DE2458257C2 - 1'-Desmethyl-1 '- (β-hydroxyethyl) clindamycin-2-phosphate, process for its preparation and pharmaceutical compositions containing this compound - Google Patents

Description

A) 1 '-desmethyl-1 - (beta-hydroxyethyl) clindamycin with an alkyl or aryl aldehyde or -ketone converts,

B) that obtained in process step A)

I '■ Desmethyl-1' - (beta-hydroxyethyl) -3,4-O-alkylidene- or -O-arylidene-clindamycin with a trityl halide, a control agent or reacts with dihydropyran,

C) the 1'-desmethyl-! '- (trityloxyethyl) - or l'-desmethyl- obtained according to process step B) ! '- {silyloxyethyl) - or I' -desmethyl-! '- (tetrahydropyranyloxyethyl) -3,4-0-alkylidene- or -O-arylidene-clindamycin reacts with a Phosphoryliemngsmittel and

D) the protective groups are split off by acid hydrolysis

4. Medicaments containing one of the compounds according to claim I or 2 as active ingredient and customary Carriers or diluents.

The invention relates to Γ-desmethyl-1 '- (beta-hydroxyethyl) clindamycin-2-phosphate with the formula given in claim I and its salts Process for the preparation thereof and medicaments containing these compounds.

The new compound and its salts have an antibacterial activity similar to that of clindamycin and the antibacterial spectrum of 1'-desmethyl-1 '- (beta-hydroxyethyl) clindamycin and lead to particularly high concentrations of the Compound in the urinary tract, which makes it particularly valuable for treating bacterial infections of the upper and lower urinary tract as well as the L-shapes in the kidney, being particularly beneficial for are parenteral administration. They are used to treat bacterial infections, in particular by systematic administration, suitable which in the can generally be treated with clindamycin or 1'-desmethyl-Γ- (beta-hydroxyethyl) clindamycin, although they are much less painful than when injected cause this.

The starting material for the preparation of the compound according to the invention is 1'-desmethyl- V- (beta-hydroxyethyl) -clindamycin. This connection is known and can be established according to the method of DE-OS 22 30 427.

The compound according to the invention can be prepared by in a manner known per se

A) 1 '-desmethyl- l' - (beta-hydroxyethyl) -clind-

amycin with an alkyl or aryl aldehyde or ketone.

B) the 1'-desmethyl- 1 '- (beta-hydroxyethyl) -3,4-O-alkylidene obtained according to process step A) or -O-arylidene-clindamycin with a trityl halide, reacts with a silylating agent or with dihydropyran,

C) the I'-desmethyl 1 '- (trityloxyethyl) - or 1' -desmethyl-1 '- (si- lyloxyäthyl) - or l'-DesmethyI-r- (tetrahydropyranyloxyäthyl) -3,4-O-alkyIiden- or -O-arylidenclindamycin with a phosphorylating agent implements and

D) the protective groups are removed by acid hydrolysis.

In stage (A) the 1 '-desmethyl- l' - (beta-hydroxyethyl) -clindamycin, advantageously in the form of Hydrochloride, to protect the 3,4-hydroxy groups with an alkyl or aryl aldehyde or ketone condensed upon gentle heating to form the 3,4-O-alkylidene or 3,4-O-arylidene derivative. if If the hydrochloride is used, acid catalysis of the reaction is not necessary as this salt the reaction is sufficiently catalyzed by an organic solvent, e.g. B. benzene, toluene, chloroform or ethylene chloride, the reaction can through azeotropic water removal can be completed. Such an azeotrope forming solvent

so can then be omitted when water is on another Way, e.g. B. by evacuation, evaporation with an inert gas or simply by distillation together is removed with a solvent that has a higher boiling point than water. That an azeotrope forming solvent is mixed with a highly polar solvent, e.g. B. N.N-dimethylformamide, Ν, Ν-dimethylacetamide, Dimethyl sulfoxide or

