoxy~L-threo- -galacto-; and 6-amino-2,7-di-0~alkyl~6,8-dideoxy-L-threo-D-galacto-octopyranose· The compounds of formula I can be used as a buffer or as an antacid* They react with isocyanates to form urethanes and can be used to modify polyurethane resins. The thiocyanic acid addition salt when condensed with formaldeh de forms resinous materials useful as and 2,606,155· The free oases also make good vehicles for toxic acids* For example, the fluosilicic acid addition salts are useful as mothproofing agents according to U.S. Patents 1,915,334 and 2,075,359 and the hexafluo-roarsenic acid and hexafluorophosphoric acid addition salts are useful as parasiticides according to U.S.Patents 3,122,536 and 3,122,552.

Various acid-addition salts of the free base form of the compounds of formula X can be made by neutralizing flow the free base with the appropriate acid /to below about pH 7.0, and advantageousl to about pH 2 to pH 6, Suitable acids for this purpose include hydrochloric, sulphuric, phosphoric, thiocyanic, fluosilicic, hexafluoroarsenie, lactic hexafluorophosphoric, acetic, succinic, citric,/maleic, fumerlo, pamoic, cholic, palmitic, mucic, camphoric, flutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, 3-phenylsalicylic» 5-phenylsalicylic, 3-methyl-glutaric, orthosulfobenzoic, cyclohexanesulphamic, cyclopentanepropionic, 1,2-cyclohexanedicarboxyli , 4-cyclohexenecarboxylic, octadecenylsuceinic, octenylsuccinic, methanesulphonlc, bensenesulphonic, helianthic, Reinecke's, dimethyldithiocarbamic, cyclohexylsulphamic, hexadecyl-sulphamic, octadecylsulphamic, sorbic, monochloroacetic, undecylenic, 4*-hydroxyazo benzene-4-sulphonic, octyldecyl-sulphuric, picric, benzoic, cinnamie, and like acids.

The acid addition salts can be used for the same purposes as the free base or they can be employed to upgrade the same. For example, the free base can be con liquid-liquid extractione , and crystallization and then used to regenerate the free base form by treatment with alkali or to make a different salt by metathesis. Or the free base can be converted to a water-soluble salt, such as the hydrochloride or sulphate and the aqueous solution of the salt extracted with various water-immiscible solvents before regenerating the free base form by treatment of the thus-extrac ed acid solution or converted to another salt by metathesis.

Claims (1)

1. WHAT WE A process which comprises reacting a of the formulas with acetone to form a compound of the oxidising with chromic acid the compound of to form a compound of the formulas converting the obtained compound to a compound of the by a borohydride and removing either the lidene group first by acid and then the Ac group by hydrazinolysis or alternatively removing the Ac group first by hydrazinolysis and then the isopropylidene group by acid hydrolysis to form a compound of the ie or alkyl or not more than 12 carbon Ac ie or aralkanoyl not more than 12 carbon Y is hydrogent not more than 12 or therein the alkyl is of not more than 12 carbon of Claim 1 in which Y ie in the a the process of Claim 1 or 2 in which is free base acid addition salt forms of a compound of the formulat wherein S3 or and are hydrogen or alkyl of d c 2 not more than 12 carbon Y is of not more than 12 carbon or alkyl where the alkyl of not more than 12 carbon and Ae provided where is not a the compounds of Claim which B is The Claim 5 wherein Ac The compounds of Claim in which B 0 The compound of Claims or 6 in which Y is in the The compound of Claim 7 or 8 and are 10 A process compr ses removing the Ac from a compound the general therein R and are or of not more than carbon Y of not than carbon atoms or wherein ie as defined and Ac ie of the general formul V wherein ie of not more than 20 of 3 to not more than 8 carbon or of not than carbon alkyl of not than 20 carbon of 3 to not mora than 8 carbon or aralkyl of not than 12 carbon by to of the general formulae and Y are as defined A process which comprises removing the Ac group a having the general OH of not than carbon atoms or of the general wherein Z a group by ie allcyl of not than 20 of 3 to not than 8 carbon atorata or of not than 12 eaxhon atoms and is allcyl of not than 20 carbon eyeloalkyl of 3 to not than carbon or aralkyl of not than 12 carbon hydrazinelysis to form a compound having the general insufficientOCRQuality