CS221801B2 - Method of praparation of the derivative of 4-deoxy-4-aminoerythromycine a - Google Patents

Abstract

New semi-synthetic derivatives of 4''-erythromycin A and their preparation are described. The new compounds of the invention correspond to the formulae I and II in which the symbols have the meaning given in Claim 1. The compounds of formulae I and II, in which X and Y are a pair H, NH2, possess antibacterial properties and can be used as medicinal products. <IMAGE>

Description

From the structure It is evident that erythromycin forms three major parts; sugar as cleavage fragment, i.e. cladinose, another sugar moiety containing a basic amino group, i.e. sosamin and fourteen lactone ring referred to as erythronolide A or B include _{macrolide, or} between cycles. The lactone ring is numbered directly, the desosamine part by numbers and one comma, and the nasal part by numbers with two commas.

In order to modify the biological and pharmacodynamic properties of erythromycin, numerous derivatives of this substance have been said.

U.S. Pat. No. 3,417,077 relates to the reaction product of erythromycin and ntylene carbonate; the product should be a very effective antibacterial agent. U.S. Pat. No. 3,884,903 describes 4 ' -deoxy-4 &apos; -oxoerythromycin derivatives A and B, which are very preferred antibiotics.

Erythromycylamine, i.e., the 9-amino derivative of erythromycin A, is of considerable interest, see British Patent No. 1,100,504 and Tetrahedron Letters 1967, 1645, hereinafter Croatlm Chem. Acta 31, 273 (1967) and there is a contradictory view of the structure, see Tetrahedron Bethlehem 1970. 157 and British Patent Specification No. 1,341,022. Sulfonamide derivatives of erythromycylamine are disclosed in U.S. Patent No. 3,983,103 as a suitable antibacterial agent. dla. Still other derivatives are described, see Ryden et al., J. Med. Chem. 3,6, 059 (1973), and Massey et al., J. Med. Chem. 17, 105 (1974), which are characterized by pM UHU in vitro and in vivo antibacterial activity.

It has now been found that some novel 4''-deoxy-4''-aminoerythromycin A derivatives are extremely potent antibacterial agents. These compounds correspond to the general formula (||

(III) where

Rl and RG are hydrogen atoms or alkanoyl of 2 to 3 carbon atoms, R3 is hydrogen or Rg ^® к з together form a group -C-, R is hydroxy and R form a bond with the carbon atom to which it is attached, R * or R * is O and R is hydrogen, wherein when R8 is hydrogen, R is hydrogen.

In the description of the present invention, the stereochemical labeling substituents on both the sugar moieties and the macrolide ring, except for the epimerization at the 4 ** position, where stereochemistry is indicated, always correspond to natural erythromycin A.

Also included within the scope of the present invention are erythromycin B derivatives. The amines of the group of erythromycin B corresponding to the compounds of formula III are also suitable antibecterial agents.

Several synthetic routes may be used to prepare antibacterial agents of formula III from the corresponding ketones of formula I. One of them is the subject of the present invention. SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the 4 ** -deoxy-4-miinoerythromycin A derivatives of formula III

(III) and the corresponding fax-pharmaceutically acceptable acid salts, wherein R1 and _R2 are hydrogen or e.tomy alkanoyl of 2-3 carbon atoms, R is hydrogen, or R ₂ and R together form a SKU ^p in ^u -C-, R * is hydro-la R form with the atom Weigh oppression to Seremo ^j e ^R * attached or R * is = 0 and R is hydrogen, wherein if R ₂ is hydrogen, R is hydrogen, characterized by there that the compound of formula I

(I) where

R, R * R, Rj and Rj are as defined above, reacted with ammonium alkanoic acids and the imine formed as intermediate is reduced by hydride or catalytic reduction and optionally if R or ^R 2 is hydrogen, optionally converted to alkanoyl and / or when R 1 or R 8 is alkanoyl, optionally converted to hydrogen and optionally prepared pharmaceutically acceptable with an acid;

In practice, an ammonium salt of an alkanoic acid, such as acetic acid, is added to a solution of the ketone of formula I in a lower alkanol such as m-Beylalkoboo, or is is added, and sodium is added to the cooled reaction mixture. The reaction mixture is allowed to proceed for several hours at room temperature, then the reaction mixture is quenched by the addition of water and the product is isolated from the reaction mixture.

Although 1 mole of ammonium salt of alkamic acid is to be taken per mole of ketone, it is advantageous to work with an excess of ammonium salt, up to 10 times for the reaction to proceed completely and completely to form rapidly. influence.

If the amount of the reducting agent is concerned, it is preferred to use about 2 moles of sorbitol per mole of ketone.

The reaction time varies with the concentration, reaction temperature and reactivity of the reactants. At room temperature, which is the preferred reaction temperature range, the reaction is essentially complete in 2-3 hours.

As described above, complete cleavage of any cleavage group at the 2 * position occurs, as mentioned above. To avoid this phenomenon, it is recommended to use isopropyl alcohol as the reaction solvent.

The preferred ammonium moiety of the diacid is, as already mentioned, octosulfate

The isolation of the 4 &apos; -isyl-4 &lt; 4 &gt; -C &lt; 4 &gt; -carbocrystalline A derivatives and separation from non-conventional by-products or starting materials is advantageously utilized in the basic nature of the final product. In this mixture, the aqueous solution of the product is extracted at a gradually increasing pH so that the neutral or non-basic fractions are extracted at lower pHs, and the product is extracted at-pH above 5. The reaction mixture is either ethyl acetate or ethyl acetate. or diethyl ether, washed back with sodium chloride solution and water, and after drying the organic solution with anhydrous sodium sulfate, the product is isolated by stripping off the solvent. Longer possible cleaning is carried out. using column chgomaCo1rβC‘in to ^ Ш ^ п ^ using known procedures.

As mentioned above, it is possible to perform the solvolytic cleavage of a group of 1 (2-dimethylamino-4 * -noyl-4 * C-) _{and (} III) non-cyclophocyte A so that a solution of said compound in the of methanol was allowed to stand overnight at room temperature.

Reductive amination of the ketones of formula (1), wherein R 8 and R 8 together represent a carbornyl group of R 3, represents an alkenyl group having 2 to 3 carbon atoms or hydrogen, amines of formula III-IV are formed. The reaction is shown in the following scheme:

(AND)

O ^ nh ₂ and ₃ (III &gt;)

(R ₂ + R = -C-) * ^J 11 o

(IV) o

As the products of amines III and IV obtained, they can usually be separated by selective crystallization from diethyl ether. Crystallization of a mixture of compounds of formula III and IV from a mixture of acetone and water produces hemiketal for the amine of formula IV, and it is possible to isolate the amine of formula III as a single product.