N-methylpyrrolidone,

used to solubilize the hydrochloride of the initial compound and thus a homogeneous solution to manufacture. The condensation reaction can take place at temperatures from about 15 to 18O ⁰ C, preferably about 15 to 50 ° C at Alkylidenderivaten and 90 to 110 ⁰ C at Arylidenderivaten be performed. The optimal temperature depends on the ratio of polar to non-polar

Solvent, as well as the special properties of the non-polar solvent, such as the boiling point of the azeotrope formed with water and the boiling point of the non-polar solvent Even the moisture-containing non-polar solvent can be continuously distilled withdrawn and periodically replaced with fresh, dry solvent. The water can too can be removed by condensation and separation with a water separator, or a drying agent can be used, thereby allowing the dried solvent to enter the Reaction flask can be recycled.

The time required for complete condensation will vary with the composition of the Solvent and the effectiveness of water removal. When using azeotropic forming Solvents the course of the reaction can be followed by measuring the amount of water released. But you can also periodically from the Take samples from the reaction flask and perform chromatography. When using mixed solvents of benzene and dimethylformamide, reaction times of 1 to 16 hours can be used, with in usually 2-3 hours are optimal. Typical alkyl ketones used in the process are acetone, diethyl ketone or methyl butyl ketone. It can also be the most diverse aromatic Aldehydes can be used, e.g. B. furfural, 5-methylfurfural, benzaldehyde or the others in DE-PS 16 95 970 listed aromatic aldehydes. Aldehydes in which the carbonyl group is replaced by an or several double bonds separated by an aromatic radical are also useful.

The condensation with the ketone or Aldehyde-made acetals count as first crystalline hydrochloride isolated Stable acetals, e.g. B. the 3,4-benzylidene and 3,4-p-chlorobenzylidene derivatives can be used as hydrochloride with hot ethylene glycol monomethyl ether. Dimethylformamide or chloroform and similar solvents are recrystallized. The less stable acetals, e.g. B. the 3,4-p-anisylidene, 3,4-cinnamylidene and 3,4-toluylidene derivatives must be converted into the free base before isolating the acetal.

The hydrochloride of the 3,4-position z. B. with a Arylidene protected compound can be converted into the free Base can be converted by mixing the salt with a basic substance, e.g. B. aqueous sodium hydroxide, It is mixed with a quaternary ammonium hydroxide, ammonium hydroxide or a strong amine base however, a basic ion exchange resin can also be used. The insoluble arylidene base can filtered off or with solvents which are immiscible with water, e.g. B. chloroform, methylene chloride, Ethylene dichloride or ether. The hydrochloride protected in 3,4-Steltang can also be used in the free base can be converted by first putting the salt after putting it in a solvent such as Has brought dimethylformamide, dimethylacetamide or propylene glycol into solution with a base neutralized. The base can be an alkoxide, ammonia, or a solid inorganic base, e.g. B. Sodium hydroxide or potassium hydroxide. The free base can be used from the solution obtained of water-miscible solvents by diluting with water to the cloud point and subsequent crystallization of the acetal and at Use of solvents, which with water are immiscible by diluting with a non-polar solvent, e.g. B. hexane or isomers Hexanes, or by simple evaporation of the solvent. The latter method of forming the free base from the hydrochloride the compound protected in 3,4-position is suitable for the isolation of very unstable acetals, since this is done without water.

Most of the pools protected in 3,4-sealing can by dissolving the compound in acetone, diluting the resulting solution with ether and Purified addition of hexane up to the cloud point with initiation of spontaneous crystallization

is to be.

In stage B) the trityl ether can be in the 3,4-position Protected derivatives are prepared by having an excess of trityl halide or substituted trityl halide with the 3,4-arylidene or 3,4-AlkyIidenderivat of stage A) in the presence of a strong base and a suitable solvent. The preferred molar ratio of trityl halide or substituted trityl halide to the 3,4-arylidene or 3,4-alkyd compound is 4: 1. Higher Ratios of tritylating agent to 3,4-position protected compounds can be used (up to about 10: 1), albeit with large excesses Tritylating agents increasing amounts of ditrytylated By-products are formed. Lower Molver ratios of tritylating agent to in 3,4-position

protected connection (less than 1: 1) lead to a incomplete implementation as well as the formation of additional, unidentified by-products.

As a preferred trityl halide is in the

Tritylation Trityl Chloride Used However, other trityl halides and substituted trityl halides can also be used.

The preferred solvent for the tritylation is acetone. Other solvents, which are also ver can be used

2-butanone, 2-pentanone, 3-pentanone, ether, benzene, N, N-dimethylformaniid, Ν, Ν-dimethylacetamide, pimethyl sulfoxide, methyl acetate

Ethyl acetate and pyridine.

However, the use of the higher-boiling polar solvents often leads to additional by-products in the reaction, while the lower boiling solvent no complete conversion

so allow.

The preferred base is triethylamine. Other strongly basic trialkylamines can also be used are, for example triethylenediamine, N-alkylmorpholine derivatives, tripropylamine and tributylamine. Ter-

allow tertiary bases with a pKa value greater than 8 a faster conversion, since a better solubility of the starting compound protected in the 3,4-position is guaranteed. Weaker bases, such as pyridine, require longer reaction times, since those in the 3,4-position protected starting compound as hydrochloride in the presence of such a base almost insoluble is.

The response time is determined by various factors, e.g. B. by the boiling point of the solvent rock, the base strength, the concentration and that Ratio of trityl halide to the compound protected in the 3,4-position and the polarity of the solvent. For example, at a molar ratio

from Tritylchlond rom anisylidendvat to triethylamine to the acetone of 72; ) 5; 16; 34 the preferred reaction time at reflux temperature is 24 hours. It Response times of up to 48 hours can also be used. However, increasing s Amounts of ditrityl derivatives formed lead to noticeable reaction times of less than 6 hours Amounts of unreacted anisylidene derivatives. In the case of other molar ratios, the reaction times used can be 1 to 100 hours. The to The reaction can be carried out by paper or thin layer chromatography to be tracked.

After the end of the tritylation, the l '- (trityloxyäthylj -substituted, derivative protected in the 3,4-position by adding a non-polar solvent, e.g. hexane, heptane, pentane, cyclohexane or benzene, precipitated The crude reaction product becomes several Paint from hot acetonitrile and finally from a hot mixture of acetone and water in proportion recrystallized from 1: 1, the derivative being obtained in pure form. Can be used for recrystallization also other organic solvents, e.g. B. 2-butanepn, 3-Pentanone, n-Propanoi, 2-Propanoi, Butyiaceuu, Benzene, Butyronitrile or a mixture of hi, N-dimethyl formamid and water, Ν, Ν-dimethylatetamid and Water, methanol and water, or ethanol and water can be used.

In stage B) the primary hydroxyl group of the hydroxyethyl radical on the pyrrolidine nitrogen atom of the tetrahydropyranyl ether are protected. The reaction is carried out at room temperature in an inert Solvents, e.g. B. diethyl ether, carried out with a few drops of concentrated hydrochloric acid as a catalyst After stirring for several hours, the acid is neutralized with sodium hydroxide, and that Solvent is removed under vacuum. The solid residue can be crystallized or chromatographed However, usually it is pure enough to be cleaned in the following stage without further Treatment to be used.

In stage C) the compound with the protected hydroxyl groups is phosphorylated by known methods, by z. B. with a phosphorylating agent in the presence of an acid-binding agent, e.g. B. a tertiary amine, for r-DesmethyI-l '- (trityloxyäthyI) -3,4-O-alkylidene- or -arylidene-clindamycin-2-phosphate converts examples of phosphorylating agents are

Phosphorus oxychloride,
Dianilino-chlorophosphoric acid ester, anilino-dichlorophosphoric acid. ester, di-tert-butyi-chlorophosphoric acid ester, dimorpholino-bromophosphoric acid ester and cyanoethyl phosphate

Dicyclohexylcarbodiimide.