Compounds of formula III wherein R, Rp R2, R3 and R * are as defined above are also prepared by reduction of the above imine using hydrogen and a suitable hydrogenation catalyst. In this process, a suitable ketone of formula I is dissolved in a lower alkanol, such as methanol or isopropyl alcohol, to the solution is added an ammonium salt of a lower alkanoic acid such as acetic acid, a hydrogenation catalyst, and the reaction mixture is shaken under a hydrogen atmosphere until the reaction is substantially complete.

Although 1 mole of ammonium salt of alkanoic acid per mole of ketone is required, it is preferable to use an excess of ammonium salt, up to 10 times, so that the reaction is complete and that the imine formation proceeds rapidly.

The hydrogenation catalyst can be selected from a wide variety of reagents such as Raney nickel or 5-10% palladium on activated carbon, which catalysts are preferred. They can be used in varying amounts depending on how fast the reaction is to proceed. The amount of catalysts ranges from 10 to 200% by weight.

The hydrogen pressure in the hydrogenation device also affects the rate of reaction. It is advantageous from the standpoint of reaction time to use an initial hydrogen pressure of 50 psi, and from the standpoint of embodiment it is also preferred to operate at room temperature.

The reaction time depends on a number of factors such as reaction temperature, pressure, concentration of the reactants and their immediate reactivity. Under suitably selected conditions, the reaction is complete in 12 to 24 hours ·

The product is isolated by filtering off the catalyst used, distilling off the solvent in vacuo, adding water to the residue, and separating the product from the non-basic components by extracting the basic product from water at varying pH values as previously described.

As already mentioned, when methanol is used as a lower alkanol, the solvolytic cleavage of the alkanoyl groups from the 2 * position will essentially occur. Isopropyl alcohol is used as reaction solvent to prevent cleavage.

As default

The compounds Ia and Ia correspond to the general formulas

(Ia) (Ib) wherein A 2 and R ₂ are alkanoyl and 2 to 3 carbon atoms, R 1 is hydrogen and R ₂ and R 1 are both carbonyl and are prepared by treating a compound of formula Ia * and Ib *

(Ia *)

one mole of dimethylsulfoxide and trifluoroacetic anhydride in a reaction-inert solvent at a temperature of about -30 to about -65 ° C, followed by contacting the reaction mixture with at least one mole of triethylamine;

A preferred embodiment of this process for oxidizing these compounds is to work in methylene chloride as a reaction-inert solvent.

In another method, compounds of formulas Ia or Ib above wherein Ac a is C 2 -C 3 alkanoyl, Ry is hydrogen, and R ₂ together with R 1 is carbonyl are prepared by reacting the compound of formula (Ia *) or (Ib *) with one mole of succinic acid N-chloroimide and dimethylsulfide in a reaction-inert solvent at a temperature ranging from 0 to -25 ° C, then contacting the reaction mixture with at least one mole of triethylamine.

A preferred embodiment of this process is the use of toluene and benzene as reaction-inert solvents.

In practice, trifluoroacetic anhydride and dimethyl furyl are first cured in a reaction-inert solvent medium at about -65 ° C. After 10 to 15 minutes, the alcohols 1a 'and Ib' are added to such engraving. that the temperature is maintained at about -65 ° C and does not rise above -30 ° C. The reaction temperature is maintained at -30 to -65 ° C for 15 minutes, then lowered to about -70 ° C, tertiary amine is added all at once, and tertiary amine is added all at once. The temperature of the reaction mixture is allowed to rise slowly to room temperature over a period of 10-15 minutes. The reaction mixture is then diluted with water and treated.

With respect to the amount of reactants, 1 mol of both trichloroacetic acid anthyldride and dimethyl sulfoxide should be used for each mole of alcohol as a subbrate of 1 mol. . The amount of tertiary amine used should correspond to the molar amount and multiplication! of the acid arihydride used

The solvent which is inert under the reaction conditions of the process should be a solvent that dissolves the reactants well and does not react more extensively with any of the reactants without the reaction product. Since the oxidation process is carried out with cooling in the range of -30 to -65 ° C, it is preferable that, in addition to the above properties, the solvent used has a solidification point below said reaction temperature. Similar solvents, or mixtures that meet these requirements, are Toluene, methylene chloride, ethyl acetate, chloroform, or tetrosulfuric solvents which meet the above requirements but have a solidification temperature above the above reaction temperature may be used in smaller amounts together with any of the preferred solvents mentioned above. solvent in this process can be characterized by meelidochloria · time is not critical and is dependent on reaction temperature and - immediate reactivity of starting reagents · At -30 to -65 ° C the reaction is completed in 15-30 minutes ·

Regarding the order of addition of the reactants, it is preferable to first mix the trifluoroacetic acid anthyride with dimethyl sulfoxide, followed by the addition of the reducing alcohol as described above. reaction temperature below -30 ° C; this is in line with the data reported by Omira and sppK, J · Org · Chem. - 41 · 957 (1976) ·

The second method used to prepare the starting compounds for the preparation of antibiotic agents is characterized by the following scheme:.

O

O

221601

The second method is an oxidation reaction wherein the 4 &apos; -hydroxy derivative of a compound wherein A &lt; ₂ &_gt; and R &lt; _{2 &gt;} is C2-C3 alkanoyl, R &lt; ₂ &_gt; 4 ** - deoxy-4 ** - cxoerythromycin group A.

N-chloro succinic acid and dimethylsulfide are used as oxidizing agents in this process, and in the practice of the reaction, the two reactants are first mixed together in a solvent inert to the reaction conditions and cooled to about 0 ° C. After 10 to 20 minutes, the temperature of the reaction mixture is lowered from 0 ° C to -25 ° C and the hydroxy derivative is added while still maintaining the above-mentioned temperature. After a reaction time of 2-4 hours, a tertiary amine, such as triethylamine, is added to the reaction mixture, and the reaction mixture is quenched with water and worked up.

Considering the amount of reactants, each mole of alcohol as a substrate has a mole of both succinic acid N-chloroimide and dimethylsulfide, but it is preferred to use up to 20 times the succinic acid and sulfide imide derivatives as reactants, taking into account Acceleration of reaction · The amount of tertiary amine should correspond to the molar amount of succinic acid N-chlorimide used.