Examples of tertiary amines are heterocyclic amines, such as pyridine, quinoline and isoquinoline trialkylamines, such as trimethylamine, triethylamine and triisopropylamine;

also in a manner known per se by silylation 30 Ν, Ν-dialkylanilines, such as dimethylaniline, diethylaniline;

be protected, e.g. B. with a trimeth / isilyl group. The silylation is carried out by converting the 3,4-protected compound in a suitable Reacts solvent with a silylating agent A typical method is the reaction of the in 3,4-position protected derivative with an excess of hexamethylsilazane (bifunctional silylating agent) in pyridine solution, using trimethylchlorosilane as a catalyst. The implementation and N-alkylpiperidines, such as N-ethylpiperidine or N-methylpiperidine. The preferred base is pyridine.

The phosphorylation is advantageously carried out by adding a solution of the compound with the protected hydroxyl groups in a tertiary amine, e.g. B. pyridine, with a phosphorylating agent, e.g. B. Phosphorus oxychloride, treated and the reaction mixture cools to rule out excessive side reactions. The implementation in

runs smoothly at ambient temperatures and leads to pyridine at low temperatures, weü the reaction to form the one with a trimethylsilyl protecting group in pyridine at low temperatures, preferably

down to -42 ° C

labeled derivative. Other silylating agents that can be used are, for example, diorgano-monochlorosilanes, z. B.

Diphenyl monochlorosilane,

Dibenzyl-monochlorosilane and methylphenyl-monochlorosilane

[see. GB-PS 8 22 970, report in Chemical Abstracts Volume 44, page 658 (1950)] and other trisubstituted chlorosilanes from trimethyl to tribenzylchlorosilane [cf. Cram and Hammond, "Organic Chemistry," page (1959); Comprehensive Inorg. Chem, Volume 7, page (1958); Roberts and Caserio, "Basic Principles of Org. Chem.", P. 1182 (1964)]. Another suitable solvent is piperidine. To clean the silyl-ether dts reaction mixture is vacuum evaporated to dryness, taken up in chloroform, washed with water, filtered through silica gel and evaporated Another purification in a conventional manner is also possible. After completion of the 2-phosphorylation according to stage C), the silyl protective group introduced in the! • position is removed together with the protective group in the 3,4-position by acid hydrolysis, for example by treatment with a mixture of acetic acid and water.

In stage B), the primary hydroxyl group of the Hydroxyüthylresus at the pyrrolidine nitrogen atom may also be prepared by reacting with dihydropyran to form -38 to -42 ° C carried out temperatures to -50 ⁰ C and +10 ⁰ C are acceptable, although at higher temperatures sometimes noticeable Amounts of by-products occur. The 2-dichlorophosphoric acid ester obtained is hydrolyzed with water at temperatures from -40 to + 10 ° C. to give the corresponding phosphoric acid ester. In order to reduce the formation of by-products to a minimum, lower temperatures are preferred. Thus, in the implementation of 1 '-desmethyl-1' - (beta-trityloxyethyl) -3,4-O-alkylidene or -arylidene-clindamycin in the presence of a tertiary amine with at least one mole of phosphorylating agent 1 '-desmi: thyl- l '- (beta-trityloxyethyl) -3,4-O-aL \ y: Jden- or -arylidene-chlindamycin-2-phosphate obtained.

The 2-phosphate can come from the latter compound

selective removal of the trityl and other protecting groups can be obtained. The removal of this Protecting groups can be achieved by a mild acidic hydrolysis

take place. For example, the heating of

r '= r desmethyl "(beta-trityloxyäthyl) -3,4-O-anisyli' denchlindamycin-2-phosphate with 80% acetic acid at a temperature of 100 ⁰ C for 0.5 to eir.er hour to r-desmethyl -l '- (beta-hydroxyethyl) -clindamvc · :; 2-phosptnt. Acids such as formic, propionic, dilute hydrochloric and dilute sulfuric acid can also be used.

The desired 2-phosphate can be isolated from the reaction mixture by various known methods or by the specific method below. A suitable process consists in subjecting the reaction mixture to ion exchange chromatography with slufen elution over quaternary ammonium resins. The I'-desmethyll '- (beta-hydroxyethyl) clindamycin-2-phosphate is separated from by-products by linear elution of water from pH 9 to ammonium acetate with a pH of 9. The fraction rich in this product is collected and freeze-dried. The ammonium acetate is removed by heating and the inorganic phosphate is removed by saturating the aqueous solution of r-desmethyl-1 '- (beta-hydroxyethyl) clindamycin-2-phosphate with ammonia gas, whereby diammonium phosphate is precipitated. Freeze-drying this aqueous solution gives I'-desmethyl-1 '- (beta-hydroxyethyl) clindamycin-2-phosphate I ^ -cyclohexanedicarboxylic acid.
4-cyclopentane propionic acid.
I ^ -Cyclohexanedicarboxylic acid,
4-cyclohexenecarboxylic acid,
■> Octadecenylsuccinic acid.
Octeny! Succinic acid,
Methanesulfonic acid,
Benzenesulfonic acid,
Dimet hy Idi thiocarbamic acid, ίο cyclohexylsulfamic acid,
Hexadecylsulfamic acid.
Octadecylsulfamic acid,
Sorbic acid, undtv vlenic acid,
Octyldecylsulfuric acid,
Picric acid, benzoic acid and

Cinnamic acid.

Examples of acidic and neutral salts are the alkali metal (including ammonium) and alkaline earth metal salts (including magnesium salts), which

ti iiaitcii,

len. When the mixture is heated 3 hours at 100 ⁰ C this salt mixture Hemiammoniumsalz of l'-desmethyl-1 '- (beta-hydroxyethyl) -clindamycin-2-phosphate obtained. The ammonia-free zwitterionic form of I'-desmethyl-l'-ibeta-hydroxyethyO-clindamycin-2-phosphate is obtained when the ammonium salt is heated to 118-120 ° C. for 8-24 hours under high vacuum and the zwitterionic form crystallizes out .

But you can also remove the inorganic phosphates before the acid hydrolysis. This method has the advantage that 1 '-desmethyl-1' - (beta-hydroxyethyl) -clindamycin-2-phosphate can sometimes be crystallized directly without it being necessary to use the Ammonium salt form to go.

The compound according to the invention is an amino acid and can be protonized or non-protonized Form, depending on the pH of the environment. If the pH value is lower, the Compound in the form of an acid addition salt, while at a higher pH in zwitterionic Form and, at an even higher pH value, in the form of a metal salt. The metal salt can be a neutral salt (2 equivalents of base per each mole

r-Desmethyl-r- (beta-hydroxyethyl) -clindamycin-2-phosphate) or a hemisalt (half an equivalent of base per every mole of r-desmethyl-1 '- (beta-hydroxyethyl) clindamycin-2-phosphate).

Each of these various forms can be formed by adding an appropriate amount of a suitable one Acid and base are isolated. Examples of acid addition salts are the following acids:

Hydrochloric acid, sulfuric acid,

Phosphoric acid, acetic acid,

Succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, t, l-methylene-bis-2-hydroxy-3-naphthoic acid, cholic acid, palmitic acid,

Mucic acid, camphor acid,

Glutaric acid, glycolic acid,

Phthalic acid, tartaric acid,

Lauric acid, stearic acid,

Salicylic acid, 3-phenyl-salicylic acid, 5-phenylsalicylic acid,

3-methylgIutaric acid,

o-sulfobenzoic acid.

Cyclohexanesulfamic acid,

Cyclopentane propionic acid.

sauri.il ι Ulm with uti

corresponding base, such as. B. ammonium hydroxide, sodium and potassium hydroxide or alkoxide, calcium or magnesium hydroxide can be obtained. The acidic and neutral sakes also include the amine salts, which are obtained by neutralizing an acidic form with a basic amine, for example one of the following amines: mono-, di- and T-imethylamines, mono-, '">; - and triethylamines,
ίο mono. Di- and tripropylamines

(iso- and normal-form),
Ethyldimethylamine,
Benzyl diethylamine,
Cyclohexylamine,