The reaction-inert solvent used in the process of the present invention should be one which dissolves the two reactants well and does not react substantially to any of the reactants without the products formed. Since the reaction is carried out at a temperature of 0 to -25 ° C, it is preferred that the solvent used, besides the above properties, have a freezing point below the reaction temperature and such solvents or mixtures which meet the above requirements are toluene, ethyl acetate, chloroform, methylene chloride. or tetrahydrofuran. Solvents that meet the above requirements but have a freezing point above the reaction temperature are also useful, but in smaller amounts together with one or more of the preferred solvents mentioned. A particularly preferred solvent for use in the above process is a mixture of toluene and benzene.

Of course, when utilizing the chemotherapeutic efficacy of those salt-forming compounds of Formula III, it is preferred to use pharmaceutically acceptable salts. Although, in view of water insolubility, high toxicity and crystallization difficulties, some of the salts may be inappropriate or less desirable for use as a drug, the salts, if water-insoluble or toxic, may be converted to the corresponding pharmaceutically acceptable bases by decomposition salts as described above, or further can be converted to any other pharmaceutically acceptable acid salt.

Hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric or sulfuric acid, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic and aspartic acids are examples of acids whose anions are pharmacologically suitable.

221601

As already mentioned, the stereochemistry of the starting compounds leading to the antibacterial agents of the invention corresponds to the natural substances. Oxidation of the 4'-N-hydroxyl group to the keto group followed by converting the obtained ketone to the 4 ** -fiminodiviate gives the possibility of granular stereochemistry of the 4 ** -substitute, a substance different from the natural product. Accordingly, if a compound of formula I is converted to amines in the manner described herein, it is possible that two epimeric amines are formed. It has been experimentally confirmed that both epimeric amines are mixed in the final product, i.e., in a melt. on the procedure. If the recovered product predominantly spills one of the epimers, the eptmer may be purified by repeated recrystallization from a suitable solvent until the melting point is constant. The second epimer, the one that represents a smaller subset in the initially hardened solid, is predominantly contained in the mother liquors. It can be isolated therefrom in accordance with generally known methods, for example by concentration of the mother liquor - and by repeated crystallization of the residue until a product with a constant melting point is obtained.

Although the mixture of eptomers can be separated using methods known to those skilled in the art, for practical reasons it is preferable to use the mixture obtained as it is isolated from the reaction mixture. However, it is often preferred to purify the mixture of esters by at least one crystallization from a suitable solvent, or by column chromatography or high pressure liquid chromatography, solvent partitioning, or comminution in a suitable solvent. In said purification, although not necessarily leading to epimer separation, unwanted compounds such as starting material and unsuitable by-products are removed.

Abbslut stereochemistry of eptmers has not been resolved yet. However, both epters of one or another compound are characterized by the same type of activity, i.e., they are the aliibackerial agent.

Novel derivatives of 4 ** - * dloxyl4 mlinoeryhhlooyctiu L-A, as described above, are marked in vitro against numerous účinnoosí Grao-polZtivni mikroorgansMiům, 'such as Staphylococcus aureus and Streptococcus pyogenes, as well as activity against _a Gram-negative micro- to directions such as coca. Their efficacy is readily demonstrated by in vitro assays against multiple micelorgaltimus for brain and heart infusion environments and double dilution techniques. In view of their in vitro potency, they are suitable for topical use in the form of ointments, creams; for diagnostic purposes, for example for the inventory of the most corners of rooms, and as an industrial antibiotic, for example in water treatment, sludge control, paint and wood preservation.

In in vitro assays, i.e., for example, in the case of fevered taste, it is often preferred to add the active compound in admixture with a pharmaceutically acceptable carrier, such as a vegetable or mineral oil, or a rub-in cream. Similarly, they may be dissolved or dispersed in a liquid carrier or diluent. such as water, alcohols, glycols or their sulfides, or other pharmaceutically acceptable inert media; that is, an environment which does not reveal a detrimental effect on the active ingredient. For such purposes, an active ingredient concentration of from about 0.01% to about 10%, as a function of the weight of the composition per se, is generally suitable.

Furthermore, the numerous compounds of the present invention, as well as their acid addition salts, exhibit superior activity against gram-positive and some gram-negative microorganisms, such as Piasetuella outtlciia and Neisseria sicca, both in vivo and / or in vivo. en not proper application to animals, including humans. Their in vivo efficacy is more reliable with respect to susceptible organisms, and is established by conventional procedures of infecting approximately the same amount of test organism and then administered orally or subcutaneously with the test compound. In practice, for example, a group of 10 flies is inoculated appropriately with a dilute culture of up to about 10 bD (the lowest concentration of organism required for 100% death). At the same time it was carried out ^ η ^ οΐη! Inoculation tests, inoculated with a lower dilution to evaluate possible variations in the vivacity of the test microorganism. The test compound is administered 30 minutes after seeding and is repeated at 4, 24, and 46 hours post-exposure. Mli who survive are maintained for 4 days after the final treatment, after which the number of survivors is recorded. For use in vivo, the compounds of the invention may be administered orally or enterally, for example, by subcutaneous or intramuscular injections, at a dosage range of from about 1 mg / kg to about 200 µg / kg body weight per day. A preferred dosage range is from about 5 m 2 / kg to about 100 mg / kg body weight per day, most preferably from about 5 m 2 / kg to about 50 mg / kg body weight per day.

Suitable carriers for ethereal injections may be aqueous, such as water, isutonic sodium chloride solution, isutonic glucose solution, or RLnger's ruztuk, or non-aqueous, such as olejeШ ^ oils, for example cottonseed, underwent, maize, sesame gray. Diluents which do not interfere with the therapeutic effect of the preparation and are non-toxic in the used image or article, such as glycerol, prupplernlycol, soubitol. Preparations suitable for the occasional administration of crescent may also be prepared. Such formulations comprise liquid diluents, such as prupydiethylester, glycerol, surbitulum, etc., as well as suspending agents. tyalurucate, topical aneesetics and inorganic salts The compounds may also be comto. - with various and pharmaceutically acceptable inert carriers, including solid diluents, aqueous solutions, non-toxic urganic solvents, and may be capsules, tablets, x-rucs, pills, dry silica, suspensions, risers, or oral solutions or suspensions in the formulation. The compounds of the present invention may be used in varying doses in conjunction with from about 0.5% to about 90%. calculated on ¹ weight of total product ·

Further examples are appended only to illustrate the process of the present invention without departing from the scope of the invention, since numerous variations are possible without departing from the scope of the appended definition. l · í k 1 and d 1