Benzylamine, dibenzylamine,

N, N'-Dibenzy! Äthy! Endiamine,
Bis (o-methoxyphenylisopropyl) amine and similar lower aliphatic, lower cycloaliphatic and lower araliphatic amines, the lower aliphatic and lower cycloaliphatic radicals containing up to eight carbon atoms inclusive; heterocyclic amines such as piperidine, morpholine, pyrrolidine and the lower alkyl derivatives in which the lower alkyl radical contains 1-8 carbon atoms, inclusive, such as
1-methylpiperidine,
4-ethylmorpholine,
1 -isopropylpyrrolidine,
1,4-dimethylpiperazine,
1-n-butylpiperidine,

2-methylpiperidine and
1-ethyl-2-methylpiperidine;

Amines with water-solubilizing or hydrophilic groups, such as. B.

Mono-, di- and triethanolamines, ethyl diethanolamine,
n-butyl monoethanolamine,
2-amino-1-butanol,
2- amino-2-ethyl ■ 1,3-propanediol, 2-amino-2-methyl-1-propanol,

Tris (hydroxymethyl) aminomethane (THAM), phenylmonoethanolamine,
p-tert-amylphenyl diethanolamine; Galactamine, N-methylglucamine, N-methylglucosamine as well

Tetraethylammonium hydroxide.
The various forms can be used interchangeably, but will work for most

230266/107

The zwitterionic form and the THAM and hemiammofluoric salts are preferred for this purpose.

The protective groups can be removed by hydrolysis (cf. stage D), preferably by mild acidic hydrolysis. For example, from the protected 2-phosphate by heating with 80% acetic acid to 100 ⁰ C for 10- 15 minutes, the 1 '-Desmethyl-1' - (beta-hydroxyethyl) -clindamycinpl '. _u will get sphat. It can also acids, such as. B. formic, propionic, dilute hydrochloric and dilute sulfuric acid can be used.

The compound according to the invention shows an antibacterial activity similar to that of clindamycin; H. a similar spectrum, but unexpectedly a high concentration in the urinary tract after administration, d. H. d? about the kidney and the upper and lower urinary tract, making them both an effective treatment of bacterial infections of the upper and lower internal tract as well as L-forms or mycoplasma in uci lower enables. S ;; can! "fckt; one" des Urinary tract, such as B. Cystitis, Pyelonephrytis, and Pyelitis are treated when they like on organisms E. coli, S. aureus, enterococci and strains of Klebsieila, Aerobacter, Proteus and Pseudomonas as Causer are to be attributed. The daily dose, based on non-esterified free base, can be at a such treatment between 75-30OmI, or 1-4 mg / kg based on weight Body weight.

The example serves to provide a more detailed explanation.

example

1'-Desmethyl-1 '- (beta-hydroxyethyl) clindamycin-2-phosphate

A. Preparation of 1'-desmethyl- l '- (beta-hydroxyethyl) -3,4-isopropylidene-clindamycin

100g Γ-desmethyl-l '- (beta-hydroxyethyl) -clindamycin. 100 g p-toluenesulfonic acid hydrate and 61 g acetone were stirred at 25 ° C for 60 hours. The unreacted starting material was filtered off, and that The filtrate was adjusted to pH 7 with 5% sodium bicarbonate solution. The acetone was taking Removed vacuum and the aqueous phase was extracted with chloroform. The chloroform extracts were evaporated in vacuo to give a residue which was chromatographed on silica gel using a solvent system of chloroform and methanol in the ratio of 6: 1 has been cleaned. The product fractions were identified by thin layer chromatography, combined and evaporated, 34 g of 1 '-desmethyl-1' - {beta-hydroxyethyl) -3,4-isopropyIiden-clindamycin (Yield: 31%).

B. Preparation of 1 '-desmethyl-l' - (trityloxyethyl) -3,4-isopropylidene-clindamycin

A mixture of 34 g of Γ-desmethyl-l '- (beta-hydroxyethyl) -3,4-isopropylidene-clindamycin, 115 g of chlorotriphenylmethane, 1 l of acetone and 200 ml of triethylamine was heated under reflux for 4 hours. The reaction mixture was heated with 11 hexane mixture and allowed to cool to 25 ° C. The precipitate of triethyiamine hydrochloride was filtered off and discarded. The filtrate was under vacuum

evaporated and the residue was chromatographed on silica gel using a solvent system purified from hexane mixture and acetone in a ratio of 2: 1. The product fractions were identified by thin layer chromatography, combined and evaporated to give 20 g (yield: 40%) I '-desmethyl-1' - (triyloxyethyl) -3,4-isopropylideneclindamycin were obtained.

C. Preparation of l'-desmethyl-1 '- (betahydroxyethyl) clindamycin-2-cyanoethyl phosphate

Under a nitrogen atmosphere, a mixture of 40 g of 1'-desmethyl-1 '- (trityloxyäthxl) -3,4-isopropylidene-clindamyein, 400 ml of a 1 η solution of pyridinium cyanoethyl phosphate in pyridine, 160 g of dicyclohexylcarbodiimide and 1 l of pyridine was stirred at 25 ° C. for 60 hours. The reaction mixture was then 300 ml Water was added, the mixture was stirred well and cooled to 5 ° C. within 18 hours. The precipitate was filtered off, washed with 400 ml of pyridine, and the combined filtrates and wash water were taken to dryness under vacuum evaporated. The residue was dissolved in 500 ml of dimethylformamide and dried under vacuum evaporated. The residue was dissolved in 400 ml of acetic acid and 100 ml of water and kept at 95 ° C. for 30 minutes warmed up; it was then evaporated to dryness in vacuo. The resulting residue was dissolved in 300 ml of dimethylformamide and taken under

jo vacuum again evaporated to dryness. The residue obtained in this way was treated with 300 ml of ethanol shaken, filtered and the filtrate evaporated to dryness. The residue was washed with 100 ml of ethanol plus 200 ml of water at 25 ° C for one hour, filtered, and the filtrate was added under vacuum Evaporated to dryness. The resulting residue was by chromatography on silica gel under Use of a solvent system composed of chloroform, methanol and water in a ratio of 4: 3: 1 The product functions were purified by thin layer chromatography identified, combined and evaporated under vacuum, whereby 30 g (yield: 94 ', o)

1'-desmethyl-1 '- (beta-hydroxyethyl) clindamycin) -2-cyanoethyl phosphate were obtained.

D. Preparation of 1'-desmethyl-1 '- (betahydroxyethyl) -clindamycin-2-phosphate hydrate

A mixture of 30 g of l'-desmethyl-l '- (beta-hydroxyäthylj-clindamycin ^ -cyanethylphosphate, 500 ml of concentrated ammonium hydroxide and 1 l of water was stirred at 25 ° C. for 24 hours. The reaction mixture was filtered and the filtrate was vacuumed evaporated to a volume of about 1 I. This solution was freeze-dried, and the residue was dissolved in 1 liter of water and passed through a column of 1400 g of an ion exchange resin in acetate form with a particle size of 0.29 to 033 mm Washed water, and the product was then eluted from the resin with a 3% acetic acid solution. The effluent was monitored by thin layer chromatography and the product fractions were combined and freeze-dried. The residue was crystallized from a mixture of acetone and water, 9.5 gt ' -Desmethyl- V- (beta-hydroxyethyl) -clindamycin-2-phosphate hydrate were obtained as a white crystalline product in a yield of 35%; melting point: 194-196 ° C

Analysis: for C ₁₉ Hj ₆ ClN ^ OqPS · (χ) H ₂ O

ber.

C 42.65; H 6.78; N 5.24; S 5.99;

Cl 6.63; P 5.79.
found

C 42.85; H 6.60; N 5.33; D 5.86; Cl 6.51; P 5.99.

(Corrected for water) [α] »2 ° + 116 ° (.., 0.9428).

Claims (1)

Claims; 1. r-Desmethyl-r- (beta-hydroxyethyl) clindanjycin-2-phosphate of the formula CH ₃ and its salts. Z Hydrochloric! the compound of claim 1. 3. A method for preparing the compound according to claim 1, characterized in that one in a manner known per se