S -aeuyl-4 ** - deuxy-4 * * -uxuery thtumycin A

A mixture of 3 ml of meylene chloride and 0.328 ml of dimethyl sulfuxide was cooled to about -65 ° C and 0.652 ml of trisic acid anhydride was added thereto under nitrogen. A solution of 1.0 g of 2 * -actylerythuomyclic A adduct with ethyl acetate of acetic acid, obtained by crystallization of 2 * -acetylethylthyoyl acetate A from ethylacetate acetic acid, in 7 ml, was added dropwise to the ice and the suspension. The reaction mixture is stirred for 15 minutes with cooling to about -60 ° C, stored at -70 ° C, and the reaction mixture is rapidly stirred at -70 ° C. 1.61 ml of triethylmnt is added, the cooling bath is stirred and the reaction mixture is stirred for 15 minutes; then the reaction mixture is diluted by adding 10 ml of water and the pH of the aqueous phase is adjusted to 10. The organic phase is washed successively with water (3 x 10 ml) and sodium chloride solution (once with 10 ml) and dried dry. símem sodium. OdíínSilován: m solvent from the filtrate under reduced pressure to isolate 929 mg of crude product P · ^ ekryttalovác m sjo081 oeeylénclnoriíu from hexane gave ²⁰ mg of 3 dštěného product ^t · ^t · ¹⁰⁵ and ^{from 108} ° C ·

NK-spectrum (<5, CIDCl3 3.28 (3H) single), 2.21 (6H) single, 2.03 (3H) single * ·

In a similar manner as deserts adduct 2 * -propiocyleryth1omycicu A ntylntterem acid ^alkyl вeli ^{cy. and} potužtí výěe foregoing procedure ZIS ^ka 2 '-prupi1t ^{rУ "4 d} ** ^<4 ** ^no uχУ- ^uOX1nr У ^Thr оу ^U / 1с. AND·

Example 2

4 ** - deoxy-4 ** - oxoerythromycin A

A solution of 4.0 g of 2 ' -acetyl-4 &apos; -deoxy-4 &apos; _O xeerythromycin A in 75 ml of methyl alcohol was stirred at room temperature for 20 hours. After removal of the solvent in vacuo, the residual white foam was recrystallized from methylene chloride. oride and hexane; m.p. 170.5-172.5 ° C.

NMR spectrum (s, CDCl 3, 3.36 (3H) singlet), 2.33 (6H) singly.

The product, which is identical to the above, is isolated after the reaction of 2'-pyropanol.

-dto: oУ “4 ** ooocyroomroomycin A and methyl alcohol, and temperature

Example 3'-Acetyl-4'-deoxy-4''-oerythylroomycin A

2.3 ml of acetic anhydride are added to a stirred solution of 13.7 g of 4 ** - 4-deoxyl-4 ** -phosphoryl A in 100 ml of acetic acid and the reaction mixture is stirred for two hours. room temperature. The solution is poured into 100 ml of water and the pH of the aqueous phase is increased to a value

9.5 by adding 6N sodium hydroxide solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give 14.5 g of a white foam, which was recrystallized from ethyl acetate and hexane. The substance is identical to the product of Example 1 »

Example 4

4 '' -dts: ol-4 '* -aminotrythrooycin A

A solution of 2.17 g of 2 * -acttll-4 ** - tesoy-4 ** - vinylerythsomytin A in 50 ml of methanol is stirred at room temperature overnight, the solvent is distilled off under reduced pressure and the residue is fully concentrated. 50 ml of chloroform and 50 ml of water are added. The pH of the aqueous portion was adjusted to 9.5, the aqueous portion was treated, the chloroform layer was washed with fresh water, and the pH was adjusted to 4.0. The pH of the acidic aqueous layer surrounding the product is gradually increased to 5, 6, 7, 8 and 9 with the addition of a base, and extraction with fresh chloroforato is performed at each pH value. The extracts taken at pH 6 and 7 collect the major portion of the product, which extracts are washed with fresh water at pH 4. The aqueous layer is again brought to pH 5, 6 and 7 and extraction is carried out at each pH value. fresh chloroform. The chloroform extract, taken at pH 6, was dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness to give 249 mg of the epimer product.

NMR Spectrum (.delta., CDCl3 3.30 (1H) singlet, 3.26 (2H) Si, 2.30 (6H) 6, 1.46 and 1.46 (3H) single.

Similarly prepared was 4-4 ** ** ídesoy hmlinoeryUroml solvolysis ^{of C} in a 2 * - ^ propiony. 4 * 4 ** -ítsxy hmitnstrythromlcinu A.

EXAMPLE 5 ^[ α] ts -4 tsχ * ^ ^{z z z z z z z z z z z z z z z z}

3.16 g of dry ammonium acetate are added to a stirred solution of 3.0 g of 4-ethoxy-4-ethoxy-A in 30 ml of ethyl alcohol under nitrogen and flushed into the reaction mixture 188 mg in 5 minutes. Methyl chloride was added with 5 mL of methanol and the reaction mixture was stirred at room temperature. overnight. The light yellow solution is poured into 300 mL of water, the pH of the aqueous solution is adjusted to 6.0, the aqueous solution is extracted at pH 6, 7, 7.5, 8, 9, 10 using

125 ml diethyl ether for each extraction. The extracts obtained at pH 8, 9 and 10 are combined and washed with 125 m of fresh water. The separated aqueous layer was extracted with ether (100 ml) at pH 7, ethyl acetate (100 ml) at pH 7, ether (100 ml) at pH 7.5, again with ethyl acetate at pH 7.5 ( 100 ml), and then 100 ml of ethyl acetate each time, at pH values of 8, 9 and 10. The extracts in ethyl acetate obtained at pH values of 9 and 10 are washed with a saturated solution of sodium chloride. and dried over anhydrous sodium sulphate. The JC-epimeric mixture of the expected product, colored ivory, is isolated by removal of the solvent in vacuo.

EXAMPLE 6 4 ** Eeyrosyr-4-AminoeylethoomycinCin A (single epimer)

A solution of 10.0 g of an epimeric mixture of 2 * -acetyl-4 ** - eeoχ-4 ** - minoerythromycin A in 150 µl. of methanol was stirred at room temperature under nitrogen for 72 hours. The solvent was distilled under vacuum and the residue dissolved with stirring. in a mixture of 150 µl of water and 200 µl of chloroform. The aqueous layer is not needed, another portion of 150 ml of fresh water is added to the chloroform layer, the pH of the aqueous portion is adjusted to 5 and the chloroform layer is separated by pH of the aqueous portion is gradually adjusted to 5.5, 6. , 7, 8 and 9, and extraction was always carried out using 100 .mu.m of fresh chloroform. Chloroform extracts, taken at pH 6, 7 and 8, are washed with water and saturated sodium chloride solution successively, the organic solution is dried over anhydrous sodium sulphate and the solvent is removed in vacuo to give 2 - 9 g of epimeric mixture 4 **. A. Sample from this 1.9 g mixture was triturated with diethyl ether and some of the undissolved master product was crystallized. The solids were filtered and dried to give 67 mg of a single 4 &apos; -eu-y-4 _&lt; -1 &gt;

Example 7

6.9-Hepiketal 11, 2'-diacetyl44 * d-doyy44 * * -oxeerylwonycine A

To a solution of 10 g of 2--kceeyj * 4 ** - ** eeuχj-4 - oxoerythrorycinu A .in 250 ml of PA-pyrrolidin 40 ml KCH ^r Drieu acetic acid and the reaction mixture was allowed to stand 1O days at room temperature. The bulk of the solvents were separated in vacuo, and the remaining concentrate was poured into 150 µl of water and 100 ml of chloroform. The pH of the aqueous portion was raised to 9.0, the chloroform layer was made, dried over anhydrous sodium sulfate, and concentrated to dryness.

NM spectrum (δ, CIDCl3: 3.33 (3H) singlet, 2.26 (6H) singlet, 2.10 (3H) singlet,

2.03 (3H) single t, 1.55 (3H) single t.

Example8

6.9- heeta ^^ 11 11-ketyl-4 ** edo-yy44 ** - ouerjyhroorycicu A

A solution of 3.0 g of 9.6 g of 11.2% decacetyl-4-deoxy-4 * -acrylic acid in 50 ml of stirring was stirred. under nitrogen for a period of time, the solvent is removed in vacuo to give the expected product in a yield of 3.0 g as a yellow foam.

.delta. (CDCl3): 3.35 (3H) singlet, 2.31 (6H) singlet, 2.13 (3H), and 1.55 (3H) singlet.

Example 9

6.9- hernHltal 11-1-ethyl-4 ** erloy-44 * 1-nitrtytyrrolidine A

To a stirred solution of 4.4 g of 6,9-hemiketal 11-cetyl-4 ** edeoxy-4'-oorrttlromylamine A and 4.38 g of ammonium acetate in 75 ml-mm 2 was added 305 mg. The reaction mixture is stirred at room temperature for one night, then poured into 300 ml of water, poured into a pH of 9.8. The chloroform layer is separated. The aqueous phase is back extracted with chloroform, the chloroform extracts are combined dried with anhydrous sodium sulphate and distilled off: white foam product is isolated from chlonphomium. This is dissolved under stirring in 125 ml of water and 125 m of fresh chloroform, the pH is drained to 4.9, the chlorine solution is separated (not available). appropriate), the pH of the aqueous layer adjusted successively to a 5, 6, 7 and 8, and after each pH adjustment with aqueous Poodle extracted with fresh chloroform and the extracts, taken at pH 6 and 7 _tpplí> for ^ y ^ i with saturated sodium and dried over anhydrous sodium sulfate. Separated: the solvent is isolated 1.72 g of the expected product as a white foam. The product is isolated in a minimum amount of diethyl ether and hexane is gradually added to the oily solution until turbidity. The crystalline product thus formed is collected and dried to give 1 g. , 33 g of substance, mp 204.5 to 206.5 ° C ·

Nffi-epektrum (δ, CX1 _3): 3.31 (2H) s, 3.28 (1H) sídlet, 2.31 (6H), singlet, 2.11 (3H) and 1.5 s (3H) singet ·

Example 10

Dichloro-11,1-ester with 6,9-hemiketal of 2 * -actytyl-1-bromo-thromine A

1.8 ml of acetic anhydride are added to a solution of 13.2 g of the 6,9-hemiketal of 11,12-carbonic acid 3 with erythromicin A (see U.S. Pat. No. 3,417,077) in 150 ml of benzene, and the reaction mixture is stirred at room temperature for 1.5 hours. The solution is poured into 200 ml of water. The aqueous phase is brought to pH 9.0. The benzene layer is separated, dried over anhydrous sulphate. 15.3 g of a white foamed solid is isolated with sodium 1, concentrated in vacuo. Triuurate with 50 m of diethyl ether is foamed and filtered and dried to give 12.6 g of pure substance, m.p. to 228.5 ° C ·

NMR (.delta., CIDCl3): 3.36 (3H) singlet, 2.30 (6H) singlet, 2.06 (3H) singlet and 1.61 (3H) singlet ·

Example 11

6.9-) ^^ 10161 j ^-dextrichloro ester with 2 * -1ir-l-4 ** ^ · dooχ4-4 ** - oerУtlrOrotycir A

To a suspension of 6.19 g of N-pyrrolidine succinic acid in 150 ml of toluene and 30 ml of benzene is added 4.46 ml of ethyl acetate at -5 DEG C., the suspension is stirred for 20 minutes, then the mixture is stirred for 30 minutes. ! 12.4 g of 6 _{J of} 9-methyl-1H-carbonyl ester with 2'-diethyl-tertylmycin A, partially dissolved in 80 ml of toluene, are added dropwise to the mixture at -25 ° C. -25 ° C, then held for 2 hours. -25 ° C and at the end of this time, 6.79 ml of thiamethylamine were added (one at a time). The addition bath was removed, the temperature was allowed to rise to -10 ° C and the reaction mixture was then poured into water. The pH of the aqueous phase is adjusted from 8.4 to 9.0. The organic phase is separated, dried over anhydrous sodium sulfate. Concentrated in vacuo to a white foamed product (14.0 g). 11.3 g of tritilic malteral, mp 212-213.5 ° (.delta., IDCI3): 5.26 (1H) triplet, 3.36 (JH) single, are recovered by drying; 2.30 (6H) singles,

2.13 (3H) si, 1.63 (3H) single! 1 1.50 (3H) single ·

Example 12

6.9-herniketal of 11,12-ether Hydroxy acids with 4 '* - deoxy-4 ** - oxoeryllucycin A

800 Ol meOylalkotolu of yield 42.9 g of 6,9-11,12-temiketaLu uřhičiié ester to the acid with 2 * ^d * -acetyl44 ^o eoзς ⁴ -4 ⁰ ooeori ^tr0 rorycioem · A and the resulting solution was stirred at room iepLoi ^y After 72 hours · 41 g of product is isolated as a white foam by separating off the solvent in vacuo. The remaining material is dissolved in about 100 OL of acetone and water is added carefully until it starts to precipitate. precipitate · The crystalline solid obtained is stirred in liquid ». 40 minutes headquarters; it is then filtered off and dried to give 34.2 g of the expected product, m.p. 186.9-188 ° C.

NMR spectrum (δ, CIDCl3): 5.66 (1H) triplet, 3.35 (3H) single t, 2.35 (6H) single, 1.65 (3H) single and 1.51 (3H) single t ·

Example 13

6.9-haloalkyl 11,12-osoic acid with 44% deo ^, 4 &apos;

To a solution of 189 g of 6,9-dimethyl-11,12-ester of acid with 4'-dehydro-4-oxo-oxo-thyoycin A in 1200 ml of sodium is added under stirring at room temperature with stirring 193 g of ammonium acetate and cooled in 5 minutes. The resulting solution is about -5 ° C and 13.4 g of 85% sodium borohydride in 200 ml of methanol are added in succession over 45 minutes. The settling is discontinued, the reaction mixture is stirred overnight, concentrated in vacuo to a volume of 800 ml and the residue is poured into a mixture of 1800 ml of water and 900 ml of chloroform with stirring. The pH is adjusted from 6.2. to 4.3 with 6N hydrochloric acid solution and the chloroform layers were separated. The mixture was mixed with water, adjusted to pH 9.5, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 174. g of the white master product. The remaining oothioel is dissolved in a mixture of 1 liter of water and 500 ml of ophthalic acid ophthalmate, the pH is adjusted to 5.5, the organic solvent layers are separated, and the pH of the aqueous layer is adjusted to 5.7 and 9.5. After each pH adjustment, the reaction is carried out using 500 ml of clarified ethyl acetate of ethyl acetate, obtained at pH 9.5, dried with anhydrous sodium sulphate and concentrated in vacuo. 130 g of a foamed product are obtained. From this, 120 g are dissolved in a liter of water and a liter of water, the pH of the aqueous layer is adjusted post-treatment to 4.4, 4.9 and 9.4, after each treatment The pH was adjusted to about pH. The solution in water at pH 9.4 was dried without drying over sodium sulphate and 32 g of the product were obtained as a white solid in a vacuum. Foam · Kys 28.5 g of crystalline opioids are isolated by sensing from 250 ml of a 1: 1 mixture of acetone and water.

NMR spectrum (δ, CIDC ₃ ): 5.20 (1H) muutiplet, 3.37 (1.5H) singlet, 3.34 (1.5H)

2.36 (6H) singlet, 1.66 (3H) singles and 1.41 (3H) singles ·

Example 14

Separation of epi-6 6,9-tooiketal α 4 ^ iket г п uh uh uh 4 4 4 4 4

In high tL. The liquid chromatography ultraviolet column (1.2 cm by 9 cm) was impregnated with Gf 254 sililtgol with a formmid and coated with chloroform containing 200 g of a mixture of epimers. 4.76 ml per minute and fraction after

m. · Fractions 14 to 21 and 24 to 36 are separated.

Fractions 14 to 21 are concentrated to a volume of about 50 ml, 50 µl of water are added and the pH adjusted to 9.0. The chloroform layers are separated, dried over anhydrous sodium sulphate and concentrated to give 106 mg of white solid. Triturovtata 9 diethylether this foam becomes crystalline and after stirring for 1 hour at room temperature, the crystalline product is obtained which is obtained after solidification in a yield of 31.7 mg, mp 194-196 ° C.

NMt spectrum (100 MHz, δ, OJ D11) 5.24 (1H) duHet, 5.00 (1H) - triplet, 3.40 (3H) singlet, 2.40 (6H) singlet, 1.66 (3H) single and 1.40 (3H) single *! ·

Fractions 24-36 were combined and worked-up analogously to the above procedure to give 47.1 mg of the product as a white foam; this product - is identical to the substance of example 19 ·

Example 15,

To a suspension of 11.1 g of .beta.-hemiketal of 11 .beta.-carbonic acid with 2'-acceyl-4 &apos; -diethyl-4 &apos; -olylthiolyl-oline in 300 ml of isopropyl alcohol is added at room temperature.

Ammonium acetate (10.7 g) was then added slowly over a period of 5 minutes (30 minutes) to a solution of 747 mg of sodium chloride in isopropanol (130 ml) and the reaction mixture was stirred at room temperature overnight. the solution is poured into 1100 m of water, 400 ml of diethyl ether are added, the pH is adjusted to 4.5 and the ether layer is separated. The extract is extracted twice with chloroform, each using 500 ml of this solvent. Extracts in chlorine are collected and, after drying on anhydrous sodium sulphate, 7.5 g of a yellowish foam are concentrated and the residue is taken up in a dietary manner. eru gives 1.69 g of the substance, which is stored with the mother liquors.

75 ml of water are added to the mother liquor, the pH is adjusted to 5.0, and the ether layer is added. odcJdě! and replace the taxes! The ether is replaced with acetic acid and the pH is adjusted to pH Ю, the alkali-isolated aqueous layer is extracted twice using 75 ml of acetic acid and the first extract in acetic acid. Ethyl acetate is dried to dryness after drying with anhydrous sodium sulphate. The remaining foam-like solids are added to a mixture of 75 ml of water and 50 ml of water, adjusted to a pH of 1.00 g. 5.05, the ether layer was mixed, and the pH of the aqueous layer was adjusted to 5.4, 6.0, 7.05, and 8.0 sequentially, and extraction was performed at 50m fresh with each pH. The diethyl ether was then adjusted to pH 9.7 and the aqueous phase was extracted using 50 ml of glacial acetic acid. The ether extract taken at pH 6.0 was mixed with 75 ml of water, the pH was The ether layer was separated, dried and concentrated in vacuo to give 460 mg of white pan.

NMR spectrum (100 MHz, [delta], OIDCl3 5.20 (1H) triplet, 3.43 (2H) 3.40 (1H) Si, 2.38 (6J) Si, 2.16 (3H) singlat,

1.70 (3H) singles and 1.54 (3H) ·

The NLR-spectra data show that the product is the epoxide of 6.94% (2 * 4) of 11,12-carboxylic acid ester. _and ittll4-44ítU _βO l4p-.4a mgnjn * _About lrltUm! yicCn <m. AND·

1.69 g of the product just obtained above were dissolved in 75 ml of water and 75 ml of water and the pH was adjusted to 4.7. The ether layer was separated and the aqueous portion was extracted with fresh water. of ether at 75 ml, at pH values of 5.05 and 5.4, followed by two portions of acetic acid acetic acid (75 ml each) at pH 9.7. The combined extracts in acetic acid r-ester are dried with water. 1.26 g of a white pan product are isolated by sodium sulphate and concentrated under reduced pressure. Crystallization. 411 mg of substance are isolated by decomposition of this residue. · 193 to 196 ° O (with decomposition). the residue was dissolved in hot acetic acid, the solution was allowed to stand at room temperature overnight, the crystalline solids which separated were filtered off and dried, yield 182 ml. , t · t · 198 to 202 ° O (decomposition) ·

Nuclear Magnetic Resonance Spectrum (100 MHz, δ

CDCl3):

5.10 (1H) triplet, 3.34 (2H) singlet, 3.30 (1H) singlet, 2.30 (6H) singlet, 2.08 (3H) singlet, 1.62 (3H) singlet and 1, 48 (3H) singlet.

It is clear from NMR data that these are epimers of 11,12-carbonic acid ester with 2 * -acetyl-4 ** - deoxy-4 ** - aminoerythromycin A.

A similar procedure was repeated using the procedure of Example 15, but using 6,9-hemiketal of 1? -Carbonic acid with 2? -Propionyl-4? -Deoxy-4? -Oxoerythromycin A to give 6.9- 11,12-carbonic acid ester with 2 * -propionyl-4 ** - deoxy-4 ** - aminoerythromycin A and 11,12-carbonic acid ester with 2 * -propionyl-4 ** - deoxy-4 ** - aminoerythromycin A.

Example 16

A solution of 400 mg of 6,9-hemiketal of 11,12-carbonic acid with 2'-acetyl-4'-deoxy-4'-aminoerythromycin A in 20 ml of methanol is stirred at room temperature overnight. The reaction mixture is then poured into 100 ml of water, 50 ml of ethyl acetate are added, the pH is adjusted to 9.5 and the organic phase is separated. The extraction is repeated again using 50 ml of fresh ethyl acetate, the combined extracts in this The solvent was dried over anhydrous sodium sulfate and concentrated to give 392 mg of the product as a white foam. Trituration with diethyl ether and scratching with a glass rod forced the crystallization and after standing at room temperature for 30 minutes, the crystalline fractions were filtered off. After drying, 123 mg of substance is isolated and the mother liquor is stored. According to NMR spectrum, the product was identical to that prepared in Example 18.

Nuclear Magnetic Resonance Spectrum (100 MHz, δ, CDCl ₃ ): 3.26 (3H) singlet, 2.32 (6H) singlet, 1.61 (3H)

singlet and 1.44 (3H) singlet.

The NMR spectrum shows that the crystalline product is one of the epimers of 11,12-carbonic acid ester with 4 ** - deoxy-4 ** - aminoerythromycin A.

Concentration of the retained mother liquor in vacuo afforded 244 mg of the product as a white foam.

The product is identical to the material prepared according to Example 13.

The NMR spectrum shows that this product is a mixture of epimers. 6,9-hemiketal

The carbonic acid 11,12-ester with 4 * -deoxy-4 * * -aminoerythromycin A is identical to the product of Example 13.

Example 17

Similarly, as described in Example 16, methanol analysis of 6,9-hemiketal was performed

11,12-carbonic acid ester with 2'-propionyl-4 ** - deoxy-4 ** - aminoerythromycin A to give 11,12-carbonic acid ester with 4 ** - deoxy-4 ** - aminoerythromycin A and 6,9-hemiketal

11,12-carbonic acid ester with 4 ** - deoxy-4 ** - aminoerythromycin A.

EXAMPLE 18 g of an epimeric mixture of 11,12-esters of carbonic acid with 4 &apos; -deoxy-4 &apos; -aminoerythromphosphite A from the non-crystalline product of Example 19 are dissolved in 50 ml of diethyl ether and crystallized by scraping with a glass rod. After stirring 20 minutes the product from fcrystaLický ^ filtered and dried ^at i »výtěie ^{to 1,} 91 g" mp 198.5 to ²⁰⁰ ° C.

NCRapectrum (100 MHz, δ, CJXC-): 3.26 (3H) singlet, 2.30 (6H) singlet, 1.61 (3H) singlet and 1.45 (3H) singlet ·

From the NM-Aspeker data, it is clear that the crystalline product is one of the epimers of 11,12-esters of carbonic acid and 4 ** dibodies - 4 ** - midoerythroylsulfonate, and the substance is identical to the ketone as the product of example 16 ·

Example 19 g of the epimers of Example 18 are dissolved in 20 m of acetone and the solution is heated on a steam bath until boiling. After addition of 25 ml of water, the prepared solution is stirred at room temperature; after one hour the precipitate formed is filtered off and dried to give 581 mg of m.p. 147-149 ° C.

Λ max (100 MHz, δ, CIDC.): 5.12 (1H) d, 3.30 (3H) 2.30 (6H) singlet »

1.62 (3H) singlet and 1.36 (3H) sinjlet ·

The ЮШ-apeecra data show that the product is one of the epimers of 6,9-hemiketal of 11,12-rthioic acid ester - with 4 ** fesoDy444 ** - aminoerythroyl O, чfcincin A, and sell them the same as the epimer of 24 to 36 of Example 14 ·

EXAMPLE 20 Amino-4'-amino-amino-thromycin A-4-dimethyloxy-4'-amino-4'-amino-4'-amino-thiophene (α-mycine A, 31.6) g of ammonium acetate and 10 g of 10% palladium on charcoal are shaken at room temperature in a hydrogen atmosphere at an initial pressure of 0.35 MPa in an atmosphere of 200 mL of methanol · The slaughtered catalyst & lysator is filtered off and the filtrate is concentrated to dryness in vacuo · Between water and chloroform at pH 5.5. The aqueous phase was separated. The pH was adjusted to 9.6 and chloroform was added. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. dry white foam (19 g) was triturated with 150 m diethyl ether at room temperature for 30 minutes, the precipitated solids were filtered and dried - 9.45 g of one of the epimers which was unlike the product of the example was isolated 6 ·

The filtrate solution in diethyl ether is concentrated to dryness to give a darkness of 6.89 g of the second epimer and impurity product.

Example 21 'asminoerythromoin A

A mixture of 2 g of 4 ** - deoxy-4 ** sosoerythrosomycin A, 3.1 g of ammonium acetate and 2.0 - g -aney nickel is shaken at room temperature and a hydrogen pressure of 50 psi (50 psi) overnight. · Add an amount of 3.16 g of ammonium acetate and 2.0 g of -aney nickel, and continue the hydrogenation for a further 3 hours. · Solid solids are filtered off and the filtrate is dried to dryness under reduced pressure. water / chloroform mixture and pH is adjusted from 6.4 to 5.5. The aqueous phase is separated, the pH is raised to 9.6, fresh chloroform is added, the chloroform extract is separated, the sodium sulphate is dried over sodium sulphate. and concentrated under reduced pressure to give 1.02 g of the product as a yellow foam. it has the opposite configuration on the carbon atom in the -4 '' position - compared to the compound of Example 6.

Example 22 * -acetyl-4 * * -deo: xy-4 ** amiinoerythronycin B

To a solution of 4.5 g of 2 &apos; -acetyl-4 &apos; -deolyr-4 &lt; o &gt; oooeyeyroomroomin B (see U.S. Pat. After 10 minutes, 376 mg of sodium cyanoborohydride was added to the reaction mixture with 10 ml of epypolylalkyl, and the reaction mixture was then stirred at room temperature for one hour. The pale yellow solution is poured into 400 OL of water and value. The pH is adjusted to 6.0. The aqueous phase was extracted at pH 6, 7, 7.5, 8, 9 and 10 with 250 ml of ethyl acetate at each extraction. The extracts taken at pH 8, 9 and 10 are combined and the ether solution is washed with 250 m of fresh water. The separated aqueous solution is extracted with 100 ml of ether at pH 7, 100 ml of acetylstrotriacetic acid at pH 7, 100 ml of ether at pH 7.5, 100 ml of acetic acid at the same pH and 100 ml of ethyl ester each time. of acetic acid and pH 8, 9 and 10. The extracts in acetyl acid from pH 9 and 10 are combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. Separate the solvent from the filtrate in vacuo to isolate the epioer mixture of the expected product. in the form of cream colored foam.

A similar procedure was prepared by the -deevιχr 4 ⁴⁴ 4 ⁴⁴ -roiήeerythrem ci ^r B from 4 ** - 4 4-d0eJor 4..eoeerythromycinu B.

Example 23

4-dreoy-4 * -flyinoerytheooycin B

A solution of 4.34 g of 2-4-acyl-44d-reoyl-4 ' -mylerythhoooycini B in 100 .mu.l of ethyl ketel was stirred from room temperature for a period of time. The solvent was removed under reduced pressure and the remaining foam was mixed with 100 [mu] l of chloroform and 100 ml of water. The pH of the aqueous phase was adjusted to 9.3, the organic layer was separated, fresh water was added to the solution in chloroform, and the pH was adjusted to 4.0. In addition, the pH of the acidified aqueous layer containing the product is gradually increased to 5, 6, 7, 8 and 9 by addition of a base, and each time extraction is carried out with fresh ihloroerraro. The mixture was washed and shaken with fresh water at pH. The aqueous portion was re-alkalized to pH 5, 6 and 7 and extracted at each pH with fresh chloroform, the extract in chloroform obtained at pH 6 was dried over anhydrous sodium sulfate and concentrated to give the product. . in the form of a mixture.

Example 24

Acid salt and ^p aragov ^E ^ S ^ H-hemitotaleo -ester ichi ^ i ^ acid amide with 4 * ⁴ -doeoy 4 ** - mniereryttomyciIrвo A.

A solution of 1.0 ^{g of 6,} 9-ll ^ -ester trolketalu un-Ita acid with 4--dreзor ⁴⁴ 4 ** - aoinorrythr <myciшm 6 O in acetone, heated up to 40 ° C was added p ^ 20 OL water and then 175 mg of L-aspartic acid. The mixture was heated to reflux for 1.5 hours, hot-filmed, acetone was removed from the filtrate, and 1.1 g of the expected product was isolated as a white solid by collection of the residue.

Example 25

6,9-Hemicetyl 11,12-ester Dihydroclhoride Carbonic acid with 4 ** - deoxf-4 ** - imo Lerythromycin A

To a solution of 7.58 g of the 6,12-hemiketal of 11,12-carbonic acid with 4 ** -dewrr-4 * * -eainoerythromycin A in 50 mL of dry ethyl acetate is added 20 mL of a 1N solution of hydrogen chloride in ethyl acetate, and the resulting solution is dried to dryness under reduced pressure. The remaining material is triturated with ether and the expected salt is collected by filtration.

In a similar manner, the amino derivative of this invention is converted to the corresponding editing sol. with two equivalents of acids ·

Example 26

6,9-acetic acid 11,12-acetic acid ester and 4 * * - deo3q ^ -4 ** - aminoerythromycin A

The procedure of Example 25 is tan, with the addition of 10 mL of a 1N solution of hydrogen chloride in ethyl acetate, and the solution is taken up in vacuo in a vacuum, after which the residual blue dihydrochloride is triturated with ether and the solid is filtered off.

In a similar manner, the thio compounds of this invention can be converted to the corresponding salt with one equivalent of acid.

Claims (5)

1 · Process for preparing derivatives of 4 ** - ** íedχy-4 - tminoeiythronycinu A of formula III (III) and odpoovídaících ^f trmtceuticky suitable poo! with acids in which R and R 1 are hydrogen or C 2 -C 3 alkanoyl, R is - hydrogen or R 3 is hydrogen; and R together form a -C- group, R * is hydroxyl and R forms a bond with the carbon atom to which R * is a substituent O is attached, or R * is a group O and R is a hydrogen atom, wherein when Rg is a hydrogen atom, R is a hydrogen atom, characterized in that a compound of formula I (I) wherein R, R *, R, Rg and R 1 is as defined above, reacted with an ammonium salt of a hydroxylic acid and the imine-formed reducted product is a hydride thereof by catalytic reduction, and optionally if R 1 or R 8 is hydrogen, it is optionally converted to C 2 -C 3 alkanoyl and / or if R 8 or R 8 is alkano? containing 2 to 3 carbon atoms, optionally converted to hydrogen, and optionally - pharmaceutically acceptable acid salts are prepared. 2. The process according to claim 1, wherein the reduction is carried out with hydrogen in the presence of Raney nickel, phadium on manganese, or platinum oxide. 3. A process as claimed in claim 1, wherein an excess of ammonium salt of alkane acid, preferably ammonium acetate, is used. Process according to claim 3, characterized in that sodium reducing agent is sodium cyanoborohydride. 5. A process according to claim 1, wherein the compound of formula I is reacted with an ammonium salt of an alkanoic acid and then reduced with hydrogen in the presence of a catalyst